National Evidence Based Guidelines PDF

National Evidence Based Guidelines
for the
Management of Type 2 Diabetes Mellitus
Part 7
Lipid Control in Type 2 Diabetes
Prepared by
the Australian Centre for Diabetes Strategies
Prince of Wales Hospital, Sydney
for the Diabetes Australia Guideline Development Consortium
APPROVED BY THE NHMRC 16 SEPTEMBER 2004
Table of Contents
PART 7
1.0
Lipids Expert Working Group ................................................................................3
2.0 Guideline for Lipid Control in Type 2 Diabetes ....................................................5

2.1
Introduction..............................................................................................................5
2.2
Issues for Lipid Control in Type 2 Diabetes ............................................................7
2.3
Summary of Recommendations ...............................................................................8
2.4
Recommendations....................................................................................................9
Section 1: Lipid abnormalities associated with Type 2 diabetes ............................9
Section 2: Effect of diet and exercise on lipids ..................................................42
Section 3: Effect of improved blood glucose control on lipids.............................78
Section 4: Effects of treatment with lipid-modifying agents on lipids .................94
Section 5: Effects of treatment on outcomes ......................................................124
References ............................................................................................................167
Evidence References...................................................................................167
General References.....................................................................................184
Other References Identified........................................................................188
2.5
Lipid Control Search Strategy and Yield Table...................................................223
1.0 Lipid Control Guideline Expert Working Group

Chairperson
Professor James Best

Department of Medicine
University of Melbourne
MELBOURNE VIC
Content Experts
Dr Harvey Newnham
Monash University
MELBOURNE VIC
A/Professor Richard OBrien
Diabetes Unit
Monash Medical Centre
MELBOURNE VIC
A/Professor Gerald Watts
Royal Perth Hospital
PERTH WA
A/Professor Tony Dart
Baker Medical Research Institute
MELBOURNE VIC
ADEA
Ms Gloria Kilmartin
Department of Diabetes & Endocrinology
Royal Melbourne Hospital
MELBOURNE VIC
Consumer
Dr Graham Giles
Cancer Control Research Institute
Cancer Epidemiology Centre
MELBOURNE VIC
RACGP
Dr Peter Harris
School of Medical Education
University of NSW
SYDNEY NSW
Content and Methods Adviser
Professor Stephen Colagiuri

Department of Endocrinology
Prince of Wales Hospital
SYDNEY NSW
Research Officers
Dr Nasseem Malouf
Diabetes Centre
Prince of Wales Hospital
SYDNEY NSW
Ms Robyn Barnes
Public Health Unit
South Eastern Sydney Area Health Service
SYDNEY NSW
Ms Sarah Smith
Human Nutrition Unit
University of Sydney
SYDNEY NSW
Ms Caroline George
Human Nutrition Unit
University of Sydney
SYDNEY NSW
2.0 Guideline for Lipid Control

2.1
Introduction
Aim of the Guideline

This guideline addresses issues relating to the control of lipid levels in Type 2 diabetes. Lipid
abnormalities in people with in Type 2 diabetes can be broadly categorised into 2 groups:
those common to the general population such as elevated total and LDL cholesterol and
additional diabetes related abnormalities such as elevated triglycerides and reduced HDL
cholesterol
The aim of the guideline is to assist health practitioners, principally general practitioners, to
effectively and efficiently detect and manage lipid abnormalities in those with Type 2
diabetes.
Quality Assurance
The methods used to identify and critically appraise the evidence in order to formulate the
guideline recommendations are described in detail in Part 1 of the document. Additional
steps were taken to assure the quality of the Lipid Control Guideline eg:
the Project Management Team reviewed and checked each step of the methods process
selected searches were repeated
the chairman of the Lipids Control EWG double reviewed the majority of the articles
used as evidence references
the Medical Advisor reviewed and revised the entire final draft
the Project Management Team checked all recommendations and evidence statements and
compiled and checked the evidence tables, reference lists, and search strategy and yield
tables
Guideline Format
Issues identified by the EWG and from the literature as critical to the control of lipids in Type
2 diabetes are shown in point 7.1.2 (next page). Each of these issues is addressed in a separate
section in a format presenting:
Recommendation(s)
Evidence Statements supporting the recommendations
Background to issues for the guideline
Evidence detailing and interpreting the key findings
Summary of major evidence found
Evidence Tables summarising the evidence ratings for the articles reviewed
For all issues combined, supporting material appears at the end of the guideline topic and
includes:
Evidence references
General references
Other references identified
Search Strategy and Yield Tables documenting the identification of the evidence sources.
The prevention of macrovascular disease is a major goal in the care of

the person with Type 2 diabetes.
Multifactorial intervention is the key to the prevention of macrovascular

disease.
This document should be considered in association with the
Macrovascular Disease, Blood Pressure Control,
and Blood Glucose Control Guidelines
2.2
Issues for Lipid Control in Type 2 diabetes
What lipid abnormalities are associated with Type 2 diabetes and what are the
consequences?
What are the effects of diet and exercise on lipids in people with Type 2 diabetes?
What is the effect of improved blood glucose control on lipids in Type 2 diabetes?
What are the effects on lipids of treatment with lipid-modifying agents and hormone
replacement therapy in Type 2 diabetes?
Does treatment with lipid modifying agents or hormone replacement therapy improve
outcomes in Type 2 diabetes?
2.3
Summary of Recommendations
Recommendations
People with Type 2 diabetes should have measurement of total cholesterol, triglycerides
and HDL cholesterol levels and calculation of LDL cholesterol
If feasible, lipid levels should be measured after a 10 to 12 hour overnight fast
More than one lipid measurement should be used to make decisions to initiate or
intensify lipid modifying therapy
Specific dietary advice should be given to all people with Type 2 diabetes and elevated
lipids which emphasises weight reduction in the overweight
In people with Type 2 diabetes whose lipid levels are above target and who have
unsatisfactory diabetes control, efforts should be made to improve their blood glucose
control before considering lipid modifying medication
Statins should be used to lower LDL cholesterol when triglycerides are normal or only
slightly elevated. For severe hypercholesterolaemia, a bile acid binding resin or low dose
nicotinic acid may be added.
Fibrates should be used as first line therapy in people with predominantly elevated
triglycerides and low HDL cholesterol with normal to slightly elevated LDL cholesterol
levels. If treatment with a fibrate is not tolerated or if additional triglycerides lowering
effect is required, fish oil can be used but the effect on diabetes control should be
monitored.
Treatment with a statin and fibrate should be considered in people with moderate to
marked elevation of both LDL cholesterol and triglycerides. Because of the increased
risk of myositis, the person should be fully informed and carefully monitored.
People with Type 2 diabetes who have an LDL cholesterol >2.5mmol/L after
interventions to modify lifestyle and improve blood glucose control, should be
considered for statin therapy
People with Type 2 diabetes who have triglycerides >2.0mmol/L after interventions to
modify lifestyle and improve blood glucose control, should be considered for fibrate
therapy
2.4
Recommendations
Section 1: Lipids
Issue
What lipid abnormalities are associated with Type 2 diabetes and what are the
consequences?
Recommendations
People with Type 2 diabetes should have measurement of total cholesterol, triglycerides
and HDL cholesterol levels and calculation of LDL cholesterol
If feasible, lipid levels should be measured after a 10 to 12 hour overnight fast
More than one lipid measurement should be used to make decisions to initiate or intensify
lipid modifying therapy
Evidence Statements
Triglycerides levels are increased in Type 2 diabetes

Evidence Level III-2
HDL cholesterol is decreased in Type 2 diabetes

LDL cholesterol is similar in Type 2 diabetes and the general population, but LDL
particle size is smaller
Total cholesterol is similar in Type 2 diabetes and the general population

There are intra-individual variations over time in lipid and lipoprotein levels in Type 2
diabetes
Evidence level III-2
Apolipoprotein A1 is reduced, apolipoprotein B is increased, and lipoprotein(a) is not

altered in Type 2 diabetes
Lipid abnormalities are accentuated by increased body weight, poor glycaemic control
and diabetic renal disease
There is insufficient evidence to draw any conclusion about the importance of

lipoprotein oxidation in Type 2 diabetes
Total cholesterol and LDL cholesterol predict cardiovascular disease in Type 2 diabetes
HDL cholesterol and triglycerides predict cardiovascular disease in Type 2 diabetes

The contribution of increased lipoprotein (a) to risk of cardiovascular disease in Type 2

diabetes is uncertain
There is limited evidence linking lipid levels and diabetic nephropathy

There is limited evidence that lipid levels predict the development of hard exudates in
diabetic retinopathy
10
Background Lipid levels and Type 2 diabetes

Lipid abnormalities are common in people with Type 2 diabetes and are a major contributor
to the increase in cardiovascular disease experienced by people with Type 2 diabetes. Lipid
abnormalities in Type 2 diabetes can be broadly categorised into 2 groups:
Those which are common to the general population eg elevated total and LDL cholesterol
Additional diabetes related abnormalities eg elevated triglycerides and reduced HDL
cholesterol
Insulin resistance and central obesity are two closely linked factors (Brunzell & Hokanson,
1999) that are important in determining the additional lipid abnormalities found in Type 2
diabetes. The role of insulin resistance in the pathogenesis of Type 2 diabetes was recognised
by Himsworth (1936) over 60 years ago. Central obesity was recognised as a risk factor for
the development of Type 2 diabetes over 40 years ago (Vague, 1956) and many subsequent
studies have confirmed this association.
However, it was not until quantitative tests for insulin resistance were available that the
importance and prevalence of insulin resistance was fully appreciated (Reaven, 1988). Under
the heading of Syndrome X, Reaven linked insulin resistance with increased very-lowdensity lipoprotein (VLDL) triglycerides, decreased high-density lipoprotein (HDL)
cholesterol levels and hypertension. Subsequently, the presence of small, dense low density
lipoprotein (LDL) particles has been added to the list of lipid abnormalities associated with
insulin resistance (Reaven et al, 1993). The association of lipid abnormalities with insulin
resistance has led to an appreciation that disordered lipid metabolism is a fundamental aspect
of Type 2 diabetes (McGarry et al, 1992). There is also strong evidence linking central
adiposity with insulin resistance (Carey et al, 1996; Karter et al, 1996) so that central obesity
is now considered an integral part of the insulin resistance syndrome (Haffner, 1996).
Insulin resistance and central obesity have the potential to cause lipid abnormalities by
several mechanisms (Garg, 1996; Brunzell & Hokanson, 1999). Impaired insulin action
allows greater free fatty acid release from an increased mass of intra-abdominal adipose
tissue, promoting hepatic triglycerides synthesis and VLDL production. At the same time,
lipoprotein lipase activity, and therefore triglycerides clearance, is reduced by insulin
resistance. Reduction of HDL cholesterol levels has been attributed to triglycerides
enrichment by cholesterol ester transfer protein (CETP) and also to an increase of hepatic
triglycerides lipase activity, related to insulin resistance.
The concept that these lipid abnormalities are linked with insulin resistance and central
adiposity rather than with Type 2 diabetes per se has been supported by the finding of
elevated triglycerides and reduced HDL cholesterol levels in individuals who subsequently
develop diabetes (Haffner et al, 1990; McPhillips et al, 1990). Reduced HDL cholesterol
levels in first-degree relatives of people with diabetes have also been found (Stewart et al,
1995; Shaw et al, 1999).
There is abundant epidemiological and clinical trial evidence in people without diabetes that
lipoproteins play a major role in the pathogenesis of atherosclerotic vascular disease. The
Framingham study showed a strong, graded, continuous positive relationship between total
cholesterol and all clinical manifestations of coronary heart disease (CHD) risk (Kannel et al,
1988). This study also showed a very similar direct relationship between LDL cholesterol and
CHD risk, reporting that a 1% increase in LDL cholesterol is associated with slightly more
than a 2% increase in CHD over 6 years (Wilson, 1990). Similarly the MRFIT (Multiple Risk
11
Factor Intervention Trial) study showed a strong, graded, positive relationship between death
from CHD and total cholesterol above levels of 4.65 mmol/L for 316,099 white men followed
for an average of 12 years (Neaton & Wentworth, 1992). During the course of the study there
were 6,327 deaths from CHD. Death rates for men in the three categories of total cholesterol
levels below 4.65 mmol/L (3.1; 3.6; 4.1 mmol/L) were similar (ranging from 7.7 to 8.9 deaths
per 10,000 person-years). For cholesterol levels above 4.65 mmol/L age-adjusted death rates
due to CHD gradually increased to a peak of 54.5 deaths per 10,000 person-years for
cholesterol levels of 8.28 mmol/L or above (Neaton & Wentworth, 1992).
HDL cholesterol is inversely related to triglycerides levels and both parameters have been
linked with CHD risk in large prospective studies, the data being more consistent for low
HDL cholesterol level and increased risk of CHD than for high triglycerides. In 12 years of
follow-up for 2,748 Framingham Heart Study participants the relative risk of death from
CHD was increased 4.1-fold for men with HDL cholesterol <0.9 mmol/L (lowest quintile)
compared with men with HDL cholesterol >1.4 mmol/L (highest quintile). For women, death
from CHD was increased 3.1-fold when HDL cholesterol was <1.2 mmol/L compared with
HDL cholesterol >1.8 mmol/L (Wilson et al, 1988). Over 6 years, a 1% lower HDL
cholesterol level was associated with a 3-4% higher risk of CHD (Wilson, 1990).
The importance of HDL cholesterol level as a predictor of CHD has also been shown in the
MRFIT study (Multiple Risk Factor Intervention Trial Research Group, 1986), the placebo
arm of the Helsinki Heart Study (Manninen et al, 1990) and the Prospective Cardiovascular
Munster (PROCAM) study (Assmann & Funke, 1990).
There has been divided opinion about the importance of plasma triglycerides levels as an
independent risk factor for CHD. The evidence from three major prospective studies supports
a role for triglycerides as a synergistic risk factor. The Framingham Heart Study showed that
over a 14-year period, triglycerides >1.7 mmol/L predicted increased CHD risk in men and
women with HDL cholesterol <1.03 mmol/L after adjustment for age, systolic blood
pressure, body mass index (BMI), low HDL, and electrocardiographically determined left
ventricular hypertrophy (Castelli, 1992). For the 2,045 men in the placebo arm of the
Helsinki Heart Study, triglycerides >2.3 mmol/L in conjunction with LDL cholesterol to
HDL cholesterol ratio (LDL/HDL) >5 were associated with increased risk of death from
CHD, with a relative risk (RR) of 3.82 (CI 2.20-6.63), whereas in people with triglycerides
2.3 mmol/L and LDL/HDL >5, the increased risk was only 1.19 (CI 0.61-2.32) (Manninen
et al, 1992). The PROCAM study found very similar results (Assmann et al, 1998). People
who had major coronary events (n=258) over 8 years had higher triglycerides levels and a
greater LDL/HDL compared with those without major coronary events (n=4,381) (1.98 v 1.5.
mmol/L, p<0.001; 4.61.6 v 3.41.2, p<0.001, respectively). Therefore, the combined data
support a role for triglycerides level above 2.0 mmol/L as a risk factor when the LDL/HDL is
> 5.
In Type 2 diabetes the risk of CHD is significantly increased compared with the non-diabetic
population. The key question regarding lipids and the increased CHD risk in Type 2 diabetes
is whether the lipid and lipoprotein predictors of CHD in the general population operate in
the same way in Type 2 diabetes.
Lipid levels are not a universally recognised risk factor for cerebrovascular disease. A recent
meta-analysis failed to find hypercholesterolaemia to be a risk factor for stroke in the general
population (Prospective Studies Collaboration, 1995). On the other hand recent evidence
indicates a reduced risk of stroke after lipid-lowering interventions with statins in people with
12
pre-existing CHD (Sacks et al, 1996; LIPID Study Group, 1998; White et al, 2000; Heart
Protection Study Collaborative Group, 2002a).
A link between lipid levels and diabetic retinopathy and progression of diabetic nephropathy
has been suggested and this is also reviewed in this Section.
Evidence Lipid levels and Type 2 diabetes

Triglycerides levels are increased in Type 2 diabetes
Elevation of triglycerides levels in people with Type 2 diabetes compared with those without
diabetes has been consistently reported by most population-based and clinic-based surveys
(Table 1). In most of the studies summarised in Table 1, average triglycerides levels were
similar in men and women, although some studies indicate that hypertriglyceridaemia may be
more marked in women with Type 2 diabetes than in men (Siegel et al, 1996). In people with
Type 2 diabetes, average triglycerides levels were approximately 2.2 mmol/L compared with
1.6 mmol/L in the non-diabetic population.
The difference in prevalence of elevated triglycerides levels is illustrated by the following
sample of studies. Data from the Second National Health and Nutrition Examination Survey
(NHANES II) (Cowie et al, 1994) showed that the prevalence of hypertriglyceridaemia (>2.8
mmol/L) was 34% in men aged 40-69 years with diabetes, compared with 11% in controls
and 30% in women with diabetes compared with 6% in controls, but significance values were
not stated. Another US-based population study, the Framingham Offspring Study, (Siegel et
al, 1996) found that the prevalence of hypertriglyceridaemia (>2.75 mmol/L) was 23% in 120
men with diabetes compared with 9% in 1,878 controls (p<0.001) and 29% in 54 women with
diabetes compared with 3% in 1,879 controls (p<0.001). Marked hypertriglyceridaemia (>5.5
mmol/L) was not more prevalent in men with diabetes (1.1% v 1.5% in controls), but was
more prevalent in women with diabetes (11% v 0.2% in controls, p<0.001). In a Finnish
population-based study (Salomaa et al, 1992) triglycerides were elevated (>2.3 mmol/L) in
48% of 42 men with diabetes compared with 22% of 32 men with impaired glucose tolerance
(IGT) and 15% of 136 controls (p=0.008). Elevated triglycerides were found in 52% of 54
women with diabetes compared with 26% of 70 women with IGT and 11% of 187 controls
(p=0.0001). Overall studies show that the crude prevalence of elevated triglycerides levels in
people with diabetes is approximately 30% which is some 3-fold higher than the prevalence
in people without diabetes.
Studies of triglycerides levels after a fatty meal show increased levels in Type 2 diabetes
(Cavallero et al, 1994; Curtin et al, 1994). In the diabetic group (n=14), people with
hypertriglyceridaemia (n=8) had higher postprandial triglycerides levels compared with those
with normotriglyceridaemia (n=6) (3.280.70 v 1.200.46 mmol/L, p<0.001), whereas
diabetic people with normotriglyceridaemia (n=6) and controls (n=12) had a similar
triglycerides levels after the test meal which contained 45 to 55% fat (Cavallero et al, 1994).
Curtin et al (1994) also reported a significantly different pattern for triglycerides (p<0.05)
following a fat-rich meal in the diabetic group (n=6) compared with the control group (n=6).
Triglycerides-rich lipoprotein fraction were significantly higher after the fat-rich meal at all
time points in people with diabetes (p<0.01). This postprandial hyperlipidaemia has been
interpreted as indicating reduced chylomicron clearance and accumulation of triglyceridesrich chylomicron remnants in Type 2 diabetes.
13
Table 1: Lipid levels and Type 2 diabetes

Reference
Billingham, 1989
(UK)
Burchfiel, 1990
(US)
Byrne, 1994
(UK)
Cowie, 1994
(US)
Haffner, 1994
(US)
Hughes, 1998
(Singapore: Chinese,
Indians, Malays)
Laakso, 1985
(East Finland)
Population Studied
n=130 mean age 57yrs
New Type 2 diabetes: 22
Established Diabetes
Diet treated: 30
Sulphonylureas: 28
Insulin: 17
Control: 33
n=856, 20-74yrs, Anglo (A)
& Hispanic (H), Type 2
Diabetes: 121 M; 158 W
Control: 219 M; 269 W
n=1,156, age 40-64yrs
Type 2: 23 M; 28 W
n= 751M; 1,987W
NHANES II age 20-74 yrs
Type 2 diabetes
Control
San Antonio Heart Study
Type 2: 33 M 62 W
Control: 155 M 216 W
Singapore Heart Study;
age 30-69yrs
Type 2 diabetes 72M; 54W
Age: 45-64; Type 2
Diabetes (diet): 48 M; 40 W
Sulphonylurea: 56M; 49W
SU/Metformin: 14M; 15W
Insulin: 17 M; 38 W
Control: 65 M; 59 W
Lipid levels
Mean Total
Cholesterol (mmol/L)
Mean LDL
Mean HDL
Mean Triglycerides
(mmol/L)
6.2
4.50
1.03
1.19
1.8
6.3 (v control)
6.0
5.0 (v control)
5.7
M
W
A, H
A, H
5.42, 5.46
5.90, 5.93
5.57, 5.60
5.79, 5.82
4.70
4.30
3.30
4.00
1.29
1.34
1.60
1.55
W
A, H
1.24, 1.20
1.48, 1.44
1.5
1.6
0.7
0.9
M
A, H
3.48, 3.37
3.62, 3.51
W
A, H
3.52, 3.52
3.61, 3.62
1.12
1.07
1.33
1.36
M
A, H
0.96, 1.05
1.15, 1.23
M
A, H
2.51,2.53
1.80, 1.81
W
A, H
2.56, 2.77
1.54, 1.75
1.69
1.35
1.94
1.04
5.53
5.33
M
5.70
5.78
M
5.66
5.51
W
5.72
5.70
W
3.75
3.59
M
3.65
3.81
M
3.65
3.49
W
3.50
3.70
W
1.09
1.16
M
0.95
1.04
M
1.29
1.37
W
1.05
1.20
W
1.72
1.32
M
2.97
1.86
M
1.60
1.23
W
2.38
1.71
W
5.6
5.7
6.0
5.8
4.0
4.0
4.3
4.2
0.78
0.81
(all v control)
7.07
6.96
8.23
7.39
7.26
4.15
4.23
4.14
4.34
4.46
4.60
4.49
4.86
4.34
4.92
1.15
1.10
1.12
1.05
1.34
2.3
1.9
(all v
control)
2.17
3.52
2.53
2.45
1.49
2.2
1.6
(all v control)
6.45
6.95
6.63
6.69
6.71
0.93
0.93
(all v
control)
1.25
1.16
1.19
1.10
1.42
Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001
14
2.16
2.51
4.65
4.11
1.49

Reference
Laakso, 1990
(Finland)
Manzato, 1993
(Italy)
Mattock, 1988
(UK)
Nielsen, 1993
(Denmark)
Niskanen, 1990
(Finland)
Salomaa, 1992
(Finland)
Scheffer, 2003
(The Netherlands)
Population Studied
age 45-64yrs
Type 2: 152 M; 153 W
BMI <25:
BMI 25-27
BMI >27
Control: 65 M; 59 W
BMI <25:
BMI 25-27
BMI >27
mean age 67yrs Type 2
Diet: 54
Sulphonylurea: 26
SU/Fenformin: 17
Insulin: 23
Control: 30
Type 2 diabetes; 82M; 59W
Age 35-64yrs
30M; 7W per gp age 61yrs
Type 2+Normoalbuminuria
+Microalbuminuria
+Macroalbuminuria
Control
Type 2; mean age 56yrs
+ microalbuminuria: n=12
- micoralbuminuria: n=101
Control
Age: 45-64yrs
Type 2: 42M; 54 W
IGT: 32 M; 70 W
Age >65yrs
Type 2 diabetes, n=58
Controls, n=58
Lipid levels
Mean Total
M
Mean LDL
Mean HDL
Mean Triglycerides
(mmol/L)
(v BMI <25)
(v BMI <25)
(v BMI <25)
(v BMI <25)
6.53
6.06
6.86
7.43
7.40
7.34
4.16
3.99
4.26
4.90
4.32
4.44
1.33
1.02
1.06
1.48
1.24
1.09
1.72
1.82
3.36
1.74
3.80
3.63
6.86
6.61
6.47
7.08
7.36
7.36
4.54
4.42
4.31
4.65
4.93
5.15
1.35
1.38
1.27
1.49
1.57
1.31
1.38
1.39
1.77
1.47
1.41
1.54
6.06 (v control)
5.62
5.69
5.69
5.43
M
W
5.63
6.08
3.64
3.41
3.30
3.33
3.22
M
-
1.38
1.38
1.35
1.51
1.40
W
-
M
0.98
1.74
1.50
1.48
1.45
1.33
W
1.16
M
2.00
W
1.79
5.6
5.6
6.5
6.1
3.56
3.63
3.83
4.06
1.23
1.12
1.18
1.46
1.30
1.82 (v control)
2.01 (v control)
1.09
6.88
6.44
6.71
3.65
4.00
4.28
0.92 (v AU-)
1.07
1.28 (v AU-)
4.24 (v AU-)
2.38
1.55 (v AU-)
M
6.2
W
6.4
(v control)
(v control)
6.4
6.1
6.9
6.5
5.8
6.0
3.7
3.9
Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001. AU: microalbuminuria
15
M
1.1
W
1.3
M
2.7
W
2.7
(v control)
(v control)
(v control)
(v control)
1.2
1.3
1.4
1.6
1.8
1.6
1.8
1.4
1.29
1.54
1.5
1.2

Reference
Siegal, 1996
(US)
Suranti, 1992
(France)
UKPDS 11, 1994
(UK)
Uusitupa, 1986
(East Finland)
Population Studied
Framingham offspring
Diabetes (1+2): 120M; 54W
Control: 1,878M; 1,879W
Type 2 diabetes; n=380
- normoalbuminuria
- microalbuminuria
Age 52yra, New Type 2
Diabetes: 297 M; 210 W
Age: 45-64yrs
Type 2: 70 M; 63 W
Control: 62 M; 82 W
Lipid levels
Mean Total
M
5.45
5.51
W
5.93
5.47
Mean LDL
M
3.42
3.55
5.88
5.90
M
5.5
5.2
M
6.3
6.7
W
3.46
3.42
Mean HDL
W
5.8
5.5
W
6.5
6.7
M
3.6
3.3
M
4.08
4.45
16
W
1.09
1.48
M
1.00
1.15
Mean Triglycerides
(mmol/L)
M
2.04
1.61
1.31
1.21
W
3.9
3.40
W
4.26
4.52
M
1.01
1.09
M
0.99
1.25
W
3.33
1.15
1.67
1.82
W
1.15
1.38
W
1.17
1.41
M
1.79
1.22
M
2.46
1.90
W
1.66
1.10
W
2.37
1.38
HDL cholesterol is decreased in Type 2 diabetes

A reduced HDL cholesterol in people with Type 2 diabetes has been demonstrated in many
population-based and clinic-based surveys. Of the studies summarised in Table 1, average
HDL cholesterol levels were approximately 0.2-0.3 mmol/L higher in women than in men. In
people with Type 2 diabetes, average HDL cholesterol levels were approximately 0.2 mmol/L
lower than in the non-diabetic population.
The difference in prevalence of decreased HDL cholesterol levels is illustrated by the
following sample of studies. In the Framingham Offspring Study (Siegal et al, 1996) the
prevalence of low HDL cholesterol (<0.9 mmol/L) was 44% in diabetic men compared with
20% in controls (p<0.001) and 38% in diabetic women compared with 9% in controls
(p<0.001). NHANES II data (Cowie et al, 1994) showed HDL cholesterol was <0.9 mmol/L
in 28% of diabetic men compared with 14% of controls and 10% in diabetic women
compared with 6% in controls. In a Finnish population-based study (Salomaa et al, 1992),
HDL cholesterol was <1.02 mmol/L in 55% of men with diabetes compared with 25% of men
with IGT and 20% of controls. HDL cholesterol was <1.2 mmol/L in 52% of women with
diabetes compared with 31% of women with IGT and 18% of controls. In general studies
show that the crude prevalence of reduced HDL cholesterol levels in people with diabetes is
approximately 2-fold higher than in people without diabetes.
LDL cholesterol is similar in Type 2 diabetes and the general population, but LDL
particle size is smaller
LDL cholesterol concentration can be determined in the following ways:
Calculated:
The approach most frequently used in the reviewed studies was to separate VLDL and
HDL particles by ultracentrifugation or by precipitation of non-HDL particles.
Cholesterol content of the VLDL and HDL fractions was measured and LDL cholesterol
concentration was calculated by subtracting VLDL cholesterol and HDL cholesterol from
total cholesterol concentration (Laakso et al, 1985; Billingham et al, 1989; UKPDS 11,
1994; Siegel et al, 1996).
The main alternative approach is to calculate LDL concentration using the Friedewald
equation (Burchfiel et al, 1990; Hughes et al, 1998; Tsalamandris et al, 1998). This
method estimates the cholesterol content of the triglycerides-rich lipoproteins as
triglycerides concentration in mmol/L 2.2 (providing triglycerides 4.5 mmol/L) and
calculates LDL cholesterol by subtracting this value and HDL cholesterol from total
cholesterol (Friedewald et al, 1972).
Direct measurement:
Less commonly, LDL particles are separated by ultracentrifugation and cholesterol
concentration measured directly (Manzato et al, 1993).
There is a good correlation between calculated and measured LDL cholesterol in people with
Type 2 diabetes (Branchi et al, 1998), but the more direct measures are preferred for
epidemiological studies.
Most studies have found similar LDL cholesterol levels in people with Type 2 diabetes and
people without diabetes (Table 1). Average LDL cholesterol levels in the Caucasian
populations were 3.6 mmol/L for men with diabetes, 3.8 mmol/L for women with diabetes,
3.6 mmol/L for non-diabetic men and 3.7 mmol/L for non-diabetic women. Also the
prevalence of elevated LDL cholesterol is similar. In the Framingham Offspring Study
17
(Siegel et al, 1996), LDL cholesterol levels 4.2 mmol/L were present in 22% of men with
diabetes compared with 27% of controls and in 35% of women with diabetes compared with
22% of controls (p=NS). NHANES II data (Cowie et al, 1994) showed LDL cholesterol was
4.2 mmol/L in 38% of diabetic men compared with 39% of controls and 52% in diabetic
white compared with 35% in controls (the 95% CI were very wide for each of these figures).
However, consistent with the strong inverse correlation between triglycerides level and LDL
particle size, diabetes is associated with smaller LDL particle size. In the Framingham
Offspring Study a weighted LDL particle score 3.5 (small, dense particles) was present in
49% of women with diabetes compared with 33% of controls (p<0.05) and in 40% of men
with diabetes compared with 11% of controls (p<0.001). The presence of small dense LDL
particles was significantly associated with diabetes and hypertriglyceridaemia in both sexes
(OR 1.79, p=0.002 for men; OR 5.27, p<0.0001 for women) (Siegel et al, 1996). In the San
Antonio Heart Study of mainly Mexican-American subjects (Haffner et al, 1994), LDL
particle size was smaller in diabetic men and women, compared with non-diabetic men and
women (252.21.8 v 256.10.8 , p=0.048 for men; 254.71.3 v 259.70.7 , p=0.005 for
women). Also the percentage of small LDL particles was higher in people with diabetes (men
52%; 49% women) than in people without diabetes (38%; 33%, respectively). After
adjustment for triglycerides and HDL cholesterol levels, LDL size was only significantly
smaller in women with diabetes than in women without diabetes (p=0.043).
In a case-control study, Scheffer et al (2003) examined the relationship of in vitro LDL
oxidisability (ie lag time) and circulating in vivo oxidised LDL with LDL particle size in 58
elderly people (aged >65 years) with well-controlled Type 2 diabetes and 58 age-matched
controls with normal glucose metabolism. Mean LDL cholesterol level was similar in people
with and without diabetes (3.70.9 v 3.90.9 mmol/L, p=0.36), but the LDL particle size was
significantly smaller in people with diabetes (21.30.5 v 21.70.3 nm, p<0.001). Although
lag time did not differ between the diabetes and control group (71.59.6 v 71.77.7 min,
p=0.94), the diabetes group had a non-significantly higher level of circulating in vivo
oxidised LDL (87.226.9 v 81.022.1 U/L, p=0.18). The LDL particle size was found to be
inversely associated with oxidised LDL in people with diabetes (r= -0.35, p=0.007). This
relation remained strong after controlling for LDL cholesterol level (r= -0.52, p<0.001).
Total cholesterol is similar in Type 2 diabetes and the general population
Total cholesterol concentration represents the sum of LDL, HDL and VLDL cholesterol, with
contributions usually ranking in that order. Lower HDL cholesterol levels in Type 2 diabetes
reduce total cholesterol, while higher triglycerides levels are associated with more VLDL
cholesterol and so increase total cholesterol. The balance of total cholesterol represents LDL
cholesterol, the concentration of which is usually unaltered by diabetes. Because diabetes
induced changes in HDL cholesterol and VLDL cholesterol are in opposite directions and
LDL cholesterol is unaltered, total cholesterol levels in diabetic subjects are similar to nondiabetic populations in most studies (Table 1).
Of the studies summarised in Table 1, average total cholesterol levels in the Caucasian
populations were 6.2 mmol/L for men with diabetes, 6.6 mmol/L for women with diabetes,
6.2 mmol/L for non-diabetic men and 6.4 mmol/L for non-diabetic women.
Overall the prevalence of elevated total cholesterol is similar in diabetic and non-diabetic
people. For example, NHANES II data (Cowie et al, 1994) showed total cholesterol was 6.2
mmol/L in 46% of diabetic men compared with 35% of controls and 49% in diabetic women
18
compared with 40% in controls. In the Finnish survey by Salomaa and colleagues (1992),
total cholesterol was >6.9 mmol/L in 33% of men with diabetes compared with 31% of men
with IGT and 21% of controls. Total cholesterol >7.3 mmol/l was found in 11% of women
with diabetes, 37% with IGT and 24% of controls (Salomaa et al, 1992). However some
studies have noted some differences in total cholesterol levels in diabetes. The Framingham
Offspring Study (Siegel et al, 1996) reported total cholesterol 6.2 mmol/l in 18% of men
with diabetes compared with 23% of controls (p=NS) and in 41% of women with diabetes
compared with 23% of controls (p<0.001).
Implications for Clinical Practice
People with Type 2 diabetes frequently have higher triglycerides levels and lower HDL
cholesterol levels compared with the general population. Total and LDL cholesterol levels are
similar in people with and without diabetes and the prevalence of elevated total and HDL
cholesterol levels are also similar.
As reviewed in other Sections of this Guideline, elevated total cholesterol, LDL cholesterol
and triglycerides, and a low HDL cholesterol all predict an increased risk for coronary heart
disease in Type 2 diabetes. Therefore, a complete assessment of lipid levels in people with
Type 2 diabetes requires the measurement of total cholesterol, triglycerides and HDL
cholesterol and calculation of LDL cholesterol.
There are intra-individual variations over time in lipid and lipoprotein levels in Type 2
diabetes.
Intra-individual variations of lipid and lipoprotein levels are observed in people with Type 2
diabetes. This intra-individual variability is derived from both analytical variability
(measurement error) and biological variability with the latter accounting for most of the
variability (Smith et al, 1993). A study of biological variability in 135 people with diabetes
(both Type 1 and Type 2) (Tsalamandris et al, 1998) found that total variability expressed as
a coefficient of variation was 8.80.4% for total cholesterol, 23.91.5% for triglycerides,
10.20.5% for HDL cholesterol and 12.00.5% for calculated LDL cholesterol over an
average follow-up period of 5.1 years. Greater variability was observed in men compared
with women for total cholesterol (9.50.5% v 7.90.5%, p<0.01) and for triglycerides
(26.52.2% v 20.41.4%, p=0.03). Most of the variability in these parameters was related to
biological factors, not measurement error (Tsalamandris et al, 1998). In the United Kingdom
Prospective Diabetes Study (UKPDS), the baseline triglycerides concentration in people
allocated to diet correlated with the values six months later (rs=0.72; CI 0.68 to 0.76) while
the correlation between repeated measures of HDL cholesterol was lower (rs=0.52; CI 0.45 to
0.58) (Turner et al, 1998).
An important source of biological variability for some lipid fractions is whether or not lipids
are measured in the fasting state, particularly in relation to increasing the variability in the
triglycerides levels. Diurnal and monthly variability of serum lipids were examined in 11
healthy subjects aged 32-63 years (Wasenius et al, 1990). Blood sample were drawn at 8am
after 8 hour fasting, 12pm, 3pm, 6pm and 9pm for diurnal measurements, and were drawn
weekly at 8am after 8 hour fasting for monthly measurements. The mean diurnal variability
was 2.4% for total cholesterol, 3.5% for HDL cholesterol, 5.1% for LDL cholesterol, and
29.5% for triglycerides. The corresponding monthly variabilities were 4.2%, 4.1%, 5.2%,
20.7%, respectively.
Epidemiological and intervention studies in Type 2 diabetes have measured lipid levels after
a 10 to 12 hour overnight fast and therefore evidence relating to lipid abnormalities and their
treatment is based on this sampling method. Despite this, recommendations between
19
organisations have varied somewhat on this point. The National Cholesterol Education
Program (NCEP) (The National Cholesterol Education Program Expert Panel, 2002) and the
Heart Foundation of Australia (National Heart Foundation of Australia & The Cardiac
Society of Australia and New Zealand, 2001) recommend sampling after a 12 hour fast when
screening for lipid abnormalities. The UK Clinical Guidelines on Lipid Management for
Type 2 diabetes (Collaborative Programme between: Royal College of General Practitioners,
Diabetes UK, Royal College of Physicians, Royal College of Nursing) recommend fasting
measurement if feasible (McIntosh et al, 2002). However it should be noted that there is little
change in total cholesterol, HDL cholesterol and LDL cholesterol postprandially, so these
lipid parameters can be measured satisfactorily in the non-fasting state.
Taking the available information into account, it is recommended that lipid levels be assessed
after an overnight fast of 10-12 hours. However it is recognised that only triglycerides (and to
a small extent calculated LDL cholesterol) are affected by non-fasting. Depending on
individual and practice circumstances it may not be feasible to measure lipids in the fasting
state, however if lipid levels are not measured fasting, caution is required in interpreting an
elevated triglycerides level and calculated LDL cholesterol.
Because there is intra-individual variation over time in lipids in Type 2 diabetes, management
decisions should generally be based on more than one measurement.
There are no clinical trials on optimal frequency for re-assessment of lipid levels. The
Clinical Practice Recommendations of the American Diabetes Association (ADA, 2003) state
that levels of LDL, HDL, total cholesterol, and triglycerides should be measured every year
in adult patients. If values fall in the lower-risk levels, assessment may be repeated every 2
years. The UK Clinical Guideline for Type 2 Diabetes on Lipid Management recommends
annual assessment of lipid levels as part of the annual review (McIntosh et al, 2002).
As with all recommendations, the frequency of re-assessment should be modified by clinical
judgment. However in general, it is considered that lipid levels should be measured at the
time of diagnosis in people with Type 2 diabetes and annually as part of the annual review. In
people with lipid levels above target, levels should be re-evaluated 3 months after
recommended lifestyle (diet/exercise) changes (See Section 2) and after improving glycaemic
control (See Section 3), and after commencing lipid-lowering agents (See Sections 4 & 5). In
people on long term lipid-lowering therapy, lipid levels would usually be measured at 6
monthly intervals.
Apolipoprotein A1 is reduced, apolipoprotein B is increased, and lipoprotein(a) is not
altered in Type 2 diabetes
Apolipoprotein A1 (Apo A1) is the major apolipoprotein in HDL particles and consistent
with the lower levels of HDL cholesterol, several studies have shown lower Apo A1 levels in
Type 2 diabetes. In the Framingham Offspring Study (Siegel et al, 1996) the mean Apo A1
level was 134 mg/dl in 54 people with diabetes compared with 158 mg/dl in 1,879 people
without diabetes (p<0.001). Apo A1 levels were also consistently lower in people with
diabetes compared with people without diabetes for both sexes (100 v 105 mg/dl, p<0.01 in
men; 107 v 116 mg/dl, p<0.01 in women) in a population based study in Finland (Rnnemaa
et al, 1989). In a clinic based study (Billingham et al, 1989), the mean Apo A1 level was 94
mg/dl in 13 men at diagnosis of diabetes, compared with 114 mg/dl in 17 men without
diabetes (p<0.05). In 9 women the mean Apo A1 level at diagnosis of diabetes was 107
mg/dl, compared with 125 mg/dl in 16 women without diabetes (p<0.05). However, Dean et
al (1990) found that people with Type 2 diabetes (n=35) had a similar Apo A1 level
compared with 35 control subjects (121.424.1 v 131.436.5 mg/dl, p=NS). Another casecontrol study showed that there was no significant difference in Apo A1 level between 120
20
people with diabetes and 30 control subjects (14927 v 15128.2 mg/dl) (Manzato et al,
1993).
One apolipoprotein B (Apo B) molecule is present in each LDL and VLDL particle, so that
Apo B level is a measure of the combined total number of these particles. In the Framingham
Offspring Study (Siegel et al, 1996) mean Apo B level was 106 mg/dl in those with diabetes,
compared with 83 mg/dl in controls (p<0.001). Apo B levels were also consistently higher in
people with diabetes than in the controls (123 v 117 mg/dl in men, p<0.05; 125 v 119 mg/dl
in women, p<0.05) in a population based study in Finland (Rnnemaa et al, 1989). In a clinic
based study (Billingham et al, 1989) mean Apo B level was 95 mg/dl in 22 men and women
at diagnosis of diabetes, compared with 75 mg/dl in 33 controls (p<0.05). Another clinic
based study (Manzato et al, 1993) found mean Apo B level of 150 mg/dl in 120 people with
diabetes compared with 135 mg/dl in 30 control subjects (p=0.02). In contrast, the clinic
based study by Dean et al (1990) found no difference in Apo B between 35 people with and
35 people without diabetes (90.924.0 v 96.222.5 g/dl, p=NS). The higher Apo B levels in
Type 2 diabetes indicate higher numbers of both VLDL and LDL particles, consistent with
higher triglycerides levels and normal LDL cholesterol levels, but smaller, denser LDL
particles.
Apolipoprotein (a) is an apolipoprotein with structural homology to plasminogen. Bound to
the Apo B moiety of a lipoprotein that closely resembles a LDL particle, it forms lipoprotein
(a) [Lp(a)] that is potentially atherogenic and thrombogenic. Most studies of Lp(a) in Type 2
diabetes indicate that levels are not different to those found in the non-diabetic population
(Haffner et al, 1992a; Csaszar et al, 1993; Velho et al, 1993; Chang et al, 1995). A population
based study (Haffner et al, 1992a) showed a similar Lp(a) concentration for both men and
women in people with and without diabetes (13.61.5 v 16.11.4 mg/dl; 12.60.8 v 15.91.3
mg/dl, respectively) (p=0.361). In a case control study (Csaszar et al, 1993), the mean Lp(a)
concentration among people with Type 2 diabetes did not differ from those of control
subjects in both Hungarian (12.217.9 v 10.513.5 mg/dl) and Austrian groups (14.621.0 v
12.216.5 mg/dl). Another case control study in a Chinese population also showed no
difference in the Lp(a) levels between people with and without diabetes (22.32.2 v 20.71.9
mg/dl) (Chang et al, 1995). Velho et al (1993) compared Lp(a) levels in people with Type 2
diabetes, their normoglycaemic relatives, and healthy controls and found that Lp(a) levels
were not significantly different (27.219.3 v 27.118.2 v 23.115.1 mg/dl, p=0.38).
Lipid abnormalities are aggravated by increased body weight, poor glycaemic control,
and diabetic renal disease
In people with Type 2 diabetes, greater disturbance of lipid metabolism has been reported in
association with increasing body weight, poor glycaemic control, diabetic renal disease and
female gender.
Increasing body mass index (BMI) and waist:hip ratio (WHR) within the Type 2 diabetes
population have been linked with hypertrigyceridaemia and reduced HDL cholesterol in a
number of studies (Table 1) in both men and women (Laakso et al, 1985; Uusitupa et al,
1986; Laakso & Pyorala, 1990; Byrne et al, 1994). Laakso et al (1985) reported that BMI had
a statistically significant negative correlation with HDL levels (p<0.001 for both men &
women) and a positive correlation with triglycerides (p<0.001 in men; p<0.05 in women) in
people with Type 2 diabetes. Uusiputa et al (1986) also found a negative correlation of BMI
with HDL cholesterol levels (p=0.014 in men; p=0.066 in women) and a positive correlation
of BMI with triglycerides (p=0.023; p=0.046, respectively) in a population of 133 people
with Type 2 diabetes. In a case control study, obesity was associated with a lower HDL
cholesterol level (BMI >27.0 v <25.0 kg/m2: 1.06 v 1.33 mmol/L, p<0.001 in men; 1.09 v
21
1.48 mmol/L in women) and higher triglycerides levels (3.36 v 1.72 mmol/L, p<0.001; 3.63 v
1.74 mmol/L, p<0.001, respectively) in 305 people with Type 2 diabetes (Laakso & Pyorala,
1990). Byrne et al (1994) found that WHR had a positive association with triglycerides
concentrations in people with diabetes (p<0.001 for men; p<0.01 for women).
A correlation between measures of glycaemic control and HDL cholesterol has been reported
(Laakso et al, 1985). After adjusting for age, physical activity and BMI, fasting plasma
glucose (FPG) was significantly associated with HDL cholesterol in both men (p=0.003) and
women (p<0.001) with Type 2 diabetes (Laakso et al, 1985). The influence of glycaemic
control has important implications for determining decisions relating to the initiation of lipidmodifying therapy. Treatment of hyperglycaemia should generally precede initiation of
treatment for lipid abnormalities especially when triglycerides are elevated or HDL
cholesterol is reduced (see Lipids Section 3).
The development of diabetic nephropathy is associated with a further reduction of HDL
cholesterol and increase of triglycerides in Type 2 diabetes (Mattock et al, 1988; Niskanen et
al, 1990; Suraniti et al, 1992; Nielsen et al, 1993). A cross-sectional study of 141 people with
diabetes found there were significant correlations between albumin excretion rate and total
triglycerides (r=0.214, p<0.05) and HDL cholesterol (r=-0.243, p<0.01) (Mattock et al,
1988). Among 123 people with diabetes, there were no differences in triglycerides and HDL
cholesterol in people with (n=21) and without microalbuminuria (n=92) at baseline.
However, at the 5-year examination, people with microalbuminuria had a significantly higher
triglycerides levels (4.240.90 v 2.380.16 mmol/L, p<0.05) and a lower HDL cholesterol
level (0.920.05 v 1.070.03 mmol/L, p<0.05) compared with those without
microalbuminuria (Niskanen et al, 1990). A negative correlation of urinary albumin excretion
to HDL cholesterol (p=0.0001) was found by Suraniti et al (1992) in 380 people with Type 2
diabetes. In a case control study, people with Type 2 diabetes and macroalbuminuria (>300
mg/24h) had a higher median triglycerides levels than in people with microalbuminuria (31300 mg/24h) and people with normoalbuminuria (30 mg/24h) (2.01 [0.66-14.70] v 1.82
[0.69-3.96] v 1.30 [0.24-23.76] mmol/L, p<0.01) (Nielsen et al, 1993).
There is insufficient evidence to draw any conclusion about the importance of
lipoprotein oxidation in Type 2 diabetes
Results of studies of lipoprotein oxidation in Type 2 diabetes have been variable. Some
studies have reported increased lipid peroxidation products in plasma (Nacitarhan et al, 1995;
Ceriello et al, 1997a; Freitas et al, 1997) but others have not (MacRury et al, 1993; Haffner et
al, 1995). Nacitarhan et al (1995) measured malondialdehyde (MDA), a marker of lipid
peroxidation, among people with Type 2 diabetes (n=78, including n=34 with
hyperlipidaemia), people with hyperlipidamia (n=38), and healthy controls (n=28) and found
that serum MDA level was significantly higher in people with diabetes (7.12.5; 6.21.7
nmol/L, respectively) and hyperlipidaemia (5.71.01 nmol/L) than in healthy controls
(4.80.8 nmol/L) (all p<0.001). In the diabetic group, people with hyperlipidaemia had a
higher serum MDA level than normolipidaemic people (p<0.02). Urine MDA levels in the
diabetic group were higher than that of the non-diabetic hyperlipidaemic group (5.72.6;
5.72.3 nmol/L, respectively v 4.51.1 nmol/L, p<0.01). Ceriello et al (1997a) reported that
total radical-trapping antioxidant parameter (TRAP), a marker of plasma antioxidant
capacity, was significantly reduced in people with diabetes (n=46) compared with control
subjects (n=47) (67758 v 950.116.0 mol/L, p<0.001). However, a study conducted by
MacRury et al (1993) showed that the level of plasma antioxidant, caeruloplasmin, was
22
higher in people with diabetes than control subjects (19.36.9 v 14.25.1 mol/L, p<0.01). A
number of studies have reported increased lipid susceptibility to oxidation using plasma
(Haffner et al, 1995) or LDL (Dimitriadis et al, 1995; Leonhardt et al, 1996) from subjects
with Type 2 diabetes. Ceriello et al (1997b) reported the existence of lower antioxidant
defenses in people with Type 2 diabetes. TRAP measured by fluorescence-based method and
calculated by a mathematical formula were both lower in diabetic people (n=40) than controls
(n=40) (690.416.5 v 961.916.7 mol/L, p<0.001; 615.215.2 v 669.311.8 mol/L,
p<0.005, respectively). However, a study of 72 people with Type 2 diabetes and 94 nondiabetic controls did not find any difference in LDL susceptibility to oxidation, (Leinonen et
al, 1998a). Another study by the same group of antioxidant defenses in 81 people with Type 2
diabetes and 102 controls showed no difference (Leinonen et al, 1998b).
Nearly all studies have used non-specific measures of lipoprotein oxidation or have examined
in vitro susceptibility to oxidation or antioxidant capacity. None of these measures gives a
direct indication of the importance of lipoprotein oxidation in Type 2 diabetes. The results of
these indirect tests have been variable and it is therefore not possible to draw any evidencebased conclusion about the importance of lipoprotein oxidation in Type 2 diabetes.
Total cholesterol and LDL cholesterol predict cardiovascular disease in Type 2 diabetes
Data from cross-sectional studies provide information on the association between lipid levels
and cardiovascular disease while prospective cohort studies provide information on the
relationship of lipid levels and the future development of cardiovascular disease.
Cross-sectional studies
Cross-sectional studies provide limited evidence for total and LDL cholesterol as risk factors
for cardiovascular disease (CVD) in Type 2 diabetes (see Table 2). Nearly all studies have
used a composite of macrovascular disease indicators and few studies have included more
than 100 subjects.
Some studies have found higher total and LDL cholesterol in association with CVD in Type 2
diabetes. The Milan Study on Atherosclerosis and Diabetes excluded people on insulin
therapy, as well as those with clinical CVD or diabetes complications (MiSAD Group, 1997).
In order to detect silent myocardial ischaemia, 925 people aged 40 to 65 years underwent
exercise ECG, followed by exercise thallium scintigram if the ECG was abnormal. Total
cholesterol was 5.831.12 mmol/L in the 59 subjects with both tests positive compared with
5.481.04 mmol/L in the other 866 subjects (p=0.014). Another hospital based study in
London assessed people with Type 2 diabetes for CHD using resting ECG, history and
standard questionnaire and for peripheral vascular disease using questionnaire and ankle/arm
systolic blood pressure ratio (Seviour et al, 1988). Men with macrovascular disease (n=48)
had higher total cholesterol and LDL cholesterol levels compared with men without evidence
of macrovascular disease (n=47) (5.981.20 v 5.150.98 mmol/L, p=0.0001; 4.290.95 v
3.570.74 mmol/L, p=0.0001, respectively). The corresponding figures among women were
6.461.51 v 5.711.01 mmol/L (p=0.04); and 4.681.26 v 3.820.96 mmol/L (p=0.008),
respectively.
Two North American studies have also shown higher LDL cholesterol in association with
prevalent CHD in Type 2 diabetes. Of 227 subjects with Type 2 diabetes in the Rochester
Diabetic Neuropathy Study (O'Brien et al, 1994), 96 were defined as having CHD on the
basis of history and ECG, abnormal non-invasive cardiovascular tests or abnormal coronary
angiography. Total cholesterol was 5.261.03 mmol/L in this group, compared with
23
5.041.00 mmol/L in the 131 subjects without evidence of CHD on history and ECG
(p=0.085), while LDL cholesterol was 3.400.87 mmol/L in those with CHD, compared with
3.130.88 mmol/L in those without CHD (p=0.039). A Canadian study used coronary
angiography to classify 174 people with Type 2 diabetes as having mild, moderate or severe
CHD. Although total and LDL cholesterol were not significantly different across the three
groups, a multiple linear regression analysis model of the relation between coronary score
and lipoproteins showed that LDL cholesterol made a significant and independent
contribution to the model (p=0.008) (Tkac et al, 1997).
In an Italian study of 3,862 people with Type 2 diabetes (aged 50 years), Giansanti et al
(1999) reported that the prevalence of CHD was 20.3%. In the 50-59 year age group, more
people with CHD had hypercholesterolaemia (5.8 mmol/L) compared with people without
CHD (26 v 9.3%, p<0.001). People aged 60-69 years and 70 years with CHD had a
significantly higher prevalence of hyperlipidaemia (total cholesterol 5.8 mmol/L plus
triglycerides 2.26 mmol/L) than those without CHD in the same age group (28 v 17.9%,
p<0.001; 21 v 14.8%, p<0.001, respectively).
Some other cross-sectional studies have found little or no evidence for a link between total or
LDL cholesterol and CVD in Type 2 diabetes. A population based study of men and women
with Type 2 diabetes in East and West Finland identified subjects with previous myocardial
infarction (MI) on the basis of ECG and medical records (Ronnemaa et al, 1989). For men
with Type 2 diabetes from East Finland total cholesterol was higher in those with previous
myocardial infarction. Total cholesterol was 7.15 mmol/L in 66 men with CHD compared
with 6.71 mmol/L in 187 men without CHD (p<0.05). In men from West Finland and in
women from East or West Finland total cholesterol was not significantly raised in the CHD
positive groups. A large clinic based study of Type 2 diabetes in the US identified the
presence of CVD (coronary heart disease, cerebrovascular disease and peripheral vascular
disease) by self-administered questionnaire (Meigs et al, 1997). Mean cholesterol level was
5.92 mmol/L in 787 diabetic subjects with CVD and precisely the same in 752 subjects
without CVD.
24
Table 2: Lipid levels and cardiovascular disease in people with Type 2 diabetes
Reference
Fontbonne, 1989
(France)
Giansanti, 1999
(Italy)
Population Studied
Paris Prospective Study
n=7,038 men 43-45 yrs 11-yr follow-up
IGT 690; newly diagnosed Type 2 diabetes
158; known Type 2 diabetes 135
CHD
No CHD
n=3,862 Type 2 diabetes
aged 50 yrs, cross-sectional study
age 50-59 yrs
Total
Cholesterol
LDL
Cholesterol
HDL Cholesterol
Triglycerides
6.3 mmol/L
5.7 mmol/L
T-CHOL 5.2 mmol/L
CHD+
CHD26%
9.3%
2.07 mmol/L
1.47mmol/L
TG 2.26 mmol/L
CHD+
CHD26%
25.3%
(v CHD+)
age 60-69 yrs
17%
13.3%
age 70 yrs
12%
11.0%
28%
17.9%
21%
14.8%
(v CHD+)
(v CHD+)
Hanefeld, 1996
(Germany)
HPS Collaborative
Group, 2003
Lehto, 1997
(Finland)
n=1,846 Type 2 diabetes; 11-yr follow-up

age 30-55 yrs
during follow-up, without IHD
during follow-up, with IHD
during follow-up, with MI
n=5,963 diabetes, 90% Type 2 diabetes
age 40-80 yrs
5-yr follow-up
n=1,059 Type 2 diabetes, 7-yr follow-up
age 45-64 yrs
without CHD
with CHD
5.69 mmol/L
5.61 mmol/L
5.93 mmol/L
Before
After 5yrs
Before
After 5yrs
Before
After 5yrs
5.7
Men
4.6
Women
3.2
Men
2.3
Women
1.06
Men
1.07
Women
2.3
Men
2.0
Women
6.29
6.96
6.99
7.32
4.18
4.80
4.66
4.48
1.19
1.09
1.28
1.20
2.22
2.84
2.62
3.82
(v CHD-)
Meigs, 1997
(US)
n=1,539 Type 2 diabetes; 2-yr follow-up

age 31-91 yrs
CVD+
CVD-
1.88 mmol/L
1.78 mmol/L
2.32 mmol/L
Before
After 5yrs
(v CHD-)
5.91
5.91

The results of HPS are baseline and after treatment comparison, no p value given in the paper
25
1.09
1.14
Reference
MiSAD, 1997
(Italy)
OBrien, 1994
(USA)
Ronnemaa, 1989
(Finland)
Saito, 2000
(Japan)
Seviour, 1988
(UK)
Population Studied
n=925 Type 2 diabetes
aged 40-65 yrs, cross-sectional study
CHD+
CHDn=227 Type 2 Diabetes
cross sectional study
CAD+
CADcross sectional study, age 45-64 yrs
Type 2 East Finland: 253M;257W, MI+
MI-
Total
Cholesterol
LDL
Cholesterol
HDL Cholesterol
Triglycerides
5.831.12
5.481.04
1.160.29
1.210.32
2.141.03
1.710.99
5.04
5.26
3.13
3.40
0.98
0.82
2.33
2.66
Women
Men
3.14
2.82
3.21
2.58
(v MI+)
2.99
2.72
2.44
2.09
(v MI+)
(v MI+)
1.52
2.74
1.40
1.52
(v MI+)
1.52
1.79
1.25
1.47
(v MI+)
TG (log)
Women
8.14
7.32
Type 2 West Finland: 328M; 221W, MI+

MI-
Men
7.15
6.71
(v MI+)
6.71
6.12
Control East Finland: 313M; 336W, MI+

MI-
6.85
6.76
7.83
7.06
Control West Finland: 325M;399W, MI+

MI-
6.79
6.49
7.38
6.84
7.78
6.64
-
n=1,676 diabetes (type not stated)

8-yr follow-up
CHD+
CHDn=53 W, 95 M; mean age 63 yrs
cross-sectional study
MVD+
MVD-
5.97
5.68
Men
Women
5.98
5.15
6.46
5.71
Men
1.14
1.26
(v MI+)
1.02
1.14
(v MI+)
1.19
1.40
(v MI+)
1.36
1.32
3.83
3.63
Women
1.19
1.32
1.22
1.26
1.63
1.62
1.41
1.63
Men
Women
Men
Women
0.76
0.52
Men
Women
4.29
3.57
4.68
3.82
0.88
0.89
0.95
1.28
1.79
1.52
26
1.07
1.18
1.83
1.33
Reference
Stamler, 1993
(US)
MRFIT
Tkac, 1997
(Canada)
Turner, 1998
(UK)
Population Studied
n=5,163 men taking medication for
diabetes; aged 35-75 yrs,
12-yr follow-up
high CVD death
low CVD death
n=174 Type 2 diabetes; mean age 57yrs
cross sectional study
mild CAD
moderate CAD
severe CAD
UKPDS
n=2,963 Type 2 diabetes; 7.9-yr follow-up
age 25-65 yrs
CHD lower third
CHD upper third
Total
Cholesterol
LDL
Cholesterol
HDL Cholesterol
Triglycerides
4.66
7.25
4.88
5.12
5.15
3.00
3.17
3.16
1.04
1.02
1.01
0.84
0.93
0.98
4.88
5.77
3.02
3.89
0.95
1.15
1.22
1.87
27
Longitudinal studies
Longitudinal studies provide more compelling evidence that total and LDL cholesterol levels
predict CHD risk in Type 2 diabetes (see Table 2).
The MRFIT study included 5,163 men who reported taking medication for diabetes. Of these
men, 603 died from CVD, including 469 deaths from CHD over an average follow up period
of 12 years (Stamler et al, 1993). Total cholesterol level was a significant predictor of CVD
mortality. Mortality rates ranged from 61.7 per 10,000 person-years for a total cholesterol of
<4.66 mmol/L to 130.4 per 10,000 person-years for a total cholesterol of 7.25 mmol/L, 2.1
times greater than in men with total cholesterol of <4.66 mmol/L. Higher total cholesterol
was associated with greater absolute excess risk of cardiovascular death for men with
diabetes compared with men without diabetes, ranging from 48 per 10,000 person-years
follow up at total cholesterol <4.66 mmol/L to 84 per 10,000 person-years when total
cholesterol was 7.25 mmol/L. Even though the distribution of total cholesterol was the same
in Type 2 diabetes as in the general population, at each cholesterol level there was a higher
absolute risk of CHD in the Type 2 diabetic population than in the non-diabetic population.
Furthermore, the increase in risk associated with diabetes was greater at higher cholesterol
levels.
The Nurses Health Study provides comparable data for women with Type 2 diabetes
(Manson et al, 1991). During 8 years of follow up the rate of nonfatal myocardial infarction
and fatal CHD in women with total cholesterol 6.21 mmol/L was 452 per 100,000 personyears compared with 262 per 100,000 person-years when cholesterol was <6.21 mmol/L. The
excess risk attributable to Type 2 diabetes was 225 per 100,000 person-years at the lower
cholesterol levels and 319 per 100,000 person-years at higher levels.
Analysis of risk factors for CHD was undertaken in 2,693 people in the UKPDS who had
recently diagnosed Type 2 diabetes but no evidence of CVD at baseline (Turner et al, 1998).
With a median duration of follow up of 7.9 years, both total and LDL cholesterol predicted
development of CHD. Total cholesterol levels were divided into tertiles (<4.88 mmol/L,
4.88 to <5.77 mmol/L and 5.77 mmol/L). The hazard ratio (HR) for development of CHD
(fatal or non-fatal myocardial infarction or clinical angina with an abnormal ECG at rest or
after a treadmill test) was 1.79 for the middle tertile and 1.93 for the upper tertile compared
with the lower tertile (p<0.0001). For LDL cholesterol the lower tertile was <3.02 mmol/L,
the middle tertile 3.02 to <3.89 mmol/L and the upper tertile 3.89 mmol/L. The HRs
compared with the lower tertile were 1.48 for the middle tertile and 2.29 for the upper tertile
(p<0.0001). For each increment of 1 mmol/L in LDL cholesterol level there was a 1.57-fold
(CI 1.37-1.79) increased risk of CHD (Turner et al, 1998).
Another large prospective trial from Finland included 1,059 people with Type 2 diabetes aged
45 to 64 years who were followed for a mean of 7.2 years (Lehto et al, 1997), of whom 158
died of CHD during follow-up. The unadjusted HR for CHD mortality was 1.4 (CI 1.0-1.9,
p=0.052) and for all CHD events was 1.4 (CI 1.1-1.8, p=0.012) when total cholesterol was
6.2 mmol/L compared with <6.2 mmol/L. The corresponding unadjusted HR was 1.3 (CI
0.9-1.9, p=NS), and 1.5 (CI 1.1-2.1, p=0.009), respectively, when LDL cholesterol was 4.1
mmol/L compared with < 4.1 mmol/L.
Saito et al (2000) followed 1,676 people (mean age 54 years) with diabetes (type not stated)
and no reported history of coronary heart disease for 8 years in the Atherosclerosis Risk in
Communities Study. During the follow-up, 186 cases of coronary heart disease events were
identified. People who had a coronary event had a higher total cholesterol (5.97 v 5.68
28
mmol/L, p=0.003) and LDL cholesterol (3.83 v 3.63 mmol/L, p=0.03) than those event-free
subjects.
The WHO Multinational Study of Vascular Disease in Type 2 Diabetes (Fuller et al, 2001)
showed that among 3,483 people with Type 2 diabetes, total cholesterol predicted the
incidence of fatal and nonfatal MI after adjusting for age (RR 1.3 [CI 1.1-1.4], p=0.0001 for
men; RR 1.3 [CI 1.2-1.5], p=0.0001 for women, respectively); whereas serum triglycerides
were not significantly associated with this endpoint in any groups, with a RR of 1.2 (CI 1.01.4, p=0.08) for men and of 1.2 (CI 1.0-1.4, p=0.06) for women. The multivariate analysis
also showed total cholesterol was significantly associated with CVD mortality, with a RR of
1.2 (CI 1.1-1.3) for men and 1.3 (CI 1.2-1.5) for women. Triglycerides as a risk for increased
CVD mortality was only observed in men with diabetes (RR 1.3, CI 1.1-1.6).
In the Diabetes Atherosclerosis Intervention Study of 405 people aged 40-65 years with Type
2 diabetes, Vakkilainen et al (2003) reported that small LDL size was significantly associated
with progression of coronary artery disease (CAD), which was assessed by coronary
angiography, over a mean follow-up of 39.6 months. Small LDL size was shown to be
associated with an increase in percentage diameter stenosis (r=-0.16, p=0.002), and decrease
in mininum (r=-0.11, p=0.03) and mean lumen diameter (r=-0.16, p=0.0002). In multivariate
analysis, the combination of small LDL size and LDL cholesterol level showed a statistically
significant association with the progression of CAD (p<0.001).
In the Heart Protection Study (HPS Collaborative Group, 2003), the mean total cholesterol
was 5.7 mmol/L and LDL cholesterol was 3.2 mmol/L at baseline among 5,963 people with
diabetes (90% Type 2 diabetes). Over the 5-year treatment period, the incidence of major
vascular event in people assigned to the placebo group was 22.2% for those with initial total
cholesterol <5.0 mmol/L, and was 26.1% for those with initial total cholesterol 5.0 mmol/L
(0.05<p<0.10). The corresponding figure was 20.9% and 27.9% for those with initial LDL
cholesterol <3.0 mmol/L, and 3.0 mmol/L, respectively, and this difference was statistically
significant (p<0.001).
However, there have been occasional exceptions to this finding. Total cholesterol was not a
risk factor for CHD in the Diabetes Intervention Study, which was based in Germany and
included people with recently diagnosed Type 2 diabetes (Hanefeld et al, 1996). From data
obtained at 11 year follow up on 994 subjects aged 30 to 55 years, 112 suffered from
myocardial infarction and 197 had died. The mean total cholesterol was 5.93 mmol/L and
5.70 mmol/L in people who suffered from myocardial infarction and people without clinical
evidence of CHD respectively (p=NS). Similarly, the mean total cholesterol was 5.90
mmol/L and 5.70 mmol/L respectively among people who died during follow-up and people
who survived (p=NS).
The general conclusion from both prospective and cross-sectional studies is that total
cholesterol and its main constituent LDL cholesterol are associated with and are predictive of
CVD risk in Type 2 diabetes. Because the overall risk of CVD is greater in Type 2 diabetes,
the absolute increment of risk associated with elevated total or LDL cholesterol is greater
than in the general population and therefore the predictive importance of these parameters is
greater in Type 2 diabetes.
29
HDL cholesterol and triglycerides predict cardiovascular disease in Type 2 diabetes

HDL cholesterol and triglycerides are inversely related. There is clear evidence for an
independent relationship between HDL cholesterol and CVD risk. The situation is less clear
for triglycerides as an independent risk factor as opposed to a risk marker in people with
Type 2 diabetes. Elevations of triglycerides can be confounded by changes in other lipids
(most notably HDL cholesterol) and by non lipid factors including obesity, hypertension,
diabetes and smoking. If elevated triglycerides are an independent risk factor then this is
thought to be mediated by atherogenic triglycerides rich remnant lipoproteins which are
cholesterol enriched and have many of the properties of LDL cholesterol (NCEP 2001;
NCEP, 2002).
Cross-sectional studies
Elevated triglycerides and reduced HDL cholesterol are found in Type 2 diabetes and both
have been associated with increased risk of CHD in Type 2 diabetes in some but not all
studies (see Table 2).
In the Milan Study on Atherosclerosis and Diabetes, the mean triglycerides level was
2.141.03 mmol/L in the 59 subjects with evidence of CHD compared with 1.710.99
mmol/L in the other 866 subjects (p=0.002). The mean HDL cholesterol level in the group
with CHD was 1.160.29 mmol/L, not significantly different from the level of 1.210.32
mmol/L in the group without evidence of CHD (MiSAD Group, 1997). The study by Seviour
and colleagues (1988) found that triglycerides and HDL cholesterol were risk factors in
women but not in men. In women with macrovascular disease triglycerides were 1.83
mmol/L and HDL cholesterol 0.95 mmol/L, compared with 1.33 mmol/L and 1.28 mmol/L
(p=0.05 and p=0.0001 respectively) in women without macrovascular disease. In men with
macrovascular disease triglycerides were 1.79 mmol/L and HDL cholesterol 0.88 mmol/L,
compared with 1.52 mmol/L and 0.89 mmol/L (both p=NS) in men without evidence of
macrovascular disease.
For men from the population-based study of Type 2 diabetes in East and West Finland, higher
triglycerides and lower HDL cholesterol were both associated with CHD (Ronnemaa et al,
1989). Men with CHD from East Finland had mean triglycerides of 2.81 mmol/L compared
with 2.58 mmol/L in men without CHD and in West Finland the levels were 2.72 and 2.09
mmol/L (both p<0.001). In men from East Finland mean HDL cholesterol was 1.14 mmol/L
in those with CHD compared with 1.26 mmol/L in those without CHD and in West Finland
the levels were 1.02 and 1.14 mmol/L (p<0.001 and p<0.01 respectively). In women from
West Finland triglycerides were 2.99 mmol/L in those with CHD compared with 2.44
mmol/L in those without CHD (p<0.05), but triglycerides were not different between women
with and without CHD in East Finland. The presence of CHD was not associated with
reduction of HDL cholesterol in women from either East or West Finland.
The Rochester Diabetic Neuropathy Study reported mean triglycerides levels of 2.66 mmol/L
and HDL cholesterol levels of 0.82 mmol/L in the CHD positive group. In comparison, the
CHD negative group reported triglycerides levels of 2.33 mmol/L and HDL cholesterol levels
of 0.98 mmol/L (p=0.055 for triglycerides and p=0.0001 for HDL cholesterol) (O'Brien et al,
1994). In the Canadian angiography study triglycerides and HDL cholesterol levels were not
significantly different between the mild, moderate and severe groups, but the number of
triglycerides-rich lipoprotein particles were greater in those with moderate and severe disease
than in those with mild disease (p=0.001); and there was a correlation between the coronary
score and the triglycerides-rich lipoprotein (p=0.006) (Tkac et al, 1997). The US clinic based
study that identified CVD by self-administered questionnaire reported a mean HDL
30
cholesterol of 1.09 mmol/L in 787 diabetic people with CVD and 1.14 mmol/L in 752 people
without CVD (p=0.01). Triglycerides levels were not reported (Meigs et al, 1997).
Longitudinal studies
As with total and LDL cholesterol, longitudinal studies provide more compelling evidence
for triglycerides and HDL cholesterol levels as predictors of CHD risk in Type 2 diabetes
(see Table 2). The meta-analysis by Hokanson and Austin (1996) supports an independent
role for triglycerides after adjustment for other confounding risk factors but these analyses do
not include any specific information on diabetes. This analysis included a total of 17
population-based, prospective studies reporting the association between fasting triglycerides
levels and incident cardiovascular endpoints. Among 57,277 subjects aged 15-81 years
(diabetes not specified), a 1 mmol/L increase in mean triglycerides levels was significantly
associated with increased risk of CVD in both men (n=46,413) (RR 1.32, CI 1.26-1.29) and
in women (n=10,864) (RR 1.76, CI 1.50-2.07). After adjustment for HDL cholesterol and
other risk factors, there was still a 14% increased CVD risk (RR 1.14, CI 1.05-1.28) in men
and a 37% increased CVD risk (RR 1.37, CI 1.13-1.66) in women.
In the UKPDS, both triglycerides and HDL cholesterol levels predicted risk of development
of CHD (Turner et al, 1998). Triglycerides levels were divided into tertiles, the lower tertile
being <1.22 mmol/L, the middle tertile 1.22 to <1.87 mmol/L and the upper tertile 1.87
mmol/L. The HR for development of CHD was 1.63 for the middle tertile and 1.93 for the
upper tertile (p<0.0001). For HDL cholesterol the lower tertile was <0.95 mmol/L, the middle
tertile 0.95 to <1.15 mmol/L and the upper tertile 1.15 mmol/L. The HRs compared with
the lower tertile were 0.87 for the middle tertile and 0.51 for the upper tertile (p<0.0001).
Two European studies have emphasised the role of triglycerides levels as a risk factor in
states of abnormal glucose metabolism. The Paris Prospective Study investigated mortality
from CHD in 7,038 men, 690 with IGT and 293 with Type 2 diabetes. The mean triglycerides
levels in the 26 people with diabetes who died from CHD during 11 years of follow-up were
2.07 mmol/L compared with 1.47 mmol/L in those who did not die from CHD (p<0.006).
The RR of CHD death for subjects with triglycerides levels over 1.5 mmol/L was 3.28
(p<0.01) (Fontbonne et al, 1989). At the 11 year follow up evaluation in the Diabetes
Intervention Study, triglycerides levels were 2.32 mmol/L in people who suffered from
myocardial infarction compared to 1.88 mmol/L in those without clinical evidence of CHD
(p<0.01). Triglycerides were also higher among people who died during follow up than
people who survived (2.30 v 1.90 mmol/L, p<0.01) (Hanefeld et al, 1996). HDL cholesterol
levels were not reported for either of these studies.
The largest study from Finland found the unadjusted HR for all CHD events was 1.8 (1.4-2.3)
and for CHD mortality was 2.2 (1.6-3.1) when triglycerides were >2.3 mmol/L compared
with 2.3 mmol/L (both p<0.001). The corresponding ratio was 1.6 (1.2-2.0) and 1.9 (1.42.7), respectively when HDL cholesterol was <1.0 mmol/L compared with 1.0 mmol/L
(p=0.001; p<0.001, respectively) (Lehto et al, 1997). A 15 year follow-up of a separate,
smaller cohort in the same city, found the baseline triglycerides levels of 2.59 mmol/L in the
group who developed CHD (n=48) were not significantly different from the level of 2.31
mmol/L in the group that did not have CHD (n=85). However, baseline HDL cholesterol was
0.99 mmol/L in the group that developed CHD, significantly lower than the level of 1.12
mmol/L in the group that remained without CHD (p=0.005) (Niskanen et al, 1998).
In this prospective study of 252 people with diabetes (mean age 58 years) (Hanninen et al,
1999), the prevalence of hypertension was 42% and coronary heart disease was 23% at
baseline. During 5-year follow-up the mortality rate during was 8.3%. Initial CHD (p=0.001),
31
lower mean HDL cholesterol level (p=0.019) and higher level of albuminuria (20 g/min)
(p=0.0007) were significantly related to mortality.
In a study of 1,172 diabetic subjects with an average of 7 years follow-up after coronary
artery bypass graft surgery, women with triglycerides in the highest quartile (>3.12 mmol/L)
had a HR of 1.49 (CI 1.06-2.08, p=0.02) for adverse events (myocardial infarction,
revascularisation or death), while in men with triglycerides in the highest quartile (>2.90
mmol/L) the HR was 1.28 (CI 0.99-1.66, p=0.06). Neither total cholesterol in the highest
quartile, nor HDL cholesterol in the lowest quartile was associated with an increased HR, but
information on use of lipid modifying therapy was not available (Sprecher et al, 2000).
Saito et al (2000) showed that people who suffered from a coronary event had a higher level
of triglycerides (0.76 v 0.52 mmol/L, p<0.001) and a lower level of HDL cholesterol (1.07 v
1.18 mmol/L, p<0.001) compared with those did not have an event in a 8-year follow-up
study of 1,676 people with diabetes (type not stated) and no reported history of CHD at
baseline. In addition, after adjusting for sex, age and ethnicity, the incidence of CHD was
negatively associated with HDL3 level when comparing the highest tertile (1.02 mmol/L)
with the lowest tertile (<0.67 mmol/L), with a RR of 0.41 (CI 0.35-0.66, p<0.001).
Abu-lebdeh et al (2001) reported important predictors of macrovascular disease among 449
people with Type 2 diabetes (mean age 57 years) in a prospective cohort study. At baseline,
170 people (38%) had triglycerides levels greater than 2.7 mmol/L, and 36 (8%) greater than
4.5 mmol/L. During a mean follow-up of 13 years, 216 cases of coronary artery disease had
developed. In the multivariate analysis, the significant predictors of future CAD events were
age (per decade) (HR 1.45 [CI 1.27-1.67], p<0.001), baseline glucose level (per 1 natural log
unit) (HR 1.63 [CI 1.17-2.25], p=0.003), baseline triglycerides levels (per 1 natural log unit)
(HR 1.49 [CI 1.15-1.92], p=0.002) and smoking (HR 1.45 [CI 1.10-1.91], p=0.008).
In the Atherosclerosis Risk in Communities (ARIC) Study, Sharrett et al (2001) reported 725
CHD events occurred over a mean of 10 years follow-up among 12,339 middle-aged people
(45-64 years, number with diabetes not specified) who had no evidence of CHD and had
fasting triglycerides <4.52 mmol/L at study entry. Both men and women with subsequent
CHD had a higher baseline total, LDL cholesterol and triglyceride levels, and a lower HDL
cholesterol level than those without CHD (p<0.005 for all comparisons). A 1 mmol/L
increase in LDL cholesterol was associated with an increased risk of CHD events in both men
and women after adjusting for age and race (RR 1.40 for men, p<0.01; RR 1.23 for women,
p<0.01). The RR was similar for a 0.70 mmol/L increment in triglycerides but was only
observed in women (RR 1.29, p<0.01), not in men (RR 1.07, p=NS). In comparison, a 0.40
mmol/L increment in HDL cholesterol was associated with greater CHD protection (RR 0.64
for men, p<0.01; RR 0.69 for women, p<0.01). Overall, after adjustment for blood pressure,
smoking, and diabetes, LDL and HDL cholesterol, triglycerides were only an independent
predictor of CHD in women with a RR of 4.9 (90% CI 3.9-5.7). HDL cholesterol was an
independent CHD risk factor in both men and women in all multivariate models.
In the Heart Protection Study (HPS Collaborative Group, 2003), the mean HDL cholesterol
was 1.06 mmol/L and triglycerides was 2.3 mmol/L at baseline among 5,963 people with
diabetes. Over the 5-year treatment period, the incidence of initial major vascular event in
people assigned to the placebo group was 21.3% for those with baseline HDL cholesterol
0.9 mmol/L, and was 31.1% for those with HDL cholesterol <0.9 mmol/L (p<0.001). The
correspording figures were 22.8% and 27.6% for people with initial triglycerides <2.0
mmol/L and 2.0 mmol/L, respectively (p<0.03).
32
In the Hoorn Study (Bos et al, 2003), 408 cases of cardiovascular disease were identified in
1,817 people aged 50-75 years during a 10-year follow-up. High triglycerides concentrations
which were defined by the cut off point of 1.4 mmol/L in men and 1.3 mmol/L in women
were associated with increased risk of cardiovascular disease (HR 1.35, CI 1.11-1.64) after
adjustment for age and sex. However, triglycerides were not a risk factor in people with
normal glucose metabolism (HR 0.94, CI 0.73-1.22), but in people with abnormal glucose
metabolism which included people with Type 2 diabetes and people with IGT (number of
each not given), the HR for cardiovascular disease was 1.54 (CI 1.07-2.22).
The contribution of increased lipoprotein (a) to risk of cardiovascular disease in Type 2
diabetes is uncertain
Lp(a) consists of an LDL like particle covalently linked with an apolipoprotein that has
strong sequence homology to plasminogen. Possibly through both atherogenic and
thrombogenic properties, Lp(a) is an independent risk factor for CHD.
A number of cross-sectional studies have reported raised Lp(a) levels in association with
CHD in people with Type 2 diabetes. A hospital based study in France measured Lp(a) in 71
people with CHD, defined mainly by documented myocardial infarction or by coronary
angiogram. Mean Lp(a) levels were 29 mg/dl in this group, compared with 18 mg/dl (p=0.19)
in a comparable group of 67 people with diabetes who were defined as free from CHD
mainly on the basis of coronary angiography and dipyridamole myocardial thallium
scintigraphy tests. Elevated Lp(a) was defined as a level 30 mg/dl and 33.8% of the CHD
positive group had elevated levels, compared with 13.4% of the CHD negative group
(p=0.005) (Ruiz et al, 1994). Using the same threshold to define elevated Lp(a), a study in
Italy measured levels in 355 people with Type 2 diabetes and 145 people with Type 1
diabetes. CHD was determined by history and ECG, and peripheral vascular disease by
history, ankle arm blood pressure ratio and Doppler velocimetry, with 30.6% of the total
group found to have macroangiopathy (CHD and/or peripheral vascular disease). Median
Lp(a) level was 13 mg/dl in the group with macroangiopathy compared with 9 mg/dl in the
group without (p<0.05). Logistic regression analysis with Lp(a) 30 mg/dl as a categorical
variable showed that it was a significant predictor of macroangiopathy with an OR of 2.11
(p<0.003) and that the association was independent of the type of diabetes (James et al,
1995).
The association between elevated Lp(a) and increased risk of coronary artery disease (CAD)
has not been confirmed in elderly people. In a cross-sectional study of 400 elderly people
aged 65 to 84 years by Solfrizzi et al (2002) which included 13% with Type 2 diabetes, levels
of Lp(a) were similar in 70 people with CAD (18.319.0 mg/dl) and 330 without CAD
(17.419.4 mg/dl) (p=0.7). However, the combined effect of high Lp(a) (20 mg/dl) and high
LDL cholesterol (3.63 mmol/L) in people with Type 2 diabetes significantly increased
coronary risk, with an OR of 6.65 (CI 1.25-35.40).
However, other crosssectional studies have not found Lp(a) to be elevated in people with
Type 2 diabetes who have CHD. In the Rochester Diabetic Neuropathy Study mean Lp(a)
level was 19 mg/dl in the group with CHD, compared with 17 mg/dl in the group without
(p=0.36) (O'Brien et al, 1994).
There is little information available from longitudinal studies of Lp(a) as a risk factor for
CHD in Type 2 diabetes. From the Wisconsin Epidemiological Study of Diabetic
Retinopathy, Lp(a) was measured in 24 subjects with onset of diabetes after the age of 30
years who had died from CHD. Mean Lp(a) level was 12.7 mg/dl in this group, compared
with 15.4 mg/dl (p=0.60) for 24 people in the study, matched by age and gender, who
33
remained alive (Haffner et al, 1992b). A Japanese study defined high Lp(a) as a level 20
mg/dl and selected 113 people with low Lp(a) and 108 people with high Lp(a), all with Type
2 diabetes and apparently free of CVD. After follow-up of 2.2-3.1 years, 7 people with high
Lp(a) had a cardiac or peripheral vascular event and only 1 person with low Lp(a) had an
event (p=0.032) (Hiraga et al, 1995).
Although there is some evidence to support Lp(a) as an independent risk factor for CHD in
people with Type 2 diabetes, at present there is insufficient evidence that measurement of
Lp(a) level is useful to stratify risk of CHD and aid in the choice of lipid modifying
interventions.
A limited number of studies have examined the association between lipid and lipoprotein
levels and diabetic nephropathy in Type 2 diabetes (see Table 3). As detailed in Table 3 there
have not been any consistent findings in cross-sectional studies (Seghieri et al, 1990; Suraniti
et al, 1992; Nielsen et al, 1993).
Two prospective studies have examined different aspects of the relationship between lipid
levels and diabetic nephropathy. In a study in Israel, 574 people with recent onset of Type 2
diabetes were followed for a mean of 7.8 years. A baseline total cholesterol level 5.25
mmol/L was associated with an OR of 20.59 (CI 12.67-33.59) for the development of
microalbuminuria, LDL cholesterol 3.21 mmol/L with an OR of 6.24 (CI 4.80-13.35) and
HDL cholesterol <1.14 mmol/L with an OR of 7.76 (CI 5.17-11.64) (all p<0.001) (Ravid et
al, 1998). In a study in Finland of 133 people with Type 2 diabetes (Niskanen et al, 1990)
people with persistent microalbuminuria (>30 mg/24h) had significantly lower levels of HDL
and LDL cholesterol and higher triglycerides after 5-year follow-up (0.920.03 v 1.070.03
mmol/L, p<0.05; 3.650.22 v 4.000.11 mmol/L; and 4.240.90 v 2.350.16 mmol/L,
p<0.05, respectively). Neither study reported usage of lipid lowering therapy.
34
Table 3: Lipid levels and diabetic nephropathy

Lipid levels
Reference
Niskanen, 1990
(Finland)
Population Studied
n=133, age 45-64 yrs; Type
2 diabetes; 5-yr follow-up
no microalbuminuria
Mean LDL
Cholesterol
(mmol/L)
Baseline
5yr
Baseline
6.36
6.44
4.16
Mean HDL
Cholesterol
(mmol/L)
5yr
Baseline
4.00
1.07
(v AU+)
microabuminuria
control (n=144)
age <66 yrs;
Nephropathy
Nielsen, 1993
(Denmark)
Mean Total
Cholesterol
(mmol/L)
6.66
6.75
6.88
6.71
3.65
4.28
4.19
4.57
6.5
5yr
Baseline
1.07
2.39
5yr
2.38
(v AU+)
0.92
1.28
1.07
1.38
3.83
(v AU+)
4.24
1.55
2.45
1.44
2.01
1.18
(v AU & normal)
(v normal & control)
5.6
Microalbuminuria
Mean
Triglycerides
(mmol/L)
3.63
1.82
1.12
(v control)
Ravid, 1998
(Israel)
Seghieri, 1990
(Italy)
Suranti, 1992
(France)
Normoalbuminuria
5.6
3.56
1.23
1.30
Control
age 40-60 yrs
2-9yr follow-up
6.1
4.06
1.46
1.09
n=77 Type 2 diabetes; mean

age 57 yrs;
no microalbuminuria
microalbuminuria
age 40-75 yrs
no microalbuminuria
microalbuminuria
<5.25
>5.25
<5 yrs
diabetes
duration
5.1
6.2
OR of
nephropathy
1.0
20.59
>5 yrs
diabetes
duration
5.8
5.8
OR of
nephropathy
1.0
6.24
>5 yrs
diabetes
duration
3.7
3.7
<3.21
>3.21
<5 yrs
diabetes
duration
3.0
4.1
-
5.88
5.90
Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001. AU: microalbuminuria
35
<1.14
>1.14
<5 yrs
diabetes
duration
1.3
1.1
OR of
nephropathy
7.76
1.0
>5 yrs
diabetes
duration
1.1
1.2
1.31
1.21
1.67
1.82
There is limited evidence that lipid levels predict the development of hard exudes in
diabetic retinopathy
Very few studies have addressed the issue of a link between lipid levels and diabetic
retinopathy in people with Type 2 diabetes (see Table 4). A case-control study in the UK of
26 hypertensive people with Type 2 diabetes and exudative maculopathy, compared lipid
levels with 26 well matched diabetic hypertensive people without retinopathy. There were no
significant differences in mean LDL or HDL cholesterol, or triglycerides levels (Dodson &
Gibson, 1991). However, people with maculopathy had a higher total cholesterol level
(6.652.20 v 5.901.30 mmol/L) and a higher prevalence of hyperlipidaemia (54 v 35%) as
compared to people without maculopathy.
The US based Early Treatment Diabetic Retinopathy Study (ETDRS) measured lipid levels in
2,709 people with diabetic retinopathy, 60% of whom were classified as having Type 2
diabetes (Chew et al, 1996). At baseline, a total cholesterol 6.21 mmol/L and LDL
cholesterol 4.14 mmol/L were associated with the presence of hard exudate in eyes assigned
to deferral of photocoagulation (OR 2.00,CI 1.35-2.95; OR 1.97, CI 1.31-2.96, respectively)
compared with a total cholesterol of <5.17 mmol/L, and LDL cholesterol of <3.36 mmol/L,
respectively. Over a 7-year follow-up period, the time to development of retinal hard exudate
in eyes assigned to deferral of photocoagulation was 50% faster in people with total
cholesterol 6.21 mmol/L, or triglycerides 4.50 mmol/L, or LDL cholesterol 4.14 mmol/L
than people with total cholesterol <5.17 mmol/L (OR 1.54, CI 1.17-2.02, p<0.001), or
triglycerides <2.30 mmol/L (OR 1.46, CI 1.07-2.02, p=0.01), or LDL cholesterol <3.36
mmol/L (OR 1.36, CI 1.06-1.83).
Table 4: Lipid levels and diabetic retinopathy

Lipid levels
Reference
Chew, 1996
(US)
Dodson, 1991
(UK)
Population
Studied
5yr follow-up
n=26 Type 2 diabetes;

age 57 yrs, case control
maculopathy
control
Mean Total
Cholesterol
(mmol/L)
Range
<5.17
5.17-6.21
>6.21
Mean LDL
Cholesterol
(mmol/L)
OR
1.00
1.25
2.00
Range
<3.36
3.36-4.14
>4.14
6.652.20
5.901.30
OR
1.00
1.26
1.97
2.881.60
2.950.98
p values were not reported for the Dodson study
36
Mean HDL
Cholesterol
(mmol/L)
Range
<0.91
0.91-1.68
>1.68
OR
0.86
0.89
1.00
1.490.40
1.310.31
Mean
Triglycerides
(mmol/L)
Range
<2.3
2.3-4.5
>4.5
OR
1.00
1.07
1.27
1.731.05
1.600.70
Summary- Lipid levels and Type 2 diabetes
In people with Type 2 diabetes average triglycerides levels are approximately 2.2 mmol/L
compared with 1.6 mmol/L in the non-diabetic population
The overall crude prevalence of elevated triglycerides levels in people with Type 2
diabetes is approximately 30% which is some 3-fold higher than the prevalence in people
without diabetes
Reduced HDL cholesterol is on average approximately 0.2 mmol/L lower in people with
Type 2 diabetes compared with the non-diabetic population
The overall crude prevalence of reduced HDL cholesterol levels in people with Type 2
diabetes is approximately 2-fold higher than in people without diabetes
Most studies have found similar LDL cholesterol levels in Type 2 diabetes and nondiabetic people
LDL cholesterol composition is more atherogenic in people with Type 2 diabetes with
particle size being smaller and denser
Total cholesterol levels in people with diabetes are similar to non-diabetic people in most
studies.
Intra-individual variations of lipid and lipoprotein levels over time are observed in people
with Type 2 diabetes due mainly to biological variation
Triglycerides levels are increased in the non-fasting state but there is little change in total
cholesterol, HDL cholesterol and measured LDL cholesterol postprandially
Measurement of fasting lipids is recommended but it is recognised that only triglycerides

(and to a lesser extent calculated LDL cholesterol) are substantially affected by nonfasting
Lipid levels in people with Type 2 diabetes should be measured after a 10-12 hour
overnight fast to avoid further variability particularly in triglycerides levels
Apolipoprotein A1 levels are lower in people with Type 2 diabetes compared with the
general population
Apolipoprotein B concentrations are higher in people with Type 2 diabetes compared

with the general population
Lipoprotein(a) levels are not altered in people with Type 2 diabetes
Increased body weight, poor glycaemic control and diabetic nephropathy aggravate lipid
abnormalities in people with Type 2 diabetes
Results of lipoprotein oxidation studies in people with Type 2 diabetes have been variable
37
Total cholesterol and LDL cholesterol levels are strong predictors of cardiovascular
disease risk and death from CHD in Type 2 diabetes, just as they are in the general
population
Although the distribution of cholesterol levels is the same in Type 2 diabetes as in the
general population, at any total or LDL cholesterol level there is a higher absolute risk of
CHD than in the non-diabetic population
HDL cholesterol is inversely related to triglycerides levels and both parameters have been
linked with CHD risk in prospective studies, the data being more consistent for low HDL
cholesterol level as an independent risk factor for CHD than for high triglycerides
Although there is some evidence to support lipoprotein (a) as an independent risk factor
for CHD in people with Type 2 diabetes, there is insufficient evidence that measurement
of lipoprotein (a) level is useful to stratify risk of CHD and aid in the choice of lipid
modifying interventions
Data linking lipid levels with progression of diabetic retinopathy are limited
38
Evidence Table: Section 1

Lipid levels and Type 2 diabetes
Author
Evidence
Level of Evidence
Level
Study Type
Quality
Rating
Magnitude
Rating
Relevance
Rating
Abu-Lebdeh HS (2001)
High
III-2
Cohort
Medium
High T+
(Adults US)
High T+ C+ H+ L+
Assmann G (1998)
High
III-2
Cohort
High
Lp(a)+
(Adults Germany)
Barret-Connor E (1982)
T+
III-2
Case-control
Medium
High
High
(Adults US)
Billingham MS (1989)
III-2
Cross-sectional
Medium
High C+, L+, H+,T+
High
(Adults UK)
Bos G (2003)
High
High
III-2
Cohort
High T+
(Adults The Netherlands)
Burchfiel CM (1990)
H+, T+
III-2
Case-control
High
High
High
(Adults US)
Byrne CD (1994)
III-2
Cross-sectional
High
High T+, H+
High
(Adults UK)
Castelli WP (1992)
Low
Medium
High H+, T+
III-2
Cohort
(Adults US)
Ceriello A (1997a)
T+
III-2
Case-control
Medium
High
High
(Adults Italy)
Ceriello A (1997b)
High
III-2
Case-control
Medium
High T+
(Adults Italy)
Chang C-J (1995)
III-2
Case-control
Medium
High H+, T+
Medium
(Adults Taiwan)
Chen Z (1991)
Low
High
High C+
III-2
Cohort
(Adults China)
Chew EY (1996)
High
High
High C+ L+
III-2
Cohort
(Adults US)
Cowie CC (1994)
III-2
Cross-sectional
High
High H+, T+
High
(Adults US)
Csaszar A (1993)
(Adults Hungary &
III-2
Case-control
Medium
Low
High
Austria)
Dean JD (1990)
III-2
Case-control
Medium
High C+, H+
High
(Adults UK)
Dimitriadis E (1995)
High
III-2
Case-control
Medium
High L+
(Adults Ireland)
Dodson PM (1991)
C+
High
III-2
Case-control
Medium
High
(Adults UK)
Fontbonne A (1989)
High
High
High T+
III-2
Cohort
(Adult men France)
Freitas JP (1997)
III-2
Case-control
High
Low
High
(Adults Portugal)
Fuller JH (2001)
High
High
High T+
III-2
Cohort
(Adults UK)
Giansanti R (1999)
High
III-2
Cross-sectional
High
High C+, T+
(Adults Italy)
Haffner SM (1992a)
III-2
Case-control
High
High T+, H+
High
(Adults US)
Haffner SM (1992b)
III-2
Case-control
Medium
Low
High
(Adults US)
Haffner SM (1994)
III-2
Cross-sectional
High
High H+, T+
High
(Adults US)
Haffner SM (1995)
III-2
Cross-sectional
High
High+
Low
(Adults US)
Hanefeld M (1996)
T+
High
High
High
III-2
Cohort
(Adults Gremany)
Hanninen J (1999)
High
High
High H+
III-2
Cohort
(Adults Finland)
Heart Protection Study
High
High
II
RCT
High C+, L+
(2003)
(Adults UK)
Hiraga T (1995)
Low
High
III-2
Cohort
High Lp(a)+
(Adults Japan)
For magnitude rating:
+
abnormalities associated with Type 2 diabetes; High = clinically important & statistically significant, Medium = small clinical importance &
statistically significant, Low = no statistically significant effect.
Criteria for Quality and Relevance ratings are detailed in Appendix 9.
C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T= triglycerides.
39
Evidence Table: Cont

Evidence
Author
Level of Evidence
Level
Study Type
Hokanson JE (1996)
meta-analysis
Quality
Rating
High
Magnitude
Rating
High
T+
Relevance
Rating
Low
Hughes K (1998)
III-2
Cross-sectional
Medium
High T+
Medium
(Adults Singapore)
James RW (1995)
high
III-2
Cross-sectional
High
High Lp(a)+
(Adults Italy)
Laakso M (1985)
III-2
Case-control
Medium
High L+, H+, T+
High
(Adults Finland)
Laakso M (1990)
High
III-2
Case-control
Medium
High H+, T+
(Adults Finland)
Lehto S (1997)
High
III-2
Cohort
High
High C+, L+, H+, T+
(Adults Finland)
Leinonen JS (1998a)
III-2
Case-control
High
Low
High
(Adults Finland)
Leinonen J (1998b)
III-2
Case-control
High
Low
High
(Adults Finland)
Leonhardt W (1996)
III-2
Case-control
Medium
High T+
High
(Adults Germany)
MacRury SM (1993)
III-2
Case-control
High
High T+
High
(Adults UK)
Manninen V (1992)
Low
II
RCT
High
High T+
(Adults Finland)
Manson JE (1991)
III-2
Cohort
High
High C+
High
(Adult women US)
Manzato E (1993)
III-2
Case-control
High
High C+
High
(Adults Italy)
Mattock MB (1988)
III-2
Cross-sectional
High
High C+, H+
High
(Adults UK)
Meigs JB (1997)
High
Medium
III-2
Cross-sectional
High H+
(Adults US)
MiSAD (1997)
High
Medium
III-2
Cross-sectional
High C+ T+
(Adults Italy)
Nacitarhan S (1995)
Medium
III-2
Case-control
Medium
High C+, L+, H+, T+
(Adults Turkey)
Nielsen FS (1993)
III-2
Case-control
Medium
High T+
High
(Adults Denmark)
Niskanen L (1990)
High
III-2
Cohort
High
High H+, T+ L+
(Adults Finland)
Niskanen L (1998)
High
III-2
Cohort
Medium
High H+
(Adults Finland)
OBrien T (1994)
High
III-2
Case-control
High
High H+ L+
(Adults US)
Ravid M (1998)
C+, L+, H+, T+
Medium
III-2
Cohort
High
High
(Adults Israel)
Ronnemaa T (1989)
III-2
Case-control
Medium
High C+ H+ THigh
(Adults Finland)
Ruiz J (1994)
III-2
Case-control
High
HighC+ Lp(a)+
High
(Adults France)
Saito I (2000)
III-2
Cohort
High
High C+ L+ H+ T+
Low
(Adults Japan)
Salomaa VV (1992)
III-2
Cross-sectional
High
High C+, H+, T+
High
(Adults Finland)
Scheffer PG (2003)
III-2
Case-control
Medium
High C+, H+, T+
High
(Adults The
Netherlands)
Seghieri G (1990)
High
III-2
Case-control
High
High C+ L+ T+
(Adults Italy)
Seviour PW (1988)
High
III-2
Case-control
Medium
High C+ L+ H+ T+
(Adults UK)
Sharrett AR (2001)
Low
III-2
Cohort
High
High L+ H+ T+
(Adults Austria)
+
40

Evidence
Author
Level of Evidence
Level
Study Type
Quality
Rating
Magnitude
Rating
Relevance
Rating
Siegel RD (1996)
(Adults US)
III-2
Case-control
Medium
High C+, L+, H+, T+
High
Smith SJ (1993)
IV
Case series
Medium
High C+, T+
Low
Solfrizzi V (2002)
III-2
Cross-sectional
Medium
Low
High
(Adults Italy)
Sprecher DL (2000)
High
III-2
Cohort
High
High T+
(Adults US)
Stamler J (1993)
High
III-2
Cohort
High
High C+
(Adult men US)
Suraniti S (1992)
High
III-2
Cross-sectional
High
High H+ ApoA1+
(Adults France)
Tkac I (1997)
High
III-2
Cross-sectional
Medium
High L+
(Adults Canada)
Tsalamandris C (1998)
IV
Case series
Medium
Low
High
(Adults Australia)
Turner RC (1998)
III-2
Cohort
High
High C+, L+, H+, T+
High
(Adults UK)
UKPDS 11 (1994)
III-2
Case-control
High
High C+, L+, H+, T+
High
(Adults UK)
Uusitupa M (1986)
III-2
Case-control
Medium
High L+, H+, T+
High
(Adults East Finland)
Vakkilainen J (2003)
III-2 *
RCT
High
High L+
High
(Adults Sweden)
Velho G (1993)
III-2
Case-control
Medium
Low
High
(Adults France)
Wasenius A (1990)
IV
Case series
Medium
Low
Low
(Adults Norway)
+
C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T triglycerides.
* RCT but only the epidemiological data from this study were used in support of the relevant evidence statement
41
Section 2: Lipids
Issue
What are the effects of diet and exercise on lipids in people with Type 2 diabetes?
Recommendation
Specific dietary advice should be given to all people with Type 2 diabetes and elevated
lipids which emphasises weight reduction in the overweight
Evidence Statements
Weight loss can improve lipid levels in people with Type 2 diabetes in the short term
Evidence level I
The composition of the diet influences lipid levels in people with Type 2 diabetes
High carbohydrate (55-65%) low fibre diets increase triglycerides in the short term
but not in the longer term
Evidence level II
Low glycaemic index diets may produce small improvements in lipid levels
Evidence level II
Replacing some complex carbohydrate (up to 20% of total energy) with sucrose or
fructose does not have an adverse effect on lipid levels
Evidence level II
Replacing some complex carbohydrate (10-20% of total energy) in highcarbohydrate (50-60%) diets with mono-unsaturated fatty acids (MUFA) lowers
plasma triglycerides in the short-term
Evidence level I
42
Longer term (greater than 1 month) studies have failed to show consistent
differences in lipid levels when some complex carbohydrate in high
carbohydrate (50-60%) diets is replaced with mono-unsaturated fatty acids
(MUFA)
Evidence level II
Diets high in polyunsaturated fatty acids (PUFA) and MUFA have similar
effects on lipid levels
Evidence level II
Fish oil supplementation can reduce triglycerides but increases LDL cholesterol
Evidence level I
Increasing fish intake may improve the lipid profile although data are limited
Evidence level II
There are few data on the effects of changes in dietary protein content on lipid
levels in people with Type 2 diabetes
Evidence level II
Increasing the fibre content of the diet can lower total and LDL cholesterol but
has little effect on triglyceride or HDL cholesterol levels
Evidence level II
Plant sterol enriched margarines have a modest effect on lipid levels

Evidence level II
There is no direct evidence that alcohol alters the lipid profile in people with
Type 2 diabetes
Anti-oxidant therapy may reduce susceptibility of LDL particles to oxidation

Evidence level II
Exercise may have a modest beneficial effect on lipid levels in people with Type 2
diabetes
43
Background Diet and Exercise and Lipids

In people with Type 2 diabetes there is often a cluster of metabolic disturbances, including
lipid abnormalities, which are associated with insulin resistance (see Section 1). Lipid levels
in Type 2 diabetes are characterised by high fasting triglycerides and low HDL cholesterol
with changes in the structure of LDL particles (reviewed in Section 1), superimposed on the
range of levels of total and LDL cholesterol seen in the general population.
Insulin resistance, some components of elevated lipids and hyperglycaemia are partly
influenced by lifestyle factors including diet and physical activity. The components of the
diet that may be important include total energy intake and the quantity and quality of both fat
and carbohydrate.
Consensus statements such as those of the American Diabetes Association (2003) advocate
lifestyle measures as an initial step in the management of elevated lipids in adults with
diabetes. Although diet is important in all people with diabetes, it has particular importance in
people with elevated lipids. This Section reviews the evidence for lifestyle intervention in the
treatment of elevated lipids in people with Type 2 diabetes.
Central obesity is a major contributing factor to insulin resistance and both obesity and
insulin resistance are important determinants of lipid levels in Type 2 diabetes (Brunzell &
Hokanson, 1999). Insulin resistance not only reduces triglyceride clearance, but also allows
increased free fatty acid release from a larger mass of intra-abdominal adipose tissue
promoting hepatic synthesis of triglycerides that are secreted by the liver as very low-density
lipoproteins (Garg, 1996). Reduction of intra-abdominal fat is therefore likely to improve the
lipid profile in Type 2 diabetes.
Exercise is recommended as an adjunct to diet in the management of people with Type 2
diabetes. The American Diabetes Association recommends that individuals should
accumulate 30 min of moderate physical activity on most days of the week to improve
glycaemic control and cardiovascular risk factors (American Diabetes Association, Clinical
Practice Recommendations, 2003). Because exercise can enhance insulin sensitivity, reduce
intra-abdominal fat and improve glycaemic control, improvement of the lipid profile might be
anticipated (Ruderman & Schneider, 1992).
44
Evidence - Diet and Exercise on Lipids

Weight loss can improve lipid levels in people with Type 2 diabetes
Studies of the effects of weight loss on lipid and lipoprotein levels in Type 2 diabetes vary
greatly in study characteristics such as:
study design
study duration
nutritional composition of study diet
the use of a comparative isocaloric dietary period
combining a weight loss and exercise program

A meta-analysis of 89 research studies which promoted weight loss in people with Type 2
diabetes was conducted by Brown et al (1996). The mean initial body weight of the 1,800
subjects was 96 kg or 147% ideal body weight. The most effective weight loss strategy was
diet alone and the mean weight loss was about 9 kg, associated with a mean reduction in the
absolute value of HbA1c of 2.7%. Weighted-effect size estimates of the impact of weight
reduction on the lipid profile demonstrated significant and similar reductions of total
cholesterol (0.620.43, p<0.05, 15 studies) and triglycerides (0.560.40, p<0.05, 16 studies),
but no significant effect on LDL or HDL cholesterol levels. The beneficial effect on lipids
was greatest with very low calorie diets (VLCD), with weighted-effect size of 0.690.46
(p<0.05) for total cholesterol and 0.610.42 (p<0.05) for triglycerides. The effects were seen
immediately and for up to 6 months in some studies, but not in studies of 12 months or
longer.
The magnitude of the short term reduction in lipid levels is illustrated by the following study,
the largest study of weight loss in Type 2 diabetes which was conducted by Barnard et al
(1994). During an intensive 26-day residential lifestyle program of diet combined with
aerobic exercise, 652 people with Type 2 diabetes lost an average of 4.4 kg (5%) of initial
body weight. Participants followed the Pritikin diet which is high in complex carbohydrate
(75%) and fibre and very low in fat (<10%) but does not emphasise energy restriction. Mean
total cholesterol fell an average of 22% from 6.2 to 4.8 mmol/L, 6.1 to 4.9 mmol/L and 6.2 to
4.8 mmol/L in subjects on insulin, oral agents and diet alone respectively (all p<0.001) while
triglycerides levels fell an average of 33% from 2.8 to 2.0 mmol/L, 2.8 to 2.0 mmol/L and 3.0
to 1.8 (all p<0.001) respectively.
However in everyday clinical practice the reductions in lipids are more modest. In the
UKPDS (Manley et al, 2000), 2,906 people with newly diagnosed Type 2 diabetes underwent
3 months dietary intervention with a hypocaloric diet with 50% of energy from unrefined
carbohydrate and less than 35% of energy from fat. At baseline 58% of men and 81% of
women were obese, weighing more than 120% of their ideal body weight. After 3 months
body weight decreased by a mean of 4.5 kg (p<0.001) in both men and women. Glycaemic
control improved with HbA1c falling by 2.03% from 8.9% in men, and by 1.78% from 9.1%
in women (both p<0.001). Plasma total cholesterol fell by 0.28 mmol/L (p<0.001) in men and
0.09 mmol/L in women (p<0.01), with a similar reduction in LDL cholesterol in men and
women (both p<0.001). Triglycerides decreased by 0.41 mmol/L in men (p<0.001) and 0.23
mmol/L in women (p<0.001). HDL cholesterol rose in men by 0.02 mmol/L (p<0.001) and in
women by 0.01 mmol/L (p<0.05).
The effects on lipid levels of longer term weight loss studies are less impressive. Wing et al
(1994) have studied the effects over 12 months in a randomised cross over trial of people
with Type 2 diabetes assigned to a low calorie diet (LCD) of 1,000 to 1,200 kcal/day (4,200
to 5,040 kJ/day) with less than 30% calories as fat (n=41) or a LCD supplemented with 212
week periods of a very low calorie diet (VLCD) of 400 to 500 kcal/day (1,680 to 2,100
kJ/day) (n=38). Subjects also participated in a behavioural treatment program with weekly
45
meetings including exercise lectures that stressed walking. At one year there was a trend of
more weight loss in the VLCD group than in the LCD group (14.210.3 v 10.511.6 kg,
p=0.057). Total and LDL cholesterol decreased in the LCD group (5.3 to 5.0 mmol/L; 3.2 to
3.1 mmol/L, both p=NS). Triglycerides reduced from 2.5 to 1.7 mmol/L (p< 0.001) and HDL
cholesterol rose from 1.09 to 1.17 mmol/L (p<0.001) in the same group. In contrast, total and
LDL cholesterol did not change in the VLCD group where as triglycerides decreased
significantly from 2.2 to 1.5 mmol/L (p<0.001) and HDL cholesterol increased from 1.12 to
1.25 mmol/L (p<0.001). The mean HbA1c fell from 10.2% to 8.8% in the LCD group and
from 10.5% to 9.2% in the VLCD group after one year on diet (no p value given).
In a multi-centre randomised double-blind placebo-controlled trial, the pancreatic lipase
inhibitor orlistat (120 mg) or placebo were given 3 times daily for 52 weeks to 391 people,
mean age 55 years, with Type 2 diabetes treated with sulphonylurea therapy (Hollander et al,
1998). All participants were prescribed a mildly hypocaloric weight loss diet with about 30%
of energy intake as fat, 50% as carbohydrate and 20% as protein. After 57 weeks the orlistat
group had lost 6.2% of initial body weight (mean initial body weight 99.6 kg) compared with
4.3% in the placebo group (mean initial body weight 99.7 kg). Over the period of the study
weight loss with orlistat was significantly greater than with placebo (p<0.001). During the 52
week treatment period total cholesterol fell by an average of 0.08 mmol/L in the orlistat
group but rose by 0.39 mmol/L in the placebo group (p<0.001 for difference between orlistat
and placebo); LDL cholesterol fell by 0.13 mmol/L with orlistat and rose by 0.22 mmol/L
with placebo (p<0.001), triglycerides level fell by 0.01 mmol/L with orlistat and rose by 0.21
mmol/L with placebo (p=0.036) and HDL cholesterol rose by 0.06 mmol/L with orlistat and
rose by 0.08 mmol/L with placebo (p=NS). HbA1c was about 7.5% at randomisation in both
groups. On orlistat HbA1c fell by a mean absolute amount of 0.28% compared with an
increase of 0.18% in the placebo group (p<0.001).
Other studies which have achieved lesser weight loss (<3%) have shown little effect on lipid
levels. Franz et al (1995) used a randomised controlled trial design to compare medical
nutrition therapy using practice guidelines (n=94) with basic nutrition care (n=85) provided
by dietitians over a 6 month period. In the intensive diet therapy group body weight fell by
1.4 kg from 93.8 kg (1.5% reduction). Total cholesterol fell from 5.6 to 5.4 mmol/L (p<0.05)
and triglycerides from 2.6 to 2.4 mmol/L (p<0.05). LDL and HDL cholesterol levels did not
change significantly. HbA1c fell from 8.3% to 7.4% (p<0.001). In the basic nutrition care
group body weight fell by 1.7 kg from 93.7 kg (1.8% reduction), but none of the lipid
parameters changed significantly. HbA1c fell from 8.3% to 7.6% (p<0.001).
Another dietary intervention trial in people with Type 2 diabetes studied an energy restricted
diet (Milne et al, 1994). In the weight management group (n=21) weight was 78.3 kg at
baseline and the average between 9 and 18 months was 79.8 kg. Total cholesterol was 6.4
mmol/L at baseline and 6.1 mmol/L at 9-18 months, LDL cholesterol was 4.5 and 4.2
mmol/L, triglycerides 1.7 and 1.6 mmol/L and HDL cholesterol 1.24 and 1.18 mmol/L. HbA1
was 9.0% at baseline and 8.9% at 9-18 months. In the modified lipid diet group (n=22)
weight was 83.1 kg at baseline and the average between 9 and 18 months was 82.1 kg. Total
cholesterol was 6.0 mmol/L at baseline and 5.7 mmol/L at 9-18 months, LDL cholesterol was
4.2 and 3.6 mmol/L, triglycerides 1.8 and 2.0 mmol/L and HDL cholesterol 1.15 and 1.22
mmol/L. HbA1 was 9.8% at baseline and 9.7% at 9-18 months. None of these results was
significant.
In summary, weight loss (5%) can decrease triglycerides by 10-40% and total cholesterol by
5-15% while the effects on HDL and LDL cholesterol are variable. These improvements in
the lipid profile are seen in the short-term but are difficult to sustain in the longer term.
46
The composition of the diet influences lipid levels in people with Type 2 diabetes
Since dietary protein contributes 10-20% of total dietary energy intake the remaining 80-90%
is distributed between carbohydrate (CHO) and fat (and alcohol if consumed). A number of
studies have examined the effects on lipids of varying the quantity and quality of fat and/or
carbohydrate in people with Type 2 diabetes. There are very few studies on the effects of
different levels of protein on lipids in people with Type 2 diabetes.
Epidemiological studies provide some information on the effect on lipids of dietary
composition. A study by Mayer-Davis et al (1999) reported associations between
macronutrient intake and lipoprotein profile in people with Type 2 diabetes who participated
in two epidemiological studies. Diet was assessed by 24-hour recall in 421 participants in the
San Luis Valley Diabetes Study and by food frequency interview in 437 participants in the
Insulin Resistance Atherosclerosis Study. The major finding in all subgroups was an
association between total dietary fat and increased levels of LDL cholesterol (p<0.05).
Reported intake of total and saturated fat was associated with total cholesterol, but not
consistently across all subgroups. Higher reported carbohydrate intake was associated with
increased triglycerides levels (p<0.01) only among people with previously undiagnosed
diabetes or who gained weight (>2.5 kg).
Most intervention studies have been of relatively short duration. Only studies of at least 1
month duration are considered below.
High-carbohydrate diets
Coulston et al (1989) compared diets containing either 40 or 60% carbohydrate with
reciprocal changes in fat content from 40 to 20% (polyunsaturated/saturated ratio 1.0-1.1)
consumed for 6 weeks in random order in a crossover design study in 8 people with Type 2
diabetes treated with sulphonylureas or diet alone. The high-carbohydrate diet significantly
increased plasma glucose levels between 0800 and 1600 h (p<0.001), although the mean
fasting glucose level was not different. Fasting triglycerides levels increased by 30% from
about 1.9 to 2.4 mmol/L (p<0.001) after 1 week on the 60% carbohydrate diet and the
hypertriglyceridaemia persisted over the 6-week period. Total cholesterol remained
unchanged with both diets. These diets contained low amounts of fibre (14.3 and 18.1 g/day,
respectively) and, judging by the meal plans, high glycaemic index carbohydrates (eg
cornflakes, banana, potato).
In another study of postprandial lipid metabolism, 9 people with Type 2 diabetes treated with
sulphonylureas were randomly assigned isocaloric diets. They were low in fibre and either
high in carbohydrate (55% CHO, 30% fat and 15% protein, 15 g/day of fibre) or high in fats
(40% CHO, 45% fat including 25% monounsaturated fat and 15% protein, 11 g/day of fibre)
for a period of 6 weeks (Chen et al, 1995). As with earlier studies, they showed that the high
carbohydrate diet led to higher glucose and triglyceride levels compared with the high-fat diet
based on 24-hour measurements (both p<0.001).
Garg and colleagues have reported 2 studies of a high carbohydrate diet in men with Type 2
diabetes, but not currently on hypoglycaemic medication. Both studies were performed
during hospitalisations with crossover design using controlled isocaloric diets. One of the
studies gave 10 men with Type 2 diabetes a liquid formula diet high in carbohydrate (65% of
total energy) particularly refined carbohydrate (glucose 31%, sucrose 24%) and low in fibre
for 28 days and compared the metabolic effects with a high fat (45% of total energy), high
monounsaturated fat (MUFA) (31% of total energy) diet (Garg et al, 1992a). There was no
change in weight on either of the diets. On the high carbohydrate diet, mean fasting glucose
level was 6.6 mmol/L at baseline and 6.6 mmol/L after 28 days, but the glucose response to a
47
high-carbohydrate meal tolerance test rose significantly (p<0.05). On the high MUFA diet,
fasting glucose was 7.2 mmol/L at baseline and 6.6 mmol/L after 28 days and the glucose
response to the high carbohydrate meal tolerance test fell, but not significantly. The high
carbohydrate diet adversely affected plasma triglycerides increasing from 3.0 mmol/L at
baseline to 4.2 mmol/L. However on the high MUFA diet triglycerides fell to 2.5 mmol/L
(p=0.002). The total cholesterol did not change on the high carbohydrate diet from a baseline
of 5.2 mmol/L to 5.1 mmol/L while on the high MUFA diet it fell to 4.4 mmol/L (p=0.003).
No significant changes were observed in LDL or HDL cholesterol levels on either diet.
These short term effects are not supported by longer term studies. Milne et al (1994)
randomised 21 people with Type 2 diabetes to a high carbohydrate diet in an 18-month study.
The diet consisted of 55% carbohydrate, 30% fat and 15% protein, with 30g/day fibre and
results were compared with 22 people assigned to a modified fat diet containing 45%
carbohydrate, 36% fat (saturated fatty acid [SFA]:polyunsaturated fatty acid
[PUFA]:MUFA=1) and 19% protein. Mean triglycerides levels in the high carbohydrate diet
group were 2.5 mmol/L at randomisation and the average levels from 9-18 months were 2.4
mmol/L. Mean triglycerides levels in the modified fat diet group were 1.8 mmol/L at baseline
and the average levels from 9-18 months were 2.0mmol/L. Total cholesterol in the high
carbohydrate diet group was 6.6 mmol/L at randomisation and the average level from 9-18
months was 6.2 mmol/L; corresponding LDL cholesterol levels were 4.2 and 4.0 mmol/L and
HDL cholesterol levels were 1.23 and 1.19 mmol/L. There was no evidence that the high
carbohydrate diet had unfavourable long-term effects on the lipid profile or that it had less
favourable effects than the modified lipid diet, although the difference in carbohydrate
content of the 2 diets was not as great as in the short-term studies. It should also be noted that
the fibre content of the high carbohydrate diet was considerably higher than that of the high
carbohydrate diets in the short-term studies.
A total of 35 obese people with Type 2 diabetes (mean age 58 years, mean BMI 33 kg/m2)
were randomised to one of 3 1,600 kcal/day energy restricted diets for 12 weeks (Heilbronn
et al, 1999). The diets were high carbohydrate (n=12) (72% CHO, 10% fat, 4% saturated fatty
acids (SFA)), high MUFA (n=13) (50% CHO, 32% fat, 15% MUFA, 7% SFA) and high SFA
diet (n=10) (50% CHO, 31% fat, 17% SFA). Despite differences in dietary composition,
weight loss was significant in all groups (p<0.01) with subjects losing an average of 6.60.9
kg (CI 2.7-12.4 kg) after 12 weeks of energy restriction. Total cholesterol decreased by 7.2%
with the high carbohydrate diet and by 14.6% with the high MUFA diet (p<0.001) and
increased by 8% with the high SFA diet (p=0.002). Similarly, LDL was 10% and 17% lower
with the high-carbohydrate and high MUFA diets respectively, whereas no change was
observed with the high SFA diet (p<0.001). HDL cholesterol was transiently reduced on the
high carbohydrate diet at weeks 1, 4 and 8 (p<0.01). Triglycerides did not change during 12
weeks. Glycaemic control was also similar with the 3 diets. Compared with baseline levels,
FPG was reduced by 14% (p<0.001) and HbA1c by 14% (p<0.001) in all 3 groups at week 12.
In summary:
short-term (< 6 weeks) high carbohydrate (55 to 65% energy) low fibre diets in people
with Type 2 diabetes increase triglycerides levels by about 25%
long-term intake of a high carbohydrate diet does not appear to increase triglycerides
levels
Low glycaemic index diets
The glycaemic index (GI) is a classification of carbohydrate containing foods on the basis of
the incremental blood glucose responses produced by that food as a percentage of the
response produced by the same amount of carbohydrate as either glucose or white bread.
48
Reducing the GI of high carbohydrate diets has been found consistently to improve
glycaemic control but the effect on lipids in people with Type 2 diabetes has been variable
(see Table 5).
One of the earliest studies of the effects of a low GI diet on the lipid profile in Type 2
diabetes was an Australian study by Brand et al (1991). Sixteen people were randomly
assigned to a low GI (77) or high GI (91) diet for periods of 12 weeks in a crossover design.
The diets contained comparable amounts of carbohydrate (44-46% of energy), fat (30-31%)
and fibre (26g/day). On the low GI diet mean HbA1c was 7.0% v 7.9% on the high GI diet
(p<0.05). However, the lipid profile did not differ significantly on the 2 diets. Mean total
cholesterol was 5.8 mmol/L on the low GI diet compared with 5.8 mmol/L on the high GI
diet, LDL cholesterol was 2.7 compared with 3.0 mmol/L, triglycerides were 1.7 mmol/L
compared with 1.6 mmol/L and HDL cholesterol was 1.19 compared with 1.08 mmol/L.
None of these differences was significant.
Another Australian study by Luscombe et al (1999) randomised 21 people with Type 2
diabetes to 4-week periods on diets with low GI (GI 43; 51% CHO, 23% fat, 30g/day fibre),
high GI (GI 63; 53% CHO, 21% fat, 30g/day fibre). and high MUFA/high GI. Fasting
glucose and fructosamine levels were not significantly different between low and high GI
diets. Mean total cholesterol was 5.5 mmol/L at baseline, 5.4 mmol/L after the low GI diet
and 5.4 mmol/L after the high GI diet, LDL cholesterol was 3.8 mmol/L on low GI and 3.8
mmol/L on high GI diet and triglycerides were 1.5 mmol/L on low GI and 1.8 mmol/L on
high GI diet (no p values reported). HDL cholesterol was 0.93 mmol/L on the low GI
compared with 0.88 mmol/L on the high GI diet (p<0.05 for high GI v low GI and high
MUFA). Effects of high MUFA/high GI diet are described below in the section on high
MUFA diets.
A different study design was used by Frost et al (1994) who randomly assigned 51 people
with newly diagnosed Type 2 diabetes to receive standard dietary advice (n=26) or low GI
dietary advice (n=25) and assessed glycaemic control and lipids after 12 weeks. Dietary
advice on increased use of low GI foods (whole grains, rye bread, barley, oats, pasta, legumes
and fruit) was given, rather than a specific dietary prescription. The group assigned to low GI
advice had a carbohydrate intake of 49%, fat intake 25% and the GI of the diet was 77
compared with 44% carbohydrate, 32% fat and a GI of 82 in the standard dietary advice
group. In the low GI diet group fructosamine fell from 380 to 320 mol/L but remained at
360 mol/L in the high GI group (p<0.05 for low GI v high GI). Total cholesterol fell from
6.2 to 5.5 mmol/L in the low GI group compared with 5.6 to 5.3 mmol/L in the high GI group
(p<0.05) and triglycerides from 1.9 to 1.4 mmol/L in the low GI group compared with 2.5 to
2.1 mmol/L in the high GI group (p<0.05). LDL and HDL levels did not change significantly
on either diet.
In a study by Tsihlias et al (2000) 91 people with Type 2 diabetes were randomised to receive
10% energy from a low GI cereal, a high GI cereal, or a MUFA breakfast for 6 months. At
baseline there were no significant differences in glycaemic control or use of lipid-lowering
agents among the 3 diet groups. Changes in HbA1c, body weight, total and LDL cholesterol,
and triglycerides did not differ significantly between diets. However, HDL cholesterol was
persistently higher (about 12%) in the MUFA group than in either the high GI or low GI
cereal groups (p=0.002).
Heilbronn et al (2002) used a randomised, controlled trial design to compare a high GI (75
units) (n=21) with a low GI (43 units) diet (n=24) (1,440 kcal/day, 60% carbohydrate, 18%
fat, 5% SFA, and 22% protein) in 45 obese people with Type 2 diabetes (mean BMI 33.2
kg/m2, mean age 56.7 years). Before randomisation, all subjects consumed a high SFA diet
49
(50% CHO, 32% fat, 17% SFA, and 20% protein) for 4 weeks. During the 8-week study
period, there was significant weight loss with both high GI diet (93.2 to 88.4 kg, p<0.05) and
low GI diet (91.7 to 87.3 kg, p<0.05). HbA1c fell by 4.6% on the high GI diet (p=0.03) and by
9.1% on the low GI diet (p=0.002). Total cholesterol reduced by 8% with high GI diet and
10% with low GI diet (both p<0.05); LDL cholesterol fell by 10%, and 16%; and
triglycerides fell by 6% and 10%, respectively (all p<0.05). HDL cholesterol did not change
on both diets. Overall, there were no differences in glycaemic control, lipid profile and body
weight between the two groups.
In summary:
Lowering the glycaemic index of the diet may produce small improvements in lipid levels
of people with Type 2 diabetes
Sucrose/fructose
The study with the largest variation in sucrose intake was performed by Abraira & Derler
(1988). Dietary intake was closely regulated in 18 people with diet treated Type 2 diabetes
who were hospitalised for the 40 days of the study. After a baseline period, subjects were
randomised to diets of similar composition (50% CHO, 35% fat, 15% protein) with either
220g sucrose or 3g sucrose daily. There was no difference in glycaemic control or in total,
LDL and HDL cholesterol or triglycerides between the two groups.
An Australian study by Cooper et al (1988) compared daily supplements of 28g sucrose with
30g starch and saccharin (isocaloric and equal sweetness with sucrose) over 6 week periods
in 17 people with Type 2 diabetes on oral hypoglycaemic therapy using a randomised
crossover design. The addition of sucrose had no effect on fasting glucose (sucrose diet v
saccharin diet: 9.2 v 8.9 mmol/L) or on total (5.8 v 5.8 mmol/L), LDL (3.75 v 3.78 mmol/L)
and HDL cholesterol (1.08 v 1.06 mmol/L) or on triglycerides (2.0 v 2.0 mmol/L).
Similarly, another Australian study with randomised crossover design (Colagiuri et al, 1989)
showed that the addition of sucrose (45 g/day, 9% of total daily energy) or an equivalent
sweetening quantity of aspartame to the usual diet (43% CHO, 39% fat, 18% protein, 29
gram/day fibre) of 9 people with Type 2 diabetes on diet alone or sulphonylurea therapy had
no deleterious effects on glycaemic control (fasting glucose 6.2 v 6.0 mmol/L) or lipid levels
(total cholesterol 5.3 v 5.4 mmol/L, HDL cholesterol 0.96 v 0.93 mmol/L, triglycerides 2.1 v
2.1 mmol/L) over a 6 week period.
Bantle et al (1993) also used a randomised crossover study to assess the effect of dietary
sucrose on glycaemia and lipids in 12 people with Type 2 diabetes on diet alone, oral
hypoglycaemic therapy or insulin. The substitution of starch with sucrose (19% of total
energy in the diet compared with 3% in the control diet) in standard diabetic diets (55%
CHO, 30% fat and 15% protein) had no adverse effect on fasting glucose, total, LDL and
HDL cholesterol or on triglycerides over 4 weeks.
In a similar study by Malerbi et al (1996) a diet with 19% total energy as sucrose (55% CHO,
30% fat, 23 g/day fibre) was compared with a diet with only 5% of energy from sugars (50%
CHO, 35% fat, 23g/day fibre) in 16 people with Type 2 diabetes treated with diet alone or
sulphonylurea therapy. After 28 days there were no significant differences in fasting glucose,
total, LDL and HDL cholesterol or triglycerides. There was also a high fructose intake arm to
this study as discussed below.
The results of studies on addition of fructose to the diet in people with Type 2 diabetes are
very similar (see Table 5). Osei et al (1987) evaluated the effects of supplementation of the
50
diet with 60 g/day fructose in 2 groups of people with Type 2 diabetes most of whom were on
insulin therapy. Over 12 weeks HbA1c fell from 11.6% to 10.2% in 9 people taking fructose,
but rose from 11.5% to 13.0% in the 9 control subjects (p<0.02 for difference between the
groups). Mean total cholesterol, LDL and HDL cholesterol did not change significantly on
either diet. On the fructose diet, triglycerides remained unchanged at the baseline level of
1.04 mmol/L but in the control diet group triglycerides rose from 1.7 to 2.7 mmol/L (p<0.02).
A subsequent study by the same group (Osei & Bossetti, 1989) used a randomised crossover
design with 6-month study periods in 13 people with Type 2 diabetes treated with
sulphonylurea and/or insulin therapy. HbA1c fell from 11.3% to 9.9% on the fructose diet
(p<0.05) but rose from 10.4% to 11.2% on the control diet (p<0.02 for difference at 6 months
between the diets). No significant changes were observed in total, LDL and HDL cholesterol
or triglycerides on either diet and the 6 months results did not differ between diets.
A daily intake of 30g fructose was evaluated over 2 months by Grigoresco et al (1988) in a
randomised crossover study of 8 people with Type 2 diabetes, treated with diet alone or oral
hypoglycaemic agents. Both diets contained 50% of total energy intake as carbohydrate, 30%
fat, 20% protein, 20g/day fibre, with replacement of 30g starch with 30g of fructose in the
fructose diet. Mean HbA1c was 6.8% at baseline, 6.4% on the fructose diet and 5.9% on the
control diet (p=NS). Total and HDL cholesterol did not change significantly on either diet.
Triglycerides rose from 1.2 mmol/L to 1.5 mmol/L (p<0.05) on the fructose diet, but were not
significantly different from the level of 1.4 mmol/L on the control diet.
The study by Malerbi et al (1996) described above included a dietary period with 20% of
energy intake from fructose (same composition as the sucrose diet). Over a 28-day period
there were no significant differences in fasting glucose, total, LDL and HDL cholesterol or
triglycerides.
In summary
Inclusion of sucrose or fructose in the diet of people with Type 2 diabetes (up to 20% of
total energy) does not adversely affect lipid levels
Diets high in Monounsaturated Fatty Acids (MUFA)
Garg (1998) performed a meta-analysis comparing the effects of high MUFA diets (35-40%
CHO, 37-50% total fat, 22-33% MUFA, 14-21% protein) with high carbohydrate diets (4960% CHO, 20-32% fat, 10-13% MUFA, 14-21% protein) on carbohydrate and lipid
metabolism in people with Type 2 diabetes. Nine studies with randomised, crossover design
using isocaloric diets were included in this meta-analysis (Garg et al (1988), Rivellese et al
(1990), Garg et al (1992b), Parillo et al (1992), Campbell et al (1994), Garg et al (1994),
Lerman-Garber et al (1994) and Parillo et al (1996)). Eight out of nine studies were of short
duration (2-4 weeks) and were performed in metabolic wards. There was only one outpatient
study of 6 weeks duration which was continued for 14 weeks in a subgroup of 21 people
(Garg et al, 1994a). From this meta-analysis high MUFA diets compared with high
carbohydrate diets were accompanied by a significant 19% reduction of fasting triglycerides
(-0.36 mmol/L [CI -0.43, -0.26]), a 3% reduction of total cholesterol (-0.15 mmol/L [CI 0.24, -0.06]), a 4% increase in HDL cholesterol (+0.05 mmol/L [CI 0.03-0.07]), but no
significant change in LDL cholesterol (-0.01 mmol/L [CI -0.10, 0.08]). FPGalso fell by 0.23
mmol/L (CI -0.39, -0.06) with consumption of the high MUFA diet.
The only study of more than 4 weeks duration was an outpatient-based study by Garg et al
(1994a) which was a 4centre randomised crossover study in 42 people with Type 2 diabetes
on sulphonylurea treatment. All food was supplied for the diets which consisted of 55%
carbohydrate, 30% fat (10% MUFA), 15% protein, 15g/4,200 kJ fibre for the high
carbohydrate diet and 40% carbohydrate, 45% fat (25% MUFA), 15% protein, 11g/4,200 kJ
51
fibre for the high MUFA diet. After 6 weeks fasting glucose, HbA1 and body weight did not
differ significantly on the two diets. Mean fasting triglycerides levels were 2.2 mmol/L on the
high carbohydrate diet and 1.8 mmol/L on the high MUFA diet (p<0.0001). Total, LDL and
HDL cholesterol did not differ significantly between the two diets. Day long plasma glucose
was increased by 12% (p<0.0001) and day long triglycerides by 10% (p=0.03) on the high
carbohydrate diet. A subgroup of 21 people continued the diet for a further 8 weeks and the
differences in glucose and lipid metabolism were sustained for the total of 14 weeks.
The study by Bonanome et al (1991) was not included in the above meta-analysis because the
dietary phases were not randomised. This study included 19 people with Type 2 diabetes who
were studied during 3 dietary phases, each of two month duration. The first and third phases
were high carbohydrate diets (60% CHO, 25% fat, 15% protein, 15 g/day fibre), the second
phase was a high MUFA diet (45% CHO, 40% fat, 25% MUFA, 15% protein, 15 g/day
fibre). There was no difference in fasting glucose, glycosylated Hb, total and LDL
cholesterol, triglycerides or HDL cholesterol between the high carbohydrate and high MUFA
diets.
An Australian study published since the meta-analysis compared 4 week randomised,
crossover periods of a high MUFA, high GI diet (42% CHO, 35% fat, 18% MUFA, 21%
protein, 34 g/day fibre), a high GI diet and a low GI diet as described above in the section on
the Glycaemic Index (Luscombe et al, 1999). In the 21 people with Type 2 diabetes,
glycaemic control did not differ between the diets. Mean HDL cholesterol was higher on the
high MUFA diet (0.930.04 mmol/L) and the low GI diet (0.930.04 mmol/L) compared
with the high GI diet (0.880.04 mmol/L) (p<0.05). There was no difference in total and
LDL cholesterol or triglycerides between the diets.
One study has compared the effects on lipids of a very low carbohydrate, high MUFA and a
high carbohydrate hypocaloric diets. Low et al (1996) in a randomised controlled trial
stratified for metabolic parameters studied 8 people with Type 2 diabetes assigned to a high
carbohydrate diet (70% CHO, 10% fat, 20% protein) and 9 people assigned to a high MUFA
diet (10% CHO, 70% fat, 49% MUFA, 20% protein). Energy intake was set for 6 weeks at a
50% deficit based on pre-diet weight maintenance requirements, then for 4 weeks at weight
maintenance requirements during a period of re-feeding. Mean weight loss was similar in the
two groups (8.3 kg on the high CHO diet v 7.3 kg on the high MUFA diet). Mean fasting
glucose fell from 12.6 to 8.0 mmol/L on the high MUFA diet compared with 11.2 to 8.8
mmol/L on the high carbohydrate diet (p<0.05 for high MUFA v high CHO). Total
cholesterol fell from 5.0 to 3.9 mmol/L on the high MUFA diet compared with 4.4 to 4.0
mmol/L on the high carbohydrate diet (p<0.05 for high MUFA v high CHO) and triglycerides
from 3.2 to 1.4 mmol/L compared with 2.7 to 2.2 mmol/L (p<0.05 for high MUFA v high
CHO). LDL cholesterol and HDL cholesterol levels did not change significantly on either
diet. Changes in total cholesterol and triglycerides were better maintained with re-feeding on
the high MUFA diet than the high carbohydrate diet. The same study was subsequently
reported Gumbiner et al (1998).
In summary:
Replacing some complex carbohydrate (10-20% of total energy) in high carbohydrate
(50-60%) diets with mono-unsaturated fatty acids (MUFA) lowers plasma
triglycerides in the short-term
Studies of more than 1 month duration have failed to show consistent differences in
lipid levels when some complex carbohydrate in high carbohydrate (50-60%) diets is
replaced with mono-unsaturated fatty acids (MUFA)
52
Diets high in Polyunsaturated Fatty Acids (PUFA) or Saturated Fatty Acids (SFA)
There are few studies that have specifically examined the use of diets high in PUFA or SFA
(see Table 5).
One study compared diets high in PUFA with diets high in MUFA. In a crossover design
study, Parfitt et al (1994) randomised 13 men with Type 2 diabetes treated with diet alone or
oral hypoglycaemic agents to 6 week periods on diets with high PUFA (35% CHO, 47% fat,
17% PUFA, 18% protein) or high MUFA (35% CHO, 50% fat, 28% MUFA, 15% protein).
Mean total cholesterol was 5.3 mmol/L at baseline, 4.9 mmol/L on high PUFA and 4.7
mmol/L on high MUFA, LDL cholesterol 3.7 mmol/L, 3.5 mmol/L 3.2 mmol/L respectively,
triglycerides 1.9 mmol/L at baseline and on both diets and HDL cholesterol 0.94 mmol/L,
0.90 mmol/L and 0.99 mmol/L respectively. None of these changes was significant.
Heine et al (1989) studied 14 people with Type 2 diabetes in a crossover study with 30-week
treatment periods on diets with PUFA/SFA ratio 1.0 or 0.3. Glycaemic control did not differ
on the two diets. On the high PUFA diet (40% CHO, 38% fat, 11% linoleic acid, 17%
protein, 5% alcohol, 21 g/day fibre) total and LDL cholesterol levels were lower (5.50.4 v
5.90.5 mmol/L, p<0.01; 3.70.3 v 4.10.4 mmol/L, p<0.01, respectively) than on the low
PUFA diet (40% CHO, 38% fat, 4% linoleic acid, 17% protein, 5% alcohol, 21 g/day fibre);
whereas triglycerides and HDL cholesterol were similar with both diet.
Christiansen et al (1997) compared 3 diets with fat predominantly from SFA or MUFA (cisMUFA from nuts, avocado and olive oil in one arm and trans-MUFA from margarine in
another). Energy composition of the diets was the same, with carbohydrate 50%, fat 30%,
SFA/cis-MUFA/trans-MUFA 20%, protein 20%, 29 g/day fibre. In a randomised crossover
design, 16 people with Type 2 diabetes on diet alone followed each diet for periods of 6
weeks. Mean fasting glucose was 8.9 mmol/L with SFA, 8.1 mmol/L with cis-MUFA and 8.7
mmol/L with trans-MUFA diets. Total cholesterol was 6.3 mmol/L with SFA and 6.0
mmol/L with both cis-MUFA and trans-MUFA diets; LDL cholesterol was 3.7 mmol/L with
SFA, 3.5 mmol/L with cis-MUFA and 3.6 mmol/L with trans-MUFA diets. Triglycerides
were 2.7 mmol/L with SFA, 2.5 mmol/L with cis-MUFA and 2.7 mmol/L with trans-MUFA
diets; HDL cholesterol was 1.12 mmol/L with both SFA and cis-MUFA diets and 1.10
mmol/L with trans-MUFA diet. None of these values was significantly different between the
diets.
In summary:
Diets high in PUFA and MUFA have similar effects on lipid levels in people with
Type 2 diabetes
Diets with a high SFA have not been shown to consistently adversely affect lipid
levels in people with Type 2 diabetes
Fish and fish oils rich in -3 polyunsaturated fatty acids
Dietary supplementation with fish oil capsules has been considered as a pharmacological,
rather than a dietary intervention and has been reviewed in more detail in Section 4.
There have been many studies of the effects of fish oil supplementation on lipid levels in
people with Type 2 diabetes (see Table 5). A meta-analysis of 18 randomised, placebo
controlled trials, including 823 people with Type 2 diabetes followed for a mean of 12 weeks
on doses of fish oil ranging from 3-18 g/day (Montori et al, 2000), reported a mean reduction
of triglycerides of 0.56 mmol/L (CI -0.71 to -0.41) and a mean elevation of LDL cholesterol
53
of 0.21 mmol/L (CI 0.02-0.41). There was no significant effect on total cholesterol, HDL
cholesterol, or on glycaemic control.
There have been very few studies on the effects of dietary fish (as distinct from dietary
supplementation with fish oil) on lipid levels in people with Type 2 diabetes. Described in the
section on exercise, the Australian study by Dunstan et al, (1997) used a randomised 22
design to test the effects of moderate exercise and daily fish intake on lipid and lipoprotein
levels in 55 people with Type 2 diabetes with serum triglycerides >1.8 mmol/L and/or HDL
cholesterol <1.0 mmol/L (4 groups of 11 to 14 subjects). One fish meal per day (3.6g -3
fatty acids) for 8 weeks reduced triglycerides by 0.8 mmol/L (p=0.03) and improved the
composition of HDL cholesterol (HDL3 reduced by 0.05 mmol/L, p=0.02; HDL2 increased by
0.06 mmol/L, p=0.03). Mean HbA1c increased by an absolute amount of 0.5% (p=0.05).
In summary:
Fish oil supplementation can reduce triglycerides but increases LDL cholesterol
Increasing fish intake may also improve the lipid profile although data are limited
Diets high in protein
There have been few studies in people with Type 2 diabetes on the impact on lipids of a
higher protein intake.
Parker et al (2002) compared the effect of a high protein diet with a low protein diet on
weight loss, lipid profile and glycaemic control. 54 obese people with Type 2 diabetes were
randomised to the high protein diet (HP) (28% protein, 42% carbohydrate, 28% fat) or the
low protein diet (LP) (16% protein, 55% carbohydrate, 26% fat) in this 12-week study
including an 8-week energy restriction phase (1,600 kcal/day) and a 4-week energy balance
phase with the same macronutrient composition. Both men and women lost weight on both
diets, with an average weight loss of 5.21.8 kg. Women on the HP diet lost significantly
more weight compared with the women on the LP diet (5.3 v 2.8 kg, p=0.009) whereas there
was no difference in men between the diets (3.9 v 5.1 kg). Over 12 weeks, total and LDL
cholesterol levels decreased more on the HP diet than on the LP diet (5.2 to 4.8 v 5.2 to 5.2
mmol/L, p<0.01; 3.3 to 3.1 v 3.2 to 3.3 mmol/L, p<0.01, respectively). Triglycerides were
reduced significantly on both diets (2.0 to 1.7 mmol/L; 2.2 to 1.9 mmol/L; both p<0.001).
HbA1c decreased by 9.4% between baseline and week 12 (p<0.001) without significant
difference between diets. This effect could be related more to differences in weight loss than
to the protein composition of the diets.
Hermansen et al (2001) randomised 20 people with Type 2 diabetes to treatment with the soy
product Abalon or placebo for 6 weeks in a crossover study. Abalon provided a daily amount
of 50g isolated soy protein and cotyledon fibre (20g/d); whereas the placebo provided a daily
amount of 50g casein and 20g cellulose. After Abalon treatment significantly lower mean
values for LDL cholesterol (-1015%, p<0.05), triglycerides (-2243%, p<0.05) and
LDL/HDL ratio (-1218%, p<0.05) were obtained. The mean value for total cholesterol
tended to be lower but did not reach significance (-815%, p=0.08). No change in HDL
cholesterol occurred. There were no significant changes in glycaemic control on both
treatments.
In summary:
There are few data on the effects of changes in dietary protein content on lipid levels
in people with Type 2 diabetes
54
Diets high in fibre

Foods with high fibre content
Chandalia et al (2000) used a randomised crossover design in 13 people with Type 2 diabetes
treated with diet alone or sulphonylurea therapy to compare the ADA diet which contained
24g fibre (8g soluble/16g insoluble) with a high-fibre diet (50g/day fibre, 25g soluble/25g
insoluble). After 6 weeks, the high fibre diet reduced the mean total cholesterol by 14% (5.1
v 5.4 mmol/L, p=0.02), triglycerides by 21% (2.1 v 2.3 mmol/L, p=0.02) and VLDL
cholesterol by 5% (0.91 v 1.03 mmol/L, p=0.01). No significant changes in HDL (0.73 v 0.75
mmol/L, p=0.8) and LDL cholesterol (3.4 v 3.7 mmol/L, p=0.11) occurred. The mean plasma
glucose concentration was lower when people consumed the high-fibre diet (7.2 v 7.9
mmol/L, p=0.04) but HbA1c was similar (6.9 v 7.2%, p=0.09).
Wolever et al (2003) randomly assigned 67 people with Type 2 diabetes to receive a diet in
which 10% energy was from a low-fibre breakfast cereal (LF) (n=22), a high-fibre breakfast
cereal (HF) (n=25), or MUFA (n=22) for 6 months. Changes in total cholesterol did not differ
significantly between diets. However, triglycerides fell on the MUFA diet (-0.220.17
mmol/L, p<0.05) and increased on the LF diet (+0.040.11 mmol/L,) and the HF diet
(+0.320.18 mmol/L, p<0.05), with the difference between groups being significant
(p=0.002). LDL cholesterol increased more on the MUFA diet (+15%, p<0.05) than on either
the LF (+1.2%) or the HF (-0.8%) diets. There was no significant change in HbA1c over 6
months.
Fibre supplements
Niemi et al (1988) studied the effects of 15g/day guar gum (5g with each meal) over 12
weeks in 18 people with Type 2 diabetes. There was no improvement in glycaemic control
(HbA1c 12.1% at baseline, 11.8% at 12 weeks) but mean total cholesterol fell from 6.6 to 5.9
mmol/L (p<0.01). During the 12 weeks prior to the guar gum treatment subjects ingested
15g/day of microcrystalline cellulose, an indigestible, unabsorbable fibre. This did not have
any effect on glycaemia or cholesterol.
Groop et al (1993) have reported a long term study with guar gum 15g/day in 15 people with
Type 2 diabetes. The 48-week treatment period was preceded and followed by 8 week
periods on placebo. Glycaemic control improved during guar gum treatment with
fructosamine decreasing from 3.77 mmol/L at the end of the first placebo period to 3.31
mmol/L at the end of treatment (p=0.003) and rose again to 3.45 mmol/L after the second
placebo period (p=0.092). Mean total cholesterol fell from 6.1 to 5.7 mmol/L on guar gum
(p=0.048) and rose to 6.6 mmol/L (p=0.001) during the second placebo period. LDL
cholesterol fell from 3.9 to 3.6 mmol/L (p=0.029) and then rose to 4.3 mmol/L (p=0.001).
Triglycerides and HDL cholesterol levels did not change significantly during the study.
Plantago psyllium is a soluble, gel-forming fibre which is derived from the husks of blonde
psyllium seeds and is readily available in Australia. The effects on glycaemia and lipid levels
have been evaluated by Gupta et al (1994) in a sequential study of psyllium 3.5g twice daily
for 90 days, then follow up for a further 90 days in 24 people with Type 2 diabetes and
hyperlipidaemia. Glycaemic parameters did not change significantly but the lipid profile
improved. Mean total cholesterol fell from 7.2 to 5.8 mmol/L and LDL cholesterol fell from
5.3 to 4.0 mmol/L (both p<0.001). Triglycerides fell from 2.2 to 1.6 mmol/L (p<0.005) and
HDL cholesterol rose from 0.76 to 0.87 mmol/L (p<0.05). These positive changes almost
completely reversed during the follow up period off psyllium treatment.
Rodriguez-Moran et al (1998) performed a double-blind, placebo controlled study of the
effect of psyllium 4g three times daily for 6 weeks in people with Type 2 diabetes (over 90%
55
on sulphonylurea therapy), 63 on psyllium and 60 on placebo. At the end of the treatment

period FPG was 10.3 mmol/L in the placebo group and 7.6 mmol/L in the psyllium group
(p<0.01). Mean total cholesterol was 5.0 mmol/L in the group on psyllium and 5.6 mmol/L in
the placebo group (p=0.03); LDL cholesterol levels were 3.1 and 3.6 mmol/L (p=0.01),
triglycerides 1.6 mmol/L and 2.1 mmol/L (p=0.005) and HDL cholesterol levels 1.32 and
0.91 mmol/L (p<0.0001) respectively.
Anderson and colleagues (1999) evaluated the effects of psyllium on glucose and lipids in 34
men aged 30-70 years with Type 2 diabetes who were randomised to receive 5.1g psyllium
(n=18) or placebo (n=16) twice daily for 8 weeks. At baseline lipid profiles were comparable
in the two groups. After 8 weeks total cholesterol was significantly lower in the psyllium
group than in the placebo group (-2.1% v +6.9%, p<0.05) and LDL cholesterol was non
significantly lower in the psyllium group (-4.7% v +8.3%, p=0.07). There were no
differences in triglycerides and HDL cholesterol levels between groups. Postprandial glucose
concentration was 19.2% lower in the psyllium group (-6.5% v +12.7%, p<0.05), but HbA1c
did not differ between the two groups.
Soluble fibre in the form of oat bran concentrate can be incorporated into the diet as oat bran
concentrate bread muffins and cereal. Pick et al (1996) performed a randomised controlled
crossover trial of added fibre from oat bran concentrate over 2 periods of 12 weeks in 8 men
with Type 2 diabetes on diet alone or oral hypoglycaemic therapy. Subjects consumed diets
with either 34g/day fibre (18g from oat bran concentrate) or 19g/day fibre. The response of
fasting glucose and glycated Hb were not reported. Mean total cholesterol during the oat bran
concentrate period was 4.6 mmol/L compared with 5.3 mmol/L for the control period,
(p<0.01) and LDL cholesterol levels were 2.6 compared with 3.4 mmol/L (p<0.01).
Triglycerides and HDL cholesterol did not change significantly.
Another soluble fibre, pectin from fruit, was used by Sheehan et al (1997) in a study in 15
people with Type 2 diabetes treated over 8 weeks with 20g/day fish oil. Fish oil alone
lowered triglycerides from 3.9 to 2.3 mmol/L (p<0.01) but did not affect total, LDL or HDL
cholesterol levels. The addition of 15g/day apple pectin after 4 weeks reduced total
cholesterol from 6.2 to 5.7 mmol/L (p<0.001) and LDL cholesterol from 4.4 to 4.0 mmol/L
(p<0.05) but there was no further reduction in plasma triglycerides.
In summary:
Increasing the fibre content of the diet can lower total and LDL cholesterol but has
little effect on triglycerides or HDL cholesterol levels
Plant sterols
Plant sterols, particularly sitosterol, have been shown to reduce plasma cholesterol by
inhibiting cholesterol absorption, but the large doses required have limited its use. Sitostanol,
a 5-saturated derivative of sitosterol, is more effective than sitosterol and is completely
unabsorbed in humans. In 11 men with Type 2 diabetes treated with diet alone or oral
hypoglycaemic agents, Gylling & Miettinen (1994) showed in a double blind crossover study
with 6 week treatment periods that 3g/day of sitostanol ester dissolved in rapeseed margarine
reduced mean total cholesterol from 6.0 to 5.6 mmol/L (p<0.05) and LDL cholesterol from
3.8 to 3.5 mmol/L (p<0.05). Triglycerides were unchanged but HDL cholesterol increased
from 1.13 to 1.24 mmol/L (p<0.05). Cholesterol absorption was reduced from 25% to 9%
(p<0.001). There was no significant change in fasting glucose or glycated Hb. Another study
by the same group in 8 men with Type 2 diabetes (Gylling & Miettinen, 1996) showed that
the LDL cholesterol lowering effects of sitostanol ester margarine combined with the HMG
CoA reductase inhibitor pravastatin were greater (-44%) than sitostanol (-14%) or pravastatin
(-38%) alone.
56
In a randomised controlled trial, Lee et al (2003) compared the effect of a phytosterolenriched low-fat spread (equivalent to 1.6g phytosterols) with a low-fat spread on lipid levels
in 85 people with Type 2 diabetes with good to moderate glycaemic control (mean HbA1c
7.6%). People did not receive additional dietary counselling during the 3-month study period.
At baseline all lipid levels were comparable between the 2 groups. At week 4, total
cholesterol and LDL cholesterol were reduced by 5.2% and 6.8%, respectively (each p<0.05)
in the phytosterol group compared with an increase of 1.1% and 1.5%, respectively in the
placebo group (overall differences between the two groups p=0.003 and p=0.027
respectively). After 8 and 12 weeks, these reductions became smaller and were not significant
compared with baseline. HDL increased significantly from baseline in the phytosterol group
after 8 weeks (p<0.05), but the difference between groups did not reach significance
(p=0.057). Triglycerides was significantly lower after 4 and 8 weeks compared to baseline in
the phytosterol group (both p<0.05), but again there were no significant differences between
the groups. Glycaemic control improved in the phytosterol group, but the difference between
groups in HbA1c was statistically significant only at week 4 (p<0.05).
In summary:
Plant sterol enriched margarines have a modest effect on lipid levels in people with
Type 2 diabetes
Alcohol
The literature search found few studies of the effects of alcohol on lipid levels in people with
Type 2 diabetes. Ben et al (1991) compared lipid levels in 46 people with Type 2 diabetes
who habitually consumed an average of 45g/day of alcohol with a control group of 35 people
with Type 2 diabetes who consumed no alcohol. Chronic alcohol intake was associated with
higher fasting blood glucose levels (9.1 v 7.8 mmol/L; p<0.05) and HbA1c (6.8 v 6.1%
p<0.05). However no significant differences were found in total cholesterol (both 5.7
mmol/L), triglycerides (1.6 v 1.5 mmol/L) or HDL cholesterol (both 1.3 mmol/L) levels
between the drinkers and the control group. With admission to hospital and abstinence from
alcohol for 7 days, fasting glucose levels in the two groups both fell to about 7.4 mmol/L and
there was no change in any of the lipid parameters.
Bell et al (2000) examined the relationship between alcohol intake and cardiovascular disease
risk factors in a cross-sectional study of 1,196 people. The prevalence of diabetes ranged
from 17.3% to 39.0% among participants according to their daily alcohol consumption
(never, <0.5, 0.5-0.99, 1-2.99, and 3 drinks/day, respectively). After adjustment for age, sex,
ethnicity, smoking status and physical activity, the lowest triglycerides levels were seen in
the 1-2.99 drinks/day category (3.1 v 3.5 mmol/L in never drinkers, p<0.05). HDL
cholesterol gradually increased with increasing alcohol intake - 1.15mmol/L, 1.23 mmol/L,
and 1.36 mmol/L for 0.5-0.99, 1-2.99, and 3 drinks/day, respectively, compared with 1.01
mmol/L for never drinkers (all p<0.001).
Rimm et al (1999) conducted a meta-analysis on the effect of moderate alcohol intake on
lipids in non-diabetic people. The studies that assessed HDL cholesterol level found it
increased by 0.0034 mmol/L per gram of alcohol consumed a day. Consuming 30g of alcohol
per day would be expected to increase HDL cholesterol by 0.10 mmol/L (CI 0.08-0.12),
compared with those who abstain, an 8.3% increase from pretreatment values. The studies
which assessed triglycerides concentration found an increase of 0.0049 mmol/L per gram of
alcohol consumed or 0.15 mmol/L (CI 0.06-0.23) per 30g of alcohol consumed per day, a
5.9% increase over baseline.
57
In summary
There is no direct evidence that alcohol alters the lipid profile in people with Type 2
diabetes
Epidemiological data suggest that HDL cholesterol and triglycerides increase with
increasing alcohol intake.
Anti-oxidants
Based on the evidence that oxidation of LDL particles increases their atherogenicity, there
has been considerable interest in the use of antioxidants, either natural (vegetables and fruits)
or supplemented (vitamin C, vitamin E, -Carotene). There are significant inconsistencies
between the results of epidemiological studies and randomised controlled trials regarding the
effects of antioxidants in the prevention of macrovascular disease in Type 2 diabetes (see
Macrovascular Disease Guideline). However there may be an effect on intermediate
outcomes, such as oxidisability of lipids.
The most frequently studied antioxidant additive in Type 2 diabetes is -tocopherol. Reaven
(1995) showed that after treatment for 10 weeks with 1,600 IU/day -tocopherol, LDL lag
time to start of oxidation in 10 men with Type 2 diabetes was prolonged compared with 11
men given placebo. After 10 weeks the dense LDL subfraction from the vitamin E group was
more resistant to oxidation than that from the placebo group (p<0.05). A strong correlation
was observed between LDL vitamin E content and lag time of total LDL (r=0.69, p<0.05)
and dense LDL (r=0.78, p<0.05). Devaraj & Jialal (2000) used 1,200 IU/day -tocopherol for
3 months to treat people with Type 2 diabetes with and without macrovascular complications.
LDL oxidisability was reduced in both groups. Lipid levels did not change significantly with
vitamin E treatment in any of these studies. In this 4-week study, Upritchard et al (2000) gave
800 IU/day -tocopherol to 12 people with Type 2 diabetes for 4 weeks and found that lag
time in isolated LDL oxidation was increased by 54% (from 7416 to 11426 min, p=0.001).
Plasma total cholesterol increased significantly (0.50 mmol/L [0.19-0.81]) in people treated
with vitamin E and did not change significantly in those treated with tomato juice (-0.10
mmol/L [-0.45 to 0.25]), vitamin C (0.04 mmol/L [-0.17 to 0.25]) and placebo (0.03 mmol/L
[-0.25 to 0.30]).
Vitamin C supplementation was studied in a randomised, double blind, crossover study by
Paolisso et al (1995) in 40 people with Type 2 diabetes treated with sulphonylureas. After 4
months on vitamin C 500mg twice daily, total cholesterol was 5.8 mmol/L compared with 7.3
mmol/L on placebo (p<0.03), LDL cholesterol was 4.1 compared with 5.6 mmol/L (p<0.05),
triglycerides were 2.1 compared with 2.6 mmol/L (p<0.05) and HDL cholesterol was 1.1 v
1.0 mmol/L (p=NS). HbA1c was 7.2% on vitamin C compared with 8.0% on placebo
(p<0.05). Fasting plasma free radicals were also reduced. Similar effects were found in a
randomised, double blind, crossover study comparing the effects of vitamin C 2g/day and
magnesium 600mg/day (Eriksson & Kohvakka, 1995). On vitamin C mean total cholesterol
improved from 6.2 to 5.9 mmol/L (p<0.05) and triglycerides from 2.5 to 2.2 mmol/L
(p<0.05). HbA1c also improved from 9.3 to 8.5% (p<0.05). Magnesium had no effect on
lipids or glycaemic control. An earlier double blind crossover study with a lower dose of
vitamin C (500mg daily) for 4 months in 50 people with Type 2 diabetes did not show any
effect on cholesterol or triglycerides levels (Bishop, 1985), nor did the study by Upritchard et
al (2000) in 12 people with Type 2 diabetes on 500mg/day vitamin C for 4 weeks.
The effect of antioxidant vitamin supplementation on cardiovascular outcome was examined
in the Medical Research Council/British Heart Foundation Heart Protection Study (Heart
Protection Study Collaborative Group, 2002b). This study of 20,536 people included 5,963
people with Type 2 diabetes, randomised to treatment with simvastatin 40mg daily or placebo
58
and in a 22 factorial design to antioxidant vitamin therapy (600mg vitamin E, 250mg

vitamin C, 20mg -carotene) or matching placebo. Over a mean of 5 years follow-up, antioxidant treatment did not result in any significant differences (vitamin versus placebo) in allcause mortality (14.1 v 13.5%), death due to vascular (8.6 v 8.2%) or nonvascular event (5.5
v 5.3%). There were also no significant differences in nonfatal myocardial infarction or
coronary death (10.4 v 10.2%), and fatal or nonfatal stroke (5.0 v 5.0%) between the two
groups.
In summary:
Anti-oxidant therapy may reduce susceptibility of LDL particles to oxidation but
cardiovascular outcomes are not improved
59
Table 5: Effects of diet on lipid levels in Type 2 diabetes

Effects on Lipids
Reference
Abraira, 1988
(US)
Anderson, 1999
(US)
Bantle, 1993
(US)
Bell, 2000
(US)
Bishop, 1985
(UK)
Bonanome, 1991
(US)
Population Studied
40-day follow-up RCT
CHO diet (50-60%)
Sucrose diet (220g/day)
8-wk follow-up RCT
n=18 psyllium
n=16 placebo
28 day follow-up
Sucrose diet (19% )
Starch diet
n=1,196
17.3-39.0% with Type 2
diabetes
alcohol consumption:
never
<0.5 drinks/d
0.5-0.99
1-2.99
3 drinks/day
4-mth crossover RCT
vitamin C 500mg/d first
placebo first
2-month follow-up
CHO diet 1
MUFA fat
CHO diet 2
Mean Total
Cholesterol
(mmol/L)
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Mean Total
Triglycerides
(mmol/L)
Before
After
Before
After
Before
After
Before
After
Before
After
5.00
5.10
4.61*
5.00
3.03
3.34
3.19
2.62
0.98
0.96
0.98
0.98
2.12
1.77
2.20
1.88
85.4
82.6
83.8
80.9
5.69
5.39
5.57
5.76
3.81
3.39
3.63
3.67
0.88
0.85
0.89
0.87
2.54
2.50
2.71
2.84
89.6
87.1
5.32
5.20
5.05
4.90
3.32
3.21
3.12
3.08
1.07
1.08
1.05
1.02
2.03
2.02
1.91
1.77
86.0
86.9
6.8
6.8
6.5
6.7
6.2
6.5
6.4
1.01
1.06 (v never)
1.15 (v never)
1.23 (v never)
1.36 (v never)
4.2
4.3
4.3
1.2
1.3
1.3
Before/After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001
60
3.53
3.47
3.42
HbA1c(%)
Body Weight (kg)
Before
After
89.3
88.4
7.3
7.5
6.85
7.56
3.13 (v never)
3.07
2.76
3.25
2.35
2.35
1.8
1.9
1.7
10.0
10.0
76.8
76.7
76.6
9.8
9.7
6.2
6.0
6.5

Effects on Lipids
Reference
Brand, 1991
(Australia)
Chandalia, 2000
(US)
Chen, 1995
(US)
Christiansen,
1997
(Denmark)
Colagiuri, 1989
(Australia)
Cooper, 1988
(Australia)
Coulston, 1989
(US)
Population Studied
n= 16 Type 2 diabetes
24-wk crossover RCT
High GI (12 wks)
Low GI (12 wks)
6-wk crossover RCT
50g fibre diet v
24g fibre diet
n=9 Type 2 diabetes
6-wk cross-over
40% CHO diet
55% CHO diet
12-wk follow-up RCT
SFA diet
cis-MUFA diet
trans-MUFA diet
n=9 Type 2 diabetes
12-wk follow up RCT
Sucrose: 45g added
Aspartame added
6-wk follow-up RCT
Sucrose diet (28-30g)
Saccharin added
n=8 Type 2 diabetes
12-wk follow-up
40% CHO diet
60% CHO diet
Mean Total
Cholesterol
(mmol/L)
Mean LDL
Cholesterol
(mmol/L)
Before
After
Before
After
5.81
5.81
5.80
5.79
3.09
3.09
2.98
2.72
5.08
5.44
3.44
3.68
5.6
5.6
5.8
5.8
5.8
6.3
6.0
6.0
5.2
5.2
5.3
5.4
6.2
6.2
5.8*
5.8*
-
Mean HDL
Cholesterol
(mmol/L)
Before
After
-
0.73
0.75
-
3.66
3.66
3.66
3.68
3.48
3.58
4.10
4.10
3.75**
3.78**
decreased when
consuming the 60%
CHO diet
Body Weight (kg)
HbA1c(%)
Before
After
Before
After
Before
After
1.59
1.59
1.57
1.67
75.9
75.9
76.0
75.9
7.7
7.7
7.9
7.0
2.08
2.32
90.5
90.7
2.3
2.3
2.1
2.8
6.9%
7.2%
1.22
1.22
1.22
1.12
1.12
1.10
2.19
2.19
2.19
2.55
2.51
2.65
98
98
98
96
96
96
7.7
7.7
7.7
GHb
7.8
7.7
7.9
GHb
0.91
0.91
0.96
0.93
1.9
1.9
2.1
2.1
75.7
75.7
75.9
75.3
7.2
7.2
GHb
7.5
7.3
GHb
1.10
1.10
1.08
1.06
2.0
2.0
2.0
2.0
69.1
69.1
69.3
68.9
8.1
8.1
6.8**
8.0
decreased when
consuming the 60%
CHO diet
61
Mean Total
Triglycerides
(mmol/L)
increased when
consuming the 60%
CHO diet
FPG conc.
increased on the 60%
CHO diet

Effects on Lipids
Reference
Devaraj, 2000
(US)
Dunstan, 1997
(Australia)
Eriksson, 1995
(Finland)
Frost, 1994
(UK)
Garg, 1992a
(US)
Garg, 1994a
(US)
Population Studied
+MVD
n=25 controls
3-mth follow-up
vitamin E 1200 IU/d
8 week follow-up RCT
Fish & moderate exercise
Fish & light exercise
Moderate exercise only
Light Exercise (Control)
3-mth crossover RCT
vitamin C
magnesium
18-mth follow-up
Standard dietary advice
Low glycaemic advice
n=10 men Type 2 diabetes
28-day follow-up RCT
High CHO diet (65%)
High MUFA
8-wk follow-up RCT
High CHO diet (55%)
High MUFA
Mean Total
Cholesterol
(mmol/L)
Before
After
no sig. change
no sig. change
no sig. change
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Before
After
no sig. change
no sig. change
Before
After
no sig. change
no sig. change
no sig. change
no sig. change
Mean Total
Triglycerides
(mmol/L)
Before
After
no sig. change
no sig. change
4.74
4.81
4.47
3.2
3.3
2.8
3.47*
3.55
2.84
0.83
0.89
0.96
0.78
0.85
0.90
2.0
1.7
2.3
5.4
3.8
0.85
2.1
0.80****
0.48****
1.62 (v
control)
-
6.2
6.2
5.9*
6.2
1.16
1.16
1.10
1.13
2.5
2.5
2.2*
2.6
5.6
6.2
5.3
5.5*
1.0
1.2
1.1
1.2
2.5
1.9
2.1
1.4*
3.4
4.4
3.3
3.7
Before
After
After
GHb
GHb
85.7
89.4
85.6
83.3*
88.0
83.5*
8.3
8.0
8.8
8.11
7.51
8.77
88.4
87.8
8.1
85.0
84.9
82.9
84.8
5.09
4.44
3.09
3.09
2.73
2.67
0.85
0.85
0.83
0.9
2.98
2.98
4.18
2.49
86.3
86.2
86.1
85.4
5.07
4.97
3.36
3.36
0.92
0.96
2.19
1.75
82.3
82.2
62
Before
5.15
5.15
HbA1c(%)
no sig. change
4.9
5.0
4.7
Body Weight (kg)
9.3
9.3
8.5*
8.9
GHb
GHb
8.9
8.4
8.6
8.4
-

Effects on Lipids
Reference
Population Studied
Mean Total
Cholesterol
(mmol/L)
Before
Garg, 1998
(US)
Grigoresco, 1988
(France)
Groop, 1993
(Finland)
Gumbiner, 1998
(US)
Gupta, 1994
(India)
Gylling, 1994
(Finland)
Gylling, 1996
(Finland)
Meta-analysis of RCTs
10 studies, lasting 2-6 wks
High MUFA diet (33%) v
High CHO (65%)
n=8 Type 2 diabetes
2-mth follow-up RCT
Fructose diet (30g)
Control diet
8-wk placebo
48-wk guar gum 15g/d
8-wk placebo again
10-wk follow-up RCT
High MUFA
High CHO diet
90-day follow-up
psyllium 3.5g twice a day
6-wk crossover
rapeseed oil margarin
added sitostanol ester 3g/d
n=8 Type 2 diabetes
4 7-wk periods
margarin (control)
sitostanol ester 3g/d
pravastatin 40mg/d
sitostanol ester+pravastatin
After
Mean LDL
Cholesterol
(mmol/L)
Before
Mean HDL
Cholesterol
(mmol/L)
After
Before
After
Mean Total
Triglycerides
(mmol/L)
Before
After
high MUFA v high CHO
0.15 mmol/L
(CI-0.24, -0.06)
0.01 mmol/L
(CI-0.10, 0.08)
0.05 mmol/L
(CI 0.03-0.07)
0.36 mmol/L
(CI-0.24, -0.06)
5.74*
6.61**
3.90
3.57
5.3
4.5
*
*
6.0
5.6**
4.49
4.49
4.54
4.64
6.11
5.74
1.01
1.01
0.95
1.03
1.16
1.16
1.47*
1.36
3.57*
4.32**
1.18
1.26
1.26
1.33
2.21
2.02
2.02
2.12
3.1
2.5
1.0
1.0
*
*
2.8
2.2
*
*
3.8
3.5**
1.13
1.24*
2.2
1.6***
5.98
5.62*
6.64
5.94
4.53
4.29
3.83
3.46*
5.29
1.13
1.24*
14%
38%
44%
63
2.14
2.08
2.43
2.38
1.74
1.70
no effect
(v ester)
(v ester)
HbA1c(%)
Body Weight (kg)

Before
After
Before
After
FPG
0.23 mmol/L
(CI -0.39, -0.06)
74.3
74.3
72.5
72.4
101.8
110.4
94.5
102.1
6.8
6.8
5.9
6.4
9.0
8.5
8.5*
8.5
no sig. change
7.0
7.3
8.1
7.1

Effects on Lipids
Reference
Heart Protection
Study
Collaborative
Group, 2002b
Heilbronn, 1999
(Australia)
Heilbronn, 2002
(Australia)
Heine, 1989
(The Netherlands)
Hermansen, 2001
(Norway)
Lee, 2003
(Germany)
Low, 1996
(US)
Population Studied
n=20,536
5-yr follow-up
antioxidant vitamin
v placebo
12-wk follow-up RCT
high CHO diet
high MUFA diet
high SFA diet
mean age 56.7 yrs
12-wk follow-up RCT
high GI diet (n=21)
low GI diet (n=24)
60-wk follow-up RCT
Low P:S diet
High P:S diet
RCT, 6-wk crossover
Abalon (soy protein +
cotyledon fibre)
v placebo
3-mth follow-up
phytosterols
placebo
10-wk follow-up RCT
High CHO diet
High MUFA diet
Mean Total
Cholesterol
(mmol/L)
Before
After
during follow-up
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Before
After
during follow-up
Before
After
during follow-up
Mean Total
Triglycerides
(mmol/L)
Before
After
during follow-up
HbA1c(%)
Body Weight (kg)

Before
After
Before
4.89
4.74
2.82
2.74
1.10
1.13
0.96
0.82
1.06
0.93
0.86
1.14
2.13
3.28
2.12
5.15
4.75*
5.58
5.01*
after 24 wks
3.25
2.91*
3.45
2.91*
after 24 wks
1.10
1.25
1.12
1.26
1.78
1.60
1.96
1.84
after 24 wks
5.92
5.47
4.08
3.68
5.68
5.40
5.10***
5.40***
5.11
3.91
3.99
3.16
3.63
3.01*
2.11
2.14
2.18
3.64
3.33
during follow-up
1.33
1.28
during follow-up
1.70
1.79
during follow-up
5.2%*
1.1%
6.8%*
1.5%
4.0
3.9*
2.4
2.8
0.8
0.7
2.4
2.5
0.7
0.7
64
93.2
88.4*
91.7
87.3*
after 24 wks
1.63*
1.70
5.45
5.59
during follow-up
4.4
5.0
6.6 kg
6.6 kg
6.6 kg
2.42
2.22
1.38
1.31
2.13
1.92
3.52**
3.28**
3.46
5.82
5.97
5.00
After
2.7
3.2
6.35
6.06*
6.65
6.04*
after 24 wks
77.9
78.0
9.2
9.2
no sig. change
during follow-up
-
2.2
1.4*
7.00****
6.75****
6.55****
8.51
7.75
7.46
110.4
101.8
only at 4 wks
102.1
94.5

Effects on Lipids
Reference
Luscombe, 1999
(Australia)
Malerbi, 1996
(Brazil)
Population Studied
12-wk follow-up RCT
High GI
Low GI
High MUFA
18-wk follow-up RCT
Starch diet: (50-55% CHO)
Fructose diet: (20% CHO)
Sucrose diet: (19% energy)
Mean Total
Cholesterol
(mmol/L)
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Mean Total
Triglycerides
(mmol/L)
Body Weight (kg)
Before
After
Before
After
Before
After
Before
After
Before
After
5.46
5.44
3.75
1.94
1.80
87.1
86.5
5.46
5.46
5.38
5.35
3.79
3.62
0.88
(v both)
0.93
0.93
1.94
1.94
1.47
1.77
87.1
87.1
86.2
86.6
5.1
5.1
5.0
5.1
5.0
5.1
3.4
3.4
3.4
3.4
3.3
3.5
1.0
1.0
1.0
1.0
1.0
1.0
1.3
1.2
1.4
1.3
1.3
1.4
65.4
65.5
65.9
65.3
65.3
66.0 (v
HbA1c(%)
Before
After
FPG
FPG
7.3
7.3
6.8
7.2
6.7
7.5
GHb
GHb
starch)
Milne, 1994
(NZ)
Montori, 2000
(Meta-analysis)
Niemi, 1988
(Finland)
Osei, 1987
(US)
Osei, 1989
(US)

18-mth follow-up
Weight-management
High-CHO/fibre
Modified-lipid
n=18 RCT studies
Type 2 diabetes
Mean 12-wk follow-up
Fish oil supplementation
12-wk crossover RCT
guar gum 15g/d
microcrystalline cellulose
12-wk follow-up RCT
60g added fructose
without added fructose
6-mth follow-up RCT
Fructose: 60g
no Fructose
6.4
6.1
4.5
4.2
1.24
1.18
2.0
1.6 (v
high CHO)
79.1
79.8
9.5
8.9
6.6
6.0
6.2
5.7
4.2
4.2
4.0
3.6
1.23
1.15
1.19
1.22
2.7
2.1
2.4
2.0
80.9
82.8
80.7
82.1
9.4
10.9
8.5
9.7
0.007 mmol/L
(-0.13, 0.15)
0.21 mmol/L*
(0.02-0.41)
0.02 mmol/L
(0.01-0.05)
-0.56mmol/L*
(-0.71, -0.41)
6.6
6.1
5.9**
6.2
4.92
5.28
5.02
5.80
3.19
3.42
3.26
3.68
1.30
1.11
1.30
1.27
1.04
1.65
1.04
2.71*
82.8
82.5
5.98
5.21
5.24
5.64
3.10
2.73
3.07
3.41
0.93
1.06
1.03
0.85
1.25
1.34
1.42
1.31
87.7
88.3
65
0.15% (-0.08, 0.37)
12.1
11.4
11.8
12.2
83.8
83.0
11.57
11.48
GHb
10.20*
12.97
GHb
89.5
87.0
11.3
10.4
9.9*
11.2

Effects on Lipids
Reference
Population Studied
Mean Total
Cholesterol
(mmol/L)
Before
Rimm, 1999
(Meta-analysis)

4-mth crossover RCT
vitamin C
placebo
17-wk follow-up RCT
MUFA diet
PUFA diet
12-wk follow-up
high protein diet (28%)
low protein diet (16%)
n=8 Type 2 diabetes
12-wk crossover
oat bran bread first
white bread first
10-wk follow-up
vitamin E 1600 IU/d
placebo
n=42 experimental studies
of alcohol comsuption up to
100g/day
Rodriguez-Moran
M, 1998
(Mexico)

6-wk follow-up
n=63 psyllium 12g/d
n=60placebo
Paolisso, 1995
(Italy)
Parfitt, 1994
(UK)
Parker, 2002
(Australia)
Pick, 1996
(Canada)
Reaven, 1995
(US)
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Mean Total
Triglycerides
(mmol/L)
After
Before
After
Before
After
Before
After
7.2
7.2
5.8**
7.3
5.7
5.7
4.1*
5.6
1.1
1.1
1.1
1.0
2.6
2.6
2.1*
2.6
5.3
5.3
4.7
4.9
3.7
3.7
3.2
3.5
0.94
0.94
0.99
0.90
1.9
1.9
1.9
1.9
HbA1c(%)
Body Weight (kg)

Before
After
-
Men
Women
Before
After
8.1
8.1
7.2*
8.0
5.16
5.16
4.81
5.15
3.32
3.23
3.13
3.32
0.93
0.92
0.92
0.96
2.02
2.17
1.68****
1.94****
-3.9 kg
-5.1 kg
-5.3kg
-2.8kg
6.42
6.30
5.88****
5.79****
4.65
4.65
4.56
5.30
2.59
3.36
1.04
0.96
2.26
2.26
2.03
2.14
82.9
82.9
82.9
82.9
7.0
7.0
no sig. change
no sig. change
no sig. change
no sig. change
5.72
6.01
5.05
5.57
3.78
4.07
no sig. change
no sig. change
0.0034 mmol/L
per g alcohol/day
0.10 mmol/L
per 30g alcohol/day
3.06
3.62
0.88
0.83
1.32
0.91
66
no sig. change
no sig. change
0.0049 mmol/L
per g alcohol/day
0.15 mmol/L
per 30g alcohol/day
2.10
2.26
1.55
2.08
no sig. change
no sig. change
no sig. change
no sig. change
70.6
73.3
70.5
73.9
7.6
10.3

Effects on Lipids
Reference
Sheehan, 1997
(US)
Tsihlias, 2000
(Canada)
Population Studied
8-wk follow-up
fish oil alone 4 wks
fish oil + apple pectin 15g/d
4 wks
6-mth follow-up RCT
n=29 high GI
n=30 low GI
n=32 MUFA
Mean Total
Cholesterol
(mmol/L)
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Upritchard, 2000
(New Zealand)
Wolever, 2003
(Canada)
Body Weight (kg)
HbA1c(%)
Before
After
Before
After
Before
After
Before
After
Before
After
Before
After
6.57
6.57
6.15
5.69
4.32
4.32
4.40
4.01
0.88
0.88
0.88
0.85
3.87
3.87
2.28
2.38
76.5
76.5
76.8
76.3
7.0
7.0
6.5
6.7
5.23
5.00
5.73 (v
not
differ
b/w gps
3.18
2.95
3.69
not
differ
b/w gps
1.10
0.97
1.14
10%
2.41
2.70
2.08
not
differ
b/w gps
low GI)

4-wk follow-up RCT
tomato juice n=15
vitamin E n=12
vitamin C n=12
placebo n=13
6-mth follow-up
n=22 low fibre
n=25 high fibre
n=22 MUFA
Mean Total
Triglycerides
(mmol/L)
not differ
b/w gps
not differ
b/w gps
(v high &
low GI)
5.87
5.65
5.96
6.48
5.75
6.15*
6.00
6.51
5.63
5.37
6.14
5.64
5.25
6.35
2.56
2.37
2.83
2.59
2.35
3.26*
1.01
1.14
1.10
0.93
2.38
1.86
1.75
2.70
1.01
0.90
1.02
1.08
0.86
1.08
2.16
2.34
1.75
2.20
2.66*
1.53*
(v both)
67
75.6
79.3
78.2
74.6
79.5
77.8
6.0
6.7
6.7
6.6
8.0
7.9
8.0
8.20
8.08
8.31
Exercise may have a modest beneficial effect on lipid levels in people with Type 2
diabetes
Effects of short-term exercise programs (6 weeks to 26 weeks)
These studies are summarised in Table 6. The majority have prescribed a program of aerobic
exercise, three times a week for 20 to 60 minutes at 50-80% VO2max.
In 13 diabetic men and women with mean age 52.5 years, 45 minutes of aerobic exercise
(walking, jogging, skiing) at 70% VO2max 5-7 times per week was examined. This reduced
total cholesterol from 6.7 to 6.4 mmol/L (p=NS), LDL cholesterol from 4.6 to 4.3 mmol/L
(p<0.05), triglycerides from 2.2 to 1.9 mmol/L (p=NS) and increased HDL cholesterol from
1.22 to 1.29 mmol/L (p<0.05) after 4 months (Ronnemaa et al, 1988). There was no
significant change in the lipid profile in 12 control subjects. Mean body weight fell from 85.2
to 83.2 kg (p<0.05) but in the control group rose form 82.8 to 83.3 kg (p=NS). Mean HbA1c
fell from 9.6 to 8.6% (p<0.01) in the exercise group and from 10.0 to 9.9% (p=NS) in the
control group.
Raz et al (1994) randomly assigned 40 people with Type 2 diabetes, mean age 57 years, to
control or exercise groups in a 12 week aerobic exercise program (bicycle, treadmill and
rowing machine) for 55 minutes three times per week at 65% VO2max. There were significant
improvements in the exercise group compared with the control group in triglycerides (1.9 v
2.2 mmol/L, p<0.05) but not total or HDL cholesterol. There was no significant change in
body weight in either group, but HbA1c fell significantly in the exercise group (12.52.9 to
11.72.6%, p<0.05; exercise v control, p<0.05).
Lehmann et al (1995) studied the effects of a 3 month aerobic program (50-70% VO2max for
30-45 min three times per week) on cardiovascular risk factors in 16 people with Type 2
diabetes whose mean age was 54 years. Compared with a control group of 13 people with
Type 2 diabetes in whom the lipid profile did not change, exercise resulted in significant
improvements in lipids with a reduction in mean triglycerides levels from 2.8 to 2.2 (p<0.05).
Total cholesterol was unchanged and HDL cholesterol increased from 1.15 to 1.35 (p<0.001).
Body weight did not change during the study, but there was a significant reduction of body
fat (measured by a near-infrared interactance device) from 35.37.2% at baseline to
33.08.6% at 3 months (p<0.001) and of waist:hip ratio from 0.960.10 to 0.920.10
(p<0.001). HbA1c did not change from the baseline level of 7.5%.
In a 26 week randomised control trial, 25 people with Type 2 diabetes, mean age 63 years,
were instructed in an aerobic training program 3 times/wk for 50 min at 60-80% VO2max
(Ligtenberg et al, 1997). For 6 weeks exercise was performed under supervision, for another
6 weeks at home according to personalised training advice and for a further 14 weeks at
home, but without regular encouragement. Total cholesterol was 5.9 mmol/L at baseline, 5.6
mmol/L at 6 weeks, 5.7 mmol/L at 12 weeks and 6.0 mmol/L at 26 weeks. LDL cholesterol
was 3.7 mmol/L at baseline, 3.5 mmol/L at 6 weeks, 3.6 mmol/L at 12 weeks and 3.7 mmol/L
at 26 weeks. Triglycerides levels were 2.4 mmol/L at baseline, 2.2 mmol/L at 6 weeks, 2.7
mmol/L at 12 weeks and 2.6 mmol/L at 26 weeks. HDL cholesterol was 0.93 mmol/L at
baseline, 1.0 mmol/L at 6 weeks, 1.1 mmol/L at 12 weeks and 1.2 mmol/L at 26 weeks.
Compared with a control group of 26 people with Type 2 diabetes, triglycerides levels were
lower at 6 weeks (2.2 v 2.5 mmol/L, p=0.05) and total cholesterol was lower at 12 weeks (5.7
v 6.0 mmol/L, p=0.05). Weight, waist circumference and waist:hip ratio were unchanged in
both groups throughout the study. HbA1c was 8.9% at baseline, 8.9% at 6 weeks, 9.2% at 12
weeks and 8.7% at 26 weeks.
An Australian study (Dunstan et al, 1997) used a randomised 2x2 design to test the effects of
moderate exercise and daily fish intake on lipid and lipoprotein levels in people with Type 2
68
diabetes (4 groups of 11 to 14 subjects). Moderate exercise training consisted of 30 min

stationary cycling at 50-55% VO2max for the first week and then 55-65% VO2max for 7 weeks.
Relative to control subjects who participated in a light exercise program (heart rate <100
bpm), moderate exercise alone reduced triglycerides by 0.68 mmol/L (p=0.03) but had no
effect in combination with fish, compared with fish alone. The rise of 0.06 mmol/L in HDL
cholesterol with exercise alone was not significant (p=0.06) and again there was no effect of
exercise and fish compared with fish alone. Moderate exercise improved aerobic fitness
(VO2max) by 12% (from 1.87 to 2.07 l/min, p=0.0001). Mean weight loss was 2.1 kg in the
moderate exercise group and 0.6 kg in the light exercise group. HbA1c reduction of
0.340.07% (p=0.07) was associated with moderate exercise.
Lehmann et al (2001) examined the effects of physical activity on lipid profiles and
glycaemic control in 10 obese people with Type 2 diabetes (mean BMI 32.4 kg/m2) who
participated in a 3-month exercise program at 50-70% VO2max. The control group consisted of
6 people who were matched for sex, age, diabetes duration and therapy. All subjects had a
prescribed diabetic diet with 50% carbohydrate, 35% fat and 15% protein content. After 3
months, there was a significant decrease in waist:hip ratio (p<0.01) but no overall change in
body weight in the exercise group. With regard to lipids, triglycerides reduced from 2.40.33
to 2.00.33 mmol/L (p<0.05), HDL cholesterol increased from 1.040.07 to 1.280.12
mmol/L (p<0.001) and HDL3 cholesterol from 0.710.08 to 0.860.08 mmol/L (p=0.01);
whereas total and LDL cholesterol remained unchanged. In contrast, all lipid parameters did
not change significantly during 3 months in the control group. Glycaemia control was similar
in both groups.
In a Spanish study (Rigla et al, 2003), 13 people with Type 2 diabetes, mean age 55.8 years,
participated in a 3-month physical exercise program at the intensity of 60-65% VO2max in the
first 1 to 2 week and 65-75% VO2max for the rest of the study period. After 3 months, both
total cholesterol and LDL cholesterol decreased significantly (5.6 to 5.2 mmol/L, p<0.05;
3.7to 3.4 mmol/L, p<0.01, respectively). In contrast, HDL cholesterol and triglycerides did
not change. Glycaemic control remained stable (HbA1c 7.4% to 7.3%) and there was no
reduction in body weight (73.5 to 73.6 kg) during the study period.
The effect of resistance training, rather than aerobic endurance exercise, was studied by
Honkola et al (1997) in 18 people with Type 2 diabetes, mean age 62 years, compared with a
control group of 20 people. After 5 months of individualised, progressive, resistance training
sessions twice a week, total cholesterol decreased significantly in the intervention but not the
control group (6.0 to 5.3 mmol/L, p<0.01 and 6.1 to 5.9 mmol/L, p=NS respectively). Similar
results were observed for LDL cholesterol (3.9 to 3.4 mmol/L, p<0.01 and 3.9 to 3.8 mmol/L,
p= NS respectively) and triglycerides (1.9 to 1.5 mmol/L, p<0.01 and 2.6 to 2.2 mmol/L, p=
NS respectively). There was no significant change in HDL cholesterol levels in the
intervention group, but there was a small, significant rise in the control group (1.28 to 1.30
mmol/L, p=NS and 1.14 to 1.21 mmol/L, p<0.05 respectively). Body weight in the exercise
group fell from 87.3 to 86.6 kg (p<0.05), but not in the control group (p=NS). HbA1c in the
exercise group was 7.5% at baseline and 7.4% at 5 months, in the control group 7.7% at
baseline and 8.1% at 5 months (p<0.01).
Effects of long-term exercise programs (1-2 years)
There have been few long-term studies on the effects of exercise in people with Type 2
diabetes (see Table 6).
Schneider et al (1992) reported an outpatient exercise program which recruited 255 people
with diabetes (including 200 with Type 2 diabetes) and 58 healthy controls. Over the initial 3
months, triglycerides levels decreased during training in people with Type 2 diabetes from
2.20.18 to 1.70.25 mmol/L (p<0.01). No significant changes in total and HDL cholesterol
69
were observed. In the Type 2 diabetes group, both body weight and BMI were reduced from
baseline (83.91.5 to 81.51.9 kg, p<0.05; 28.10.5 to 25.90.9 kg/m2, p<0.01, respectively).
A lower VO2max was found in people with Type 2 diabetes compared with healthy controls
(age >40 yr: 24.50.7 v 32.21.7 ml/kg/min, p<0.01; age <40 yr: 23.11.5 v 39.91.7
ml/kg/min, p<0.05). After 3 months VO2max remained lower in people with Type 2 diabetes
than the controls. They concluded that a regular aerobic training program can be safely and
effectively used in an outpatient population with diabetes for up to 3 months.
Vanninen et al (1992) studied the effects on lipid levels of a one-year exercise program in 21
men and 17 women with Type 2 diabetes. Intervention consisted of oral and written
instructions for effective exercise training, with monitoring of daily exercise records and
encouragement at 2 monthly review visits. The goal was to achieve 3 to 4 exercise sessions
per week, each of 30 to 60 minutes. HDL cholesterol increased significantly with exercise in
both men and women (1.03 to 1.11 mmol/L, p<0.05 and 1.09 to 1.25 mmol/L, p<0.01
respectively). A significant decrease in triglycerides was found only in men (3.0 to 2.0
mmol/L, p<0.01). There was a significant relationship between changes in aerobic capacity
and HDL cholesterol, independent of changes in body weight or metabolic control. Total and
LDL cholesterol levels did not change significantly. BMI fell from 31.1 to 30.5 kg/m2 in men
(p<0.05) and from 33.4 to 32.6 kg/m2 in women (p=NS). Mean HbA1c was 7.1% at baseline
and 7.0% at 12 months in men (p=NS), 7.1% at baseline and 6.2% in women (p<0.05). The
only significant change in the control group of 24 men and 16 women was an increase of
BMI from 30.1 to 30.9 kg/m2 in men (p<0.01).
The longest reported study was a small 2 year study by Skarfors et al (1987) in which 48 men
were screened but 39 were excluded because of other diseases or treatment that made regular
training difficult and one person who took digoxin 0.25 mg daily was also excluded. Eight
men, mean age 59 years, were scheduled for exercise at 75% VO2max for 45 min twice weekly
under supervision and one training session of their own on an additional occasion per week.
The average participation rate over 2 years was 53%. Total cholesterol was 6.1 mmol/L at
baseline and 5.8 mmol/L at 2 years, LDL cholesterol was 4.1 mmol/L at baseline and 4.1
mmol/L at 2 years, triglycerides levels were 2.8 mmol/L at baseline and 2.9 mmol/L at 2
years and HDL cholesterol was 1.04 mmol/L at baseline and 1.07 mmol/L at 2 years. Fasting
glucose was 11.0 mmol/L at baseline and 9.6 mmol/L after 2 years. Body weight was 78.3 kg
at baseline, but was not reported at 2 years. Lipid profile did not change over 2 years in a
control group of 8 people.
In summary:
Exercise in people with Type 2 diabetes may have a modest effect on lipid levels
Improvement of the lipid profile with exercise is more likely to occur if there is reduction
of body weight and improvement of glycaemic control
70
Table 6: Effect of exercise on lipid levels

Effects on Lipids
Reference
Brown, 1996
Dunstan, 1997
(Australia)
Honkola, 1997
(Finland)
Lehmann, 1995
(Switzerland)
Lehmann, 2001
(Switzerland)
Population Studied
n=89 studies systematic
review Type 2 diabetes
Direction change not given
Diet only
Behaviour only
Exercise only
Diet + behaviour + exercise
8-wk follow-up RCT
Fish & moderate activity
Fish & light activity
Moderate exercise
Light Exercise (Control)
5-mth follow-up
Resistance training
Control
6-mth follow-up
Exercise training: 3
times/wk; 6 months
Control (n=13): 3 months
3-mth follow-up
n=10 exercise gp
n=6 control gp
Mean Total
Cholesterol
(mmol/L)
Before
After
Effect sizes
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Mean Total
Triglycerides
(mmol/L)
Before
After
Effect sizes
Before
After
Effect sizes
Before
After
Effect sizes
0.12
-
0.17
0.02
0.00
0.56*
0.12
0.20
0.31*
0.62*
0.09
0.06
0.11
4.9
5.0
4.7
4.74
4.81
4.47
3.2
3.3
2.8
3.47*
3.55
2.84
0.83
0.89
0.96
0.78
0.85
0.90
2.0
1.7
2.3
5.4
3.8
0.85
6.0
6.1
5.3**
5.9
3.90
3.94
3.35**
3.79
1.28
1.14
5.6
5.5
3.12
3.10
3.51
5.2
-
5.1
-
2.9
-
Body Weight (kg)

Before
After
HbA1c
Before
After
BMI
Effect sizes
FPG
Effect sizes
0.71
0.81
-
1.76*
0.31*
0.34*
0.48*
85.7
89.4
85.6
83.3*
88.0
83.5*
8.3
8.0
8.8
8.11
7.51
8.77
2.1
0.79****
0.48****
1.62 (v
control)
-
88.4
87.8
8.1
1.30
1.21*
1.91
2.60
1.53**
2.23
87.3
77.1
86.6*
78.8
7.5
7.7
7.4
8.1**
1.15
1.35**
2.81
2.36**
87.3
87.4
7.5
7.5
3.19
86.8
86.8
7.8
8.4
2.8
-
1.04
-
1.28****
-
2.38
-
1.95*
92.3
89.2
91.7
89.8
7.2
7.0
7.2
7.5
71

Effects on Lipids
Reference
Population Studied
Mean Total
Cholesterol
(mmol/L)
Before
Ligtenberg, 1997
(The Netherlands)
Raz, 1994
(Israel)
Rigla, 2003
(Spain)
Ronnemaa, 1988
(Finland)
Schneider, 1992
(US)
Skarfors, 1987
(Sweden)

26-wk follow-up RCT
n=30 training gp
n=28 control gp
supervised training,
v control at 6 wks
encouraged training,
v control at 12 wks
home training 3 times/wk
v control at 26 wks
12-wk follow-up RCT
exercise: 3 times/wk
control
mean age 55.8 yrs
3-mth follow-up
exercise program
4-mth follow-up RCT
exercise: 5-7 times/wk
controls
10-yr follow-up
case-control
exercise 3-4/wk for 3 mths
n=20 controls
n=8 men, Type 2 diabetes
2-yr follow-up
Training group (2 times/wk)
Control (n=8)
After
5.9
5.7
Mean LDL
Cholesterol
(mmol/L)
Before
After
Mean HDL
Cholesterol
(mmol/L)
Before
Before
2.4
2.5
0.93
0.87
3.7
3.7
5.6
5.7
5.7*
6.0
6.0
6.0
After
Mean Total
Triglycerides
(mmol/L)
1.0
0.97
0.94
0.90
1.02
1.03
3.5
3.6
3.6
3.7
3.7
3.7
After
2.2**
2.5
2.7
3.1
2.6
2.6
Body Weight (kg)

Before
After
HbA1c
Before
After
8.9
8.8
8.9
9.1
9.2
9.4
8.7
9.0
no sig difference
no sig difference
no sig difference
5.7
6.0
5.6
6.0
1.1
1.1
1.1
1.1
2.0
2.1
1.9*
2.2
12.5
12.4
11.7*
12.9
5.57
5.20*
3.65
3.37**
1.26
1.23
1.46
1.32
73.5
73.6
7.4
7.3
6.74
6.20
6.37
6.10
4.62
4.19
4.29*
4.11
1.22
1.22
1.29*
1.26
2.16
1.91
1.91
1.75
85.2
82.8
83.2*
83.3
9.6
10.0
8.6**
9.9
5.83
5.08
5.67
5.41
1.14
1.24
1.11
1.32
2.18
0.95
1.71**
1.01
83.9
79.3
81.5*
80.4
6.06
5.96
5.81
5.96
4.11
4.21
4.09
4.21
1.04
0.93
1.07
0.93
2.82
2.72
2.87
2.72
72

Effects on Lipids
Reference
Population Studied
Mean Total
Cholesterol
(mmol/L)
Before
Vanninen, 1992
(Sweden)

12-mth follow-up RCT
Men
- intervention (6 visits/yr)
- conventional group
Women
- intervention
- conventional group
After
6.3
6.1
6.0
6.2
6.0
6.5
6.0
6.7
Mean LDL
Cholesterol
(mmol/L)
Before
Mean HDL
Cholesterol
(mmol/L)
Mean Total
Triglycerides
(mmol/L)
Body Weight (kg)
HbA1c
After
Before
After
Before
After
Before
After
Before
After
1.00
1.10
1.11*
1.15
2.9
2.3
2.0**
2.3
7.1
7.3
7.0
7.4
1.13
1.25
1.25**
1.29
2.1
2.3
2.0
2.5
7.1
8.1
6.2*
7.2
73
Summary Diet and Exercise on Lipid Levels
Weight loss ( 5%) decreases triglycerides and to a lesser extent total cholesterol. The
effect on LDL and HDL cholesterol is variable
High-carbohydrate (55-60%), low-fat (20-30%) low fibre diets (11-18 grams/day)

increase triglycerides levels by about 25% in short term, but not longer term studies
Reducing the glycaemic index of a high carbohydrate diet improves blood glucose control
and may improve lipids in people with Type 2 diabetes but it is not possible to determine
whether these effects are interrelated or independent
The inclusion of limited amounts of refined carbohydrate (sucrose, fructose) does not
adversely affect lipid levels
Compared with high carbohydrate diets, iso-caloric diets which are high in
monounsaturated fatty acids
reduce fasting triglycerides and VLDL cholesterol in the short term
have no effect on HDL cholesterol or LDL cholesterol
The long-term effects on plasma lipids and weight in a free-living situation remain
untested
Soluble fibre consistently lowers cholesterol in people with Type 2 diabetes but has a
variable effect in lowering triglycerides
In studies which have examined the effect of exercise on lipid levels

There is often a modest improvement in lipid levels
the magnitude of change has been small (average triglycerides reduction 0.3mmol/L,
HDL cholesterol increase 0.08 mmol/L, LDL cholesterol decrease 0.2mmol/L, total
cholesterol decrease 0.3mmol/L) and,
it has been difficult to separate an independent effect of exercise from concurrent
changes in diabetes control and body weight
74

Effects of diet and exercise on lipids in people with Type 2 diabetes
Author
Evidence
Level of Evidence
Level
Study Type
Abraira C (1988)
(Adults US)
Anderson JW (1999)
(Adults US)
Bantle JP (1993)
(Adults US)
Barnard RJ (1994)
(Adults US)
Bell RA (2000)
(Adults US)
Ben G (1991)
(Adults Italy)
Bishop N (1985)
(Adults UK)
Bonanome A (1991)
(Adults Italy)
Brand JC (1991)
(Adults- Australia)
Brown SA (1996)
Quality
Rating
Magnitude
Rating
Relevance
Rating
II
RCT
High
High D+
High
II
RCT
Medium
High P+
High
II
RCT
High
Low
High
III-2
Cohort
Medium
High D,E+
High
III-2
Cross-sectional
High
High A+
Low
III-2
Case-control
Low
Medium A+
High
II
RCT
High
Low
High
III-2
Cohort
High
Low
High
III-2
RCT
Medium
MediumGI+
High
Meta-analysis
Medium
Low
Low
Chandalia M (2000)
Medium
II
RCT
Low
HighD+
(Adults- US)
Chen Y-DI (1995)
High
III-2
Cohort
Medium
High D(Adults US)
Christiansen E (1997)
II
RCT
Medium
Low
High
(Adults Denmark)
Colagiuri S (1989)
II
RCT
High
Low
High
(Adults Australia)
Cooper PL (1988)
High
II
RCT
Medium
High D+
(Adults Australia)
Coulston AM (1989)
High
II
RCT
Medium
High D(Adults US)
Devaraj S (2000)
III-2
Case-control
High
HighVE+
High
(Adults US)
Dunstan W (1997)
FO+
High
II
RCT
High
High
(Adults Australia)
Eriksson J (1995)
High
II
High
High
HighVC+
(Adults Finland)
Franz MJ (1995)
PGC+
High
II
RCT
High
High
(Adults US)
Frost G (1994)
High
II
RCT
High
High GI+
(Adults UK)
Garg A (1992a)
High
II
RCT
Medium
High MUFA+
(Adult men US)
Garg A (1994)
High
II
RCT
High
High D(Adults US)
MUFA+
I
Meta-analysis
High
High
High
Garg A (1998)
Grigoresco C (1988)
F+
High
II
RCT
Medium
Medium
(Adults France)
Groop PH (1993)
G+
High
III-1
Non RCT
Medium
High
(Adults Finland)
Gumbiner B (1998)
High
II
RCT
Medium
High D+
(Adults US)
Gupta RR (1994)
Medium
III-2
Cohort
Medium
High P+
(Adults India)
Gylling H (1994)
High
II
RCT
Medium
High PS+
(Adult men- Finland)
+
diet/exercise improves lipid levels; High = clinically important & statistically significant; Medium = small clinical importance & statistically
significant; Low = no statistically significant effect.
A= alcohol; D= low calorie diet; DD= diet & drug; E= exercise; F= fructose; FO= fish oil; G= guar gum; GI= low glycaemic index diet;
MUFA= high monounsaturated fat diet; O= oatbran concentrate; P= psyllium; PGC= practice guidelines nutrition care; PS= Plant sterolmargarine; PUFA= polyunsaturated fatty acid diet; VC= vitamin C; VE= vitamin E.
75

Author
Evidence
Level of Evidence
Level
Study Type
Gylling H (1996)
(Adult men Finland)
Gylling H (1999)
(Adult women Finland)
Heart Protection Study (2002b)
(Adults UK)
Heilbronn LK (1999)
(Adults Australia)
Heilbronn LK (2002)
(Adults Australia)
Heine RJ (1989)
(Adults Netherlands)
Hermansen K (2001)
(Adults Norway)
Hollander PA (1998)
(Adults- US)
Honkola A (1997)
(Adults Finland)
Lee Y-M (2003)
(Adults Germany)
Lehmann R (1995)
(Adults Switzerland)
Lehmann R (2001)
(Adults Switzerland)
Ligtenberg PC (1997)
Low CC (1996)
(Adults US)
Luscombe ND (1999)
(Adults Australia)
Malerbi DA (1996)
(Adults Brazil)
Manley SE (2000)
(Adults UK)
Mayer-Davis EJ (1999)
Adults US)
Milne RM (1994)
(Adults New Zealand)
Montori VM (2000)
II
RCT
Quality
Rating
Magnitude
Rating
Relevance
Rating
Medium
High PS+
High
PS+
Low
II
RCT
Medium
II
RCT
High
High
Low
High
High
MUFA+
High
II
RCT
High
II
RCT
High
High GI+
High
II
RCT
Medium
Low
High
II
RCT
High
High PS+
High
II
RCT
Medium
High DD+
High
III-2
Case-control
Low
High E+
High
II
RCT
High
High PS+
High
E+
High
III-2
Case-control
Medium
High
III-2
Case-control
Medium
High E+
High
II
RCT
Medium
High E+
High
II
RCT
Medium
Medium MUFA+
Low
II
RCT
Medium
Medium GI+
High
II
RCT
Medium
Low
Low
III-2
Cohort
High
High D+
High
III-2
Cohort
Medium
Medium D+
High
Medium
D+
High
II
I
RCT
Meta-analysis
High
Medium
High
FO+
High
Niemi MK (1988)
II
RCT
Medium
Medium G+
High
(Adults Finland)
Osei K (1987)
II
RCT
Low
Low
High
(Adults US)
Osei K (1989)
II
RCT
Medium
Low
High
(Adults US)
Paolisso G (1995)
High
II
RCT
High
High VC+
( Adults Italy)
Parfitt VJ (1994)
High
II
RCT
Medium
Medium D+
(Women UK)
Parker B (2002)
High
II
RCT
Medium
High D+
(Adults Australia)
Pick ME (1996)
II
RCT
Low
High O+
High
(Adults Canada)
Raz I (1994)
II
RCT
Low
Medium E+
Medium
(Adults Israel)
Reaven P (1995)
II
RCT
Medium
Low
High
(Adults US)
Rigla M (2003)
High
III-2
Cohort
High
High E+
(Adults Spain)
+
76

Author
Evidence
Level of Evidence
Level
Study Type
Rimm EB (1999)
Meta-analysis
Quality
Rating
Magnitude
Rating
Relevance
Rating
Medium
High A+
Low
Rodriguez-Moran M (1998)
Low
II
RCT
High
High D+
(Adults Mexico)
Ronnemaa T (1988)
High
II
RCT
Medium
Medium E+
(Adults Finland)
Schneider SH (1992)
High
III-2
Case-control
Low
Medium E+
(Adults US)
Sheehan JP (1997)
II
RCT
Low
High D+
High
(Adults US)
Skarfors ET (1987)
III-2
Case-control
Medium
Low
High
(Adults Sweden)
Upritchard J (2000)
II
RCT
High
High VC,VE+
High
(Adults New Zealand)
Vanninen E (1992)
II
RCT
Medium
Medium E+
High
(Adults Sweden)
Wing RR (1994)
II
RCT
Medium
Low
High
(Adults US)
Wolever TMS (2003)
High
II
RCT
Medium
High MUFA+
(Adults Canada)
+
77
Section 3: Lipids
Issue
What is the effect of improved blood glucose control on lipids in Type 2 diabetes?
Recommendation
In people with Type 2 diabetes whose lipid levels are above target and who have
unsatisfactory diabetes control, efforts should be made to improve their blood glucose
control before considering lipid modifying medication
Evidence Statement
Improving blood glucose control with hypoglycaemic agents has a modest beneficial
effect on lipids in people with Type 2 diabetes although the effectiveness of different
agents varies
Evidence level II
78
Background Improved blood glucose control and lipids

Poor blood glucose control may be a contributing factor to the lipid abnormalities of Type 2
diabetes and improving blood glucose control per se, irrespective of how it is achieved,
normally leads to some correction of the lipid abnormalities (Stern et al, 1992).
Type 2 diabetes results from impaired insulin secretion, reduced peripheral insulin sensitivity
or a combination of both. Treatment options include changes to diet and physical activity,
oral hypoglycaemic agents and insulin. Initially people are usually treated with advice on diet
and physical activity. If glycaemic targets are not achieved either a biguanide (metformin),
which reduces hepatic glucose production and improves insulin sensitivity, or a
sulphonylurea, which stimulates insulin secretion is commenced. The natural history of Type
2 diabetes is that glycaemic control deteriorates over time and therapy needs to be intensified
with either combination therapy (sulphonylurea plus metformin), the addition of other
hypoglycaemic agents (-glucosidase inhibitor or a thiazolidenedione) or insulin.
Improving diabetes control usually reduces triglycerides, largely due to reduced VLDL
triglycerides and sometimes increases HDL cholesterol (Haffner, 1998). However, because
ideal glycaemic control is often not achieved, lipid abnormalities frequently persist. Even
when good glycaemic control is achieved, insulin resistance generally remains and therefore
lipid abnormalities are only partially corrected.
This Section reviews the effects on lipids of biguanides, sulphonylureas, acarbose,
thiazolidenediones, insulin and combinations of these medications in people with Type 2
diabetes.
Evidence Improved blood glucose control and lipids

Improving blood glucose control with hypoglycaemic agents has a modest beneficial
effect on lipids in people with Type 2 diabetes although the effectiveness of different
agents varies
Many studies have examined the effects of improving blood glucose control with various oral
agents and insulin on lipids and lipoproteins in people with Type 2 diabetes. The overall trend
of these studies has shown a modest beneficial effect although a number of studies have not
shown any benefit. The results of studies in which there was an improvement in diabetes
control are detailed below, categorised by the individual hypoglycaemic(s) agent(s) studied.
Although the UKPDS reported and compared various intensive therapies in people with
newly diagnosed Type 2 diabetes, these analyses were performed on an intention to treat
basis and it is not possible to determine the actual treatment received by individuals during
the course of the study. Therefore the results of the UKPDS study on lipid levels are not
considered in this Section.
Metformin (Table 7)
Metformin monotherapy
Studies of 3 to 7 months duration with metformin monotherapy in people with Type 2
diabetes who had persistent hyperglycaemia despite advice on diet and physical activity, have
evaluated its hypoglycaemic and lipid modifying efficacy and its effects on body weight.
Metformin in doses of 0.5-3.0g per day significantly improved glycaemic control in all
79
studies as judged by falls in HbA1c and fasting blood glucose (FBG) levels. Metformin
caused no significant increase in body mass index (BMI) in any of these studies despite
significant improvements in blood glucose control.
Rains et al (1988) evaluated the effects of 3 months metformin treatment (1-3g/day) in 35
people with Type 2 diabetes with inadequate glycaemic control. Metformin reduced HbA1c
by 1.5% (CI -2.23, -0.83%, p<0.0001), but there was no effect on triglycerides or HDL
cholesterol. However, total cholesterol was reduced by 0.39 mmol/L (p<0.01) and LDL
cholesterol by 0.34 mmol/L (p<0.01).
The largest study of lipid changes with metformin monotherapy in Type 2 diabetes was
reported by DeFronzo et al (1995). In this 29 week study metformin 1.7 to 2.55g daily
(n=143) was compared with placebo (n=146) in people with mean BMI 29.6 kg/m2. HbA1c
was significantly lower in the metformin group than in the placebo group (7.10.1 v
8.60.2%, p<0.01). Triglycerides and HDL cholesterol levels did not change significantly
with metformin therapy, but total and LDL cholesterol levels both fell by 0.28 mmol/L and
the change was significantly different from the change in the placebo group (p=0.001 and
p=0.019 respectively).
Another randomised trial of 6 months duration (Hoffmann & Spengler, 1997) compared
metformin (n=31) with acarbose (n=31) and with placebo (n=32). Metformin 1.7g/day
significantly reduced FBG and HbA1c compared with placebo (7.8 v 9.2 mmol/L, p<0.0001;
8.7 v 9.8%, p<0.0001, respectively), but had no significant effects on triglycerides and total,
LDL or HDL cholesterol.
A direct comparison of metformin (up to 2.55g daily, n=30) with insulin therapy (twice daily,
intermediate acting insulin, n=30) was made by Fanghanel et al (1996) in people with Type 2
diabetes and secondary failure to high dose sulphonylurea therapy. HbA1c was reduced to the
same degree by metformin (12.8 to 8.9%, p=0.002) and by insulin (12.3 to 8.2%, p=0.0001).
However, metformin also reduced total cholesterol from 6.1 to 5.2 mmol/L (p=0.009), LDL
cholesterol from 3.9 to 3.2 mmol/L (p=0.0015) and triglycerides from 2.6 to 2.1 mmol/L
(p=0.0013) while raising HDL cholesterol from 1.04 to 1.12 mmol/L (p=0.05). Insulin
therapy reduced plasma triglycerides from 2.5 to 2.1 mmol/L (p=0.05), but did not improve
other lipid parameters. The authors concluded that metformin was more effective than insulin
in modifying lipids in people with Type 2 diabetes and secondary failure to sulphonylureas.
80
Table 7: The effects of metformin therapy on lipids in people with Type 2 diabetes
Effects on Lipids
Reference
Population Studied
Drug Dose
Mean Total
Cholesterol
(mmol/L)
Before
Dailey,
2002
(NS)
DeFronzo,
1995
(US)
Fanghanel,
1996
(Mexico)
Giugliano,
1993
(Italy)

52-wk follow-up
mean age 55.7 yrs
metformin+glyburide
Study1 Type 2 diabetes
n=289, mean age 53 yrs
RCT 29-wk follow up
metformin
placebo
Study 2 Type 2 diabetes
n=632, mean age 55 yrs
metformin+glyburide
bid
1.25/250mg
2.5/500mg
After
Mean LDL
Cholesterol
(mmol/L)
Before
After
HbA1c 9.0%
HbA1c 9.0%
HbA1c >9.0%
HbA1c >9.0%
0.07 *
0.34
Mean HDL
Cholesterol
(mmol/L)
Before
Before
After
Before
After
HbA1c 9.0%
0.31 *
1.10
After
HbA1c
(%)
Mean Triglycerides
(mmol/L)
no sig. changes
0.21 *
HbA1c >9.0%
0.60
8.7
7.0
Body Weight
(kg)
Before
After
NOTE
Before
3.28 kg
after treatment
After
FPG (mmol/L)
no sig. changes
2.55g/d
5.46
5.49
5.21
5.52
3.19
3.50
3.52
3.57
1.01
1.06
1.04
1.06
2.36
2.09
2.18
2.16
8.4
8.2
7.0
8.6
13.40
13.22
10.6
13.55
FPG (mmol/L)
2.55g+10mg
5.59
metformin alone (M)
2.55g/d
5.49
glyburide alone (G)

n=60 Type 2 diabetes:
RCT 3-mth follow up
mean age 52 yrs
metformin
insulin
RCT 6-mth follow up
mean age 60 yrs
metformin+Ins (n=27)
placebo+Ins (n=23)
10mg/d
5.59
5.34
(v G)
5.39
(v G)
5.70
3.32
(v G)
3.34
(v G)
3.65
3.55
3.47
3.52
1.01
1.04
2.44
0.96
1.01
2.61
0.96
0.98
2.37
2.19
(v G)
2.50
(v G)
2.57
(v G)
13.94
8.9
7.1
(v G)
8.5
14.11
10.44
(v G)
14.01
8.5
8.7
no sig. changes
13.72
14.50
8.8
FBG (mmol/L)
/day
0.85-2.55g
24u
0.85g2/d
6.09
5.91
5.90
6.03
5.23**
5.68
5.69*
6.00
3.17***
3.65
3.86
3.71
1.04
1.07
1.03
1.00
1.13
***
1.06
1.16*
1.01
2.60
2.47
2.87
2.75
Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001
81
2.28***
2.11*
2.56*
2.70
12.8
12.3
11.5
11.7
8.9***
8.2****
9.8*
11.1
no sig. changes
14.95
15.04
8.87***
7.49****
insulin dose
fasting insulin
in placebo gp
Table 7: The effects of metformin therapy on lipids in people with Type 2 diabetes
Effects on Lipids
Reference
Population Studied
Drug Dose
Mean Total
Cholesterol
(mmol/L)
Before
Hermann,
1994
(Sweden)
Hoffmann,
1997
(Germany)
Rains, 1988
(UK)

6-mth RCT, mean age 60
yrs
metformin (M) n=19
glyburide (G) n=19
M+G (GM Low) n=46
M M+G n=12
G G+M n=11
M+G (GM High) n=17
Age 35-70 yrs
RCT 6-mth follow-up
metformin n=31(M)
acarbose n=31 (A)
placebo n=32 (P)
6-mth RCT
age <70 yrs
metformin
glibenclamide
After
Mean LDL
Cholesterol
(mmol/L)
Before
Mean HDL
Cholesterol
(mmol/L)
After
Before
After
HbA1c
(%)
Mean Triglycerides
(mmol/L)
Before
After
Before
After
Body Weight
(kg)
Before
After
NOTE
Before
After
FPG (mmol/L)
1-3g/day
3.5-14mg
5.38
5.66
5.46
4.84
5.25
6.05
5.03
5.78
5.36
4.96
5.48
5.40**
3.66
3.93
3.67
3.04
3.49
4.04
3.38
4.04
3.58
3.31
3.73
3.71*
0.81
0.89
0.91
0.81
0.84
0.76
0.77
0.92
0.95
0.81
0.89
0.80*
2.02
2.01
1.97
2.60
2.05
2.40
1.95
2.10
1.89
1.85
1.92
2.10**
6.9
6.7
6.8
7.8
7.8
8.4
5.8***
5.3***
5.6***
5.4***
5.7***
6.2***
78.6
82.6
80.2
84.6
76.0
83.2
78.8
86.2***
81.0
88.1
76.3
83.3
1.7g/day
5.74
5.83
3.59
3.64
1.61
1.61
1.41
1.28
9.7
8.7
79.0
78.5
8.8
7.8
3 0.1g
6.30
5.41
4.08
3.19
1.42
1.65
1.68
1.23
9.6
8.5
73.9
73.1
9.1
7.6
5.90
5.83
3.62
3.80
1.54
1.39
1.60
1.46
9.4
9.8
74.9
75.1
8.7
9.2
6.13
5.95
5.74**
5.73
4.21
3.98
3.85**
3.86
1.06
1.03
1.03
0.97
1.70
1.73
1.68
1.67
80.3
78.9
79.9
81.6
1-3g/d
5-15mg/d
82
****
****
****
9.3
6.9***
6.6***
8.6
7.2***
9.3
7.3***
13.2
7.3***
12.0
8.5***
14.3
FPG (mmol/L)
Metformin plus sulphonylureas

There have been a number of studies that have assessed the lipid profile in people with Type
2 diabetes before and after the addition of metformin therapy to existing treatment with
sulphonylureas. In most cases, there was persistent hyperglycaemia despite maximal dose
sulphonylurea therapy.
In 213 people with Type 2 diabetes and fasting blood glucose 7.8 mmol/L despite diet and
maximal dose of glyburide, DeFronzo et al (1995) studied the effects of additional treatment
with metformin 2.55g daily over 29 weeks. The combination therapy resulted in a fall in
HbA1c of 1.6% compared to glyburide alone (n=209). Total cholesterol fell by 0.26 mmol/L,
LDL cholesterol by 0.21 mmol/L and triglycerides by 0.23 mmol/L (all p<0.001). There was
no significant change in HDL cholesterol. The combination therapy of metformin plus
glyburide was superior to either drug alone both for reducing glycaemia and improving lipid
levels.
Hermann et al (1994) compared the hypoglycaemic and lipid modifying effects of metformin
and glyburide alone and in combination. Combination therapy in 63 people with Type 2
diabetes previously treated with diet alone was titrated up to a maximum of metformin 3.0g
daily and glyburide 14mg daily, then maintained for 6 months. People on high dose
combination therapy (n=17) had a greater fall in mean HbA1c (from 8.4 to 6.2%, p<0.001)
than people in other treatment groups. In the high dose combination therapy group, total
cholesterol fell significantly from 6.1 to 5.4 mmol/L (p=0.006), LDL cholesterol from 4.0 to
3.7 mmol/L (p=0.019), and triglycerides from 2.4 to 2.1 mmol/L (p=0.010); while HDL
cholesterol rose from 0.76 to 0.80 mmol/L (p=0.025).
In a study of 828 people (mean age 55.7 years) with Type 2 diabetes (Dailey et al, 2002),
metformin and glyburide were administrated 1.25 mg/250 mg b.i.d in people with HbA1c
9.0%, and 2.5 mg/500 mg b.i.d in people with HbA1c >9.0% for 52 weeks. At the end of the
study HbA1c was reduced from 8.7% at baseline to 7.0% (no p value). The mean changes in
total cholesterol was -0.21 mmol/L (CI -0.28, -0.13 mmol/L, p<0.05) and -0.07 mmol/L (CI 0.13, -0.01 mmol/L, p<0.05) in LDL cholesterol. People with initial HbA1c >9.0% had a
greater reduction in total and LDL cholesterol, -0.60 mmlo/L (CI -0.78, -0.42 mmol/L,
p<0.05), and -0.34 mmol/L (CI -0.48, -0.21 mmol/L, p<0.05), respectively. Similarly,
triglycerides fell by 0.31 mmol/L (CI -0.48, -0.14 mmol/L, p<0.05), and 1.10 mmol/L (CI 1.72, -0.53 mmol/L, p<0.05), respectively. HDL cholesterol did not alter during the study.
Metformin plus insulin
Giugliano et al (1993) used a double blind, placebo controlled design to investigate the
efficacy and safety of metformin in the treatment of obese people with Type 2 diabetes
poorly controlled on insulin (mean daily dose of 90 units for at least 3 months) after
secondary failure to maximum doses of sulphonylureas. With metformin therapy 1.7g daily
(n=27) for 6 months there was a significant reduction in HbA1c from 11.7 to 9.8% (p<0.05),
total cholesterol from 5.9 to 5.7 mmol/L (p<0.05), triglycerides from 2.9 to 2.6 mmol/L
(p<0.05) and an increase in HDL cholesterol from 1.03 to 1.16 mmol/L (p<0.05). Metformin
also significantly reduced mean insulin requirements from 90 to 68 units per day (p<0.05).
In summary:
Metformin, whether used as monotherapy or added to sulphonylurea or insulin therapy
may result in modest improvements in the lipid profile, independent of a reduction in
body weight
Factors which predict an improvement in lipids include the absolute reduction in HbA1c
(in the order of 1.5% or more) and higher doses of metformin
Sulphonylureas (Table 8)
Sulphonylurea monotherapy
The largest study of the effect of sulphonylurea therapy on lipids in Type 2 diabetes was the
Diadem Study which examined the response to a mean dose of 160mg daily of gliclazide
over a period of 2 years in 4,265 people from general practice (Cathelineau et al, 1997).
83
Accompanying a fall of HbA1c from 8.7 to 7.3% (p<0.001), mean total cholesterol fell from
5.9 to 5.7 mmol/L (p<0.001) and triglycerides levels fell from 1.7 to 1.5 mmol/L (p<0.001).
The mean BMI decreased from 28.54.7 to 27.94.5 kg/m2 (p=0.001). However it should be
noted that some subjects were treated with lipid lowering agents but the publication does not
report separately results in the treated and untreated subjects.
Rains et al (1988) randomised 35 people with Type 2 diabetes to metformin or gliblenclamide
(upto 15mg daily) treatment for 3 months (the effect of metformin is discussed in Metformin
section above). Glibenclamide reduced HbA1c by 2.0% (CI -2.80, -1.30%, p<0.0001). There
were no significant changes in total (from 6.0 to 5.7 mmol/L), LDL (4.4 to 4.1 mmol/L) or
HDL cholesterol (1.06 to 1.09 mmol/L) or in triglycerides (1.3 to 1.1 mmol/L). Body weight
was significantly increased from 78.9 to 81.6 kg with glibenclamide therapy (p<0.001).
A recently published 12-month randomised controlled trial (Derosa et al, 2003) compared
glimepiride 1 mg/d (n=62) with repaglinide 1 mg/d (n=62) in people with Type 2 diabetes
who were not on hypoglycaemic agents at study entry. The dose of both medications was
titrated over the first 8 weeks. At 12 months, both groups had a significant reduction in FPG
(p<0.01) and HbA1c (p<0.01). There were no significant changes in total, LDL and HDL
cholesterol and triglycerides in either groups during the study period. However, Lp(a) level
was significantly reduced from baseline in both the repaglinide group (15.47.2 to 11.16.8
mg/dl, p<0.05) and the glimepiride group (17.49.1 to 10.57.2 mg/dl, p<0.05).
Sulphonylurea combination therapy
Studies assessing lipid levels after adding metformin therapy to maximal dose sulphonylureas
have been described earlier in this Section. There are no studies reporting the effects of
adding sulphonylurea therapy to maximal doses of metformin, but there are studies on
addition of sulphonylurea therapy to insulin therapy (see section on Insulin combination
therapy).
In summary:
sulphonylurea therapy may result in a modest improvement in lipids with a reduction of
HbA1c of 1.5% or more despite the potential to increase body weight
84
Table 8: The effects of sulphonylurea therapy on lipids in people with Type 2 diabetes
Effects of lipids
Reference
Population studied
Cathelineau, 1997
(France)

Cohort study
2-yr follow-up
mean age 58.5 yrs
glipizide
Derosa, 2003
(Italy)
Hermann, 1994
(Sweden)
Rains, 1988
(UK)

12-mth follow-up RCT
mean age 54 yrs
glimepiride, n=62
repaglinide, n=62
6-mth RCT
age 34-74 yrs
metformin n=19
glyburide n=19
M+G(GM Low) n=46
MM+G n=12
GG+M n=11
M+G(GM High) n=17
3-mth RCT
age <70 yrs
metformin
glibenclamide
Drug
Dose
80
320mg/day
Mean total
Cholesterol
(mmol/L)
5.90
5.74
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Mean
Triglycerides
(mmol/L)
1.66
1.46
HbA1c
(%)
8.7
7.3
Body Weight
(kg)
Notes
BMI(kg/m2)
FBG (mmol/L)
28.5
27.9
10.11
7.61
FPG (mmol/L)
-
1mg/d
1mg/d
5.70
5.57
5.21
5.10
3.68
3.60
3.52
3.41
1.14
1.11
1.11
1.17
1.92
1.73
1.75
1.53
7.8
8.0
6.7
6.8
1-3g/d
3.5-14mg/d
5.38
5.66
5.46
4.84
5.25
6.05
5.03
5.78
5.36
4.96
5.48
5.40
3.66
3.93
3.67
3.04
3.49
4.04
3.38
4.04
3.58
3.31
3.73
3.71
0.81
0.89
0.91
0.81
0.84
0.76
0.77
0.92
0.95
0.81
0.89
0.80
2.02
2.01
1.97
2.60
2.05
2.40
1.95
2.10
1.89
1.85
1.92
2.10
6.9
6.7
6.8
7.8
7.8
8.4
5.8
5.3
5.6
5.4
5.7
6.2
78.6
82.6
80.2
84.6
76.0
83.2
78.8
86.2
81.0
88.1
76.3
83.3
1-3g/d
6.13
5.74
4.21
3.85
1.06
1.03
1.70
1.68
80.3
79.9
5-15mg/d
5.95
5.73
3.98
3.86
1.03
0.97
1.73
1.67
-1.53% (-2.23, 0.83)

-2.05% (-2.80,
-1.30)
78.9
81.6
85
9.1
8.8
6.9
6.7
Insulin (Table 9)
Insulin monotherapy
The effect of insulin monotherapy on lipid levels in Type 2 diabetes has mostly involved non
randomised studies in people with poor glycaemic control despite maximal oral
hypoglycaemic agent therapy.
A study by Rodier et al (1995) followed 18 people for 6 months on insulin therapy and
included a control group which remained on maximum doses of glibenclamide plus
metformin. Intensive therapy with pre-meal regular insulin plus 1 or 2 injections of long
acting insulin reduced HbA1c from 10.7 to 8.5% (p<0.05). On insulin, total cholesterol did not
change significantly, but HDL cholesterol rose from 0.98 to 1.37 mmol/L (p<0.01) and
triglycerides levels fell from 1.5 to 1.0 mmol/L (p<0.05 compared to oral agent group).
Wolffenbuttel et al (1996) studied 95 elderly people with diabetes poorly controlled on
maximal doses of oral agents. Treatment with pre-mixed injections of regular and
intermediate acting insulin twice daily for 6 months reduced HbA1c from 11.2 to 8.2%
(p<0.05). Total cholesterol fell from 7.0 to 6.2 mmol/L (p<0.05), HDL cholesterol rose from
1.09 to 1.21 mmol/L (p<0.05) and triglycerides levels fell from 2.4 to 1.6 mmol/L (p<0.05).
Two studies have followed larger numbers of people for 2 and 5 years. Kudlacek &
Schernthaner (1992) followed 102 non-obese subjects with secondary failure to oral therapy
during 5 years of insulin therapy. Almost all were treated with intermediate insulin twice
daily and additional regular insulin as required. HbA1c fell from 8.7% at baseline to 7.1% at 5
years (p<0.0001). Total cholesterol fell from 6.2 to 5.4 mmol/L (p<0.0002) and triglycerides
levels from 2.8 to 2.4 mmol/L (p<0.01). A significant weight gain associated with insulin
treatment was observed at 5 years, with BMI change from 24.5 to 28.5 kg/m2 (p<0.0001).
Another long-term study compared standard with intensive insulin therapy over 2 years. With
standard treatment in 78 subjects HbA1c did not change significantly from the baseline level
of 9.5% while in 75 subjects with intensive therapy HbA1c fell from 9.3% to about 2.1 %
lower than that of standard treatment (p<0.001). With intensive therapy total cholesterol fell
from 5.4 to 5.0 mmol/L (p=0.06) and LDL and HDL cholesterol did not change. With
intensive insulin therapy triglycerides levels fell from 2.3 to 1.7 mmol/L at 2 years (p=0.02),
but did not change with standard therapy (Emanuele et al, 1998).
Insulin combination therapy
Landstedt-Hallin et al (1995) compared the effect of bedtime NPH insulin (0.25 U/kg/day)
(Group N) to that of regular preprandial insulin (same dose split among three injections per
day) (Group D) both combined with glibenclamide 10.5 mg on lipids in 76 people with
secondary failure to sulphonylurea therapy over a 4 month period. Both insulin regimes
significantly improved FBG compared to baseline levels (p<0.0001). Both regimes equally
and significantly (p<0.0001) reduced HbA1c. Both insulin regimes equally and significantly
reduced plasma triglycerides (Group N: 2.9 to 1.9 mmol/L, p<0.001; Group D: 2.4 to 1.8
mmol/L, p<0.01) and total cholesterol (Group N: 6.0 to 5.5 mmol/L, p<0.0001; Group D: 6.0
to 5.7 mmol/L, p<0.01). There was a slight but significant increase in HDL cholesterol from
1.1 to 1.2 mmol/L (p<0.05) with bedtime insulin but no change with preprandial insulin.
However, weight gain was more pronounced in subjects given regular preprandial insulin
during the day (3.42.1 kg v 1.91.9 kg, p<0.001).
In summary:
Insulin therapy in people with Type 2 diabetes who have failed oral hypoglycaemic
therapy has a modestly favourable effect on lipids
86
Table 9: Effects of insulin on lipids in people with Type 2 diabetes

Effects on Lipids
Reference
Emanuele, 1998
(US)
Kudlacek, 1992
(Austria)
Landstedt-Hallin,
1995
(Sweden)
Population studied
n=153 men Type 2 diabetes
age 40-69 yrs;
2-yr follow-up;
intensive insulin (n=75)
standard insulin (n=78)
5-yr follow-up
Cohort study
mean age 64 yrs
insulin therapy
16-wk RCT
age 40-80 yrs;
glibenclamide:
+ bedtime NPH insulin
+ 3 times regular insulin
Drug
dose
>2 doses
1 dose
Mean total
Cholesterol
(mmol/L)
Mean LDL
Cholesterol
(mmol/L)
Mean HDL
Cholesterol
(mmol/L)
Before
After
Before
After
Before
After
5.35
5.35
5.04
5.04*
3.36
3.44
3.16
1.09
1.11
1.03
1.01**
HbA1c
(%)
Mean
Triglycerides
(mmol/L)
Before
After
2.25
1.74*
unchanged
Before
9.3
9.5
After
Body Weight
(kg)
Before
After
<7.3****
similar
BMI (kg/m2)
-
6.2
5.4
6.0
6.0
5.5
5.7
10.5 mg
1.1
1.2
1.2
1.3
2.8
2.4
8.7
7.1
24.5
28.5
2.9
2.4
1.9
1.8
9.2
9.2
7.5
7.1
78.4
77.8
80.3
81.2
Rodier, 1995
(France)
Wolffenbuttel, 1996
(Netherland)

6-mth RCT
age 42-75 yrs
max.OHA, n=9
insulin n=9
6-mth follow-up
Cohort study
mean age 68 yrs
insulin(30/70) n=34
glib+ bedtime NPH n=28
glib+ breakfast NPH n=33
met. 1.7g/d &

glib. 15mg/d
5.28
5.02
5.70
5.65
1.06
0.98
1.06
1.37*
1.30
1.52
2.14
0.97
9.3
10.7
9.9
8.5
No sig. change
3.9kg
7.0
6.4
6.1
6.2*
6.1
5.8
1.09
1.02
1.05
1.21
1.06
1.10
2.36
2.00
2.21
1.62
1.70
1.91
11.2
10.5
11.1
8.2
8.1
8.5
67.4
76.1
69.2
glib. 15mg/d
87
71.4
80.5
72.6
Acarbose (Table 10)

Acarbose, an alpha glucosidase inhibitor, is commonly used in Europe for improving
glycaemic control in people with Type 2 diabetes but is not as widely used in Australia.
Hanefeld et al (1991) in a randomised double-blind placebo controlled trial tested the effect
of 3100mg/day of acarbose on glycaemic control and lipids in 94 people with Type 2
diabetes inadequately controlled by diet alone (FBG 7.8 mmol/L or a postprandial blood
glucose >10 mmol/L). Acarbose significantly improved glycaemic control compared with
placebo (HbA1c: 9.3 to 8.7%, p<0.01 v 9.4 to 9.3%, p=NS; FBG: 9.8 to 8.4 mmol/L v 10.2 to
9.6 mmol/L, p=0.007 for acarbose v placebo). Despite the glycaemic improvement, arcabose
had no effect on total cholesterol or fasting triglycerides. The effects on HDL, VLDL, and
LDL levels were not studied. Acarbose had no effect on body weight but caused significant
gastrointestinal side effects.
Coniff et al (1995a) tested the efficacy and safety of 3 different doses of acarbose (1003,
2003 and 3003mg/day) in a placebo controlled trial of 229 people with Type 2 diabetes
treated with diet alone. After 16 weeks of treatment there was a significant reduction in
HbA1c with all doses (relative to placebo: -0.78%, -0.73% and -1.10%, respectively, all
p<0.05). Acarbose did not affect weight in any of the 3 doses and had no significant effect on
cholesterol and triglycerides levels. Flatulence, diarrhoea and abdominal pain were
significantly higher in the acarbose treated patients compared with placebo at all 3 doses.
In a double blind-randomised control study of 89 poorly controlled people with Type 2
diabetes, Lam et al (1998) compared the effects of acarbose 50mg three times a day for 4
weeks and 100mg three times a day for another 20 weeks. Compared with placebo, acarbose
improved HbA1c (-0.5% v +0.1%, p=0.038) and was accompanied by a significant reduction
in weight (-0.54 kg v +0.42 kg, p<0.05). However there was no improvement in plasma lipid
profiles (total and HDL cholesterol and triglycerides). Acarbose caused significant
gastrointestinal side effects (p<0.05).
Acarbose was found to be superior to placebo in reducing HbA1c (-0.54 v +0.04%, p<0.05)
and 2h postprandial glucose (-3.2 v -0.8 mmol/L, p<0.05) in 67 poorly controlled people with
Type 2 diabetes (FBG >7.8 mmol/L). However, acarbose caused no changes in total
cholesterol, LDL cholesterol, HDL cholesterol or triglycerides (Coniff et al, 1995b).
In contrast Hoffmann & Spengler (1997) found a significant reduction in LDL cholesterol by
21.8% and an increase in HDL cholesterol by 16.2% in 94 people treated with acarbose 300
mg per day compared with placebo (p=0.007 and p=0.016, respectively). A pronounced
reduction in the LDL/HDL ratio of 26.7% was observed with acarbose therapy (p=0.013).
Although triglycerides fell by 26.8% and total cholesterol fell by 14.1%, the changes were
not statistically significant. After 24 weeks of treatment, HbA1c was 8.5% in the acarbose
group compared with 9.8% in the placebo group (p<0.0001).
In summary:
Acarbose therapy in people with Type 2 diabetes has little effect on lipid levels
This may reflect the more modest improvement in diabetes control achieved with
acarbose compared with other hypoglycaemic agents
88
Thiazolidinedione (Table 11)

Thiazolidinediones, a new class of insulin sensitizing agents, have recently become available
for use in Australia.
Rosenblatt et al (2001) randomised 197 people with Type 2 diabetes (mean age 54.4 years) in
whom all hypoglycaemic agents were discontinued for 6 weeks before study entry to receive
either pioglitazone 30mg/d or placebo for 16 weeks. At baseline, there were no differences
between the 2 groups in glycaemic control, lipid profiles and body weight. After 16 weeks of
treatment, the pioglitazone group demonstrated a significant decrease in HbA1c compared
with the placebo group (-0.600.165 v +0.760.171%, p=0.0001). Compared with placebo,
pioglitazone therapy resulted in a significant reduction in triglycerides (-14.8% v +1.8%,
p=0.02) and an increase in HDL cholesterol (+15.8% v +3.2%, p=0.007). The changes in
total and LDL cholesterol did not differ between the groups. The mean change in body
weight from baseline was +1.35 kg in the pioglitazone group and -1.87 kg in the placebo
group (p<0.0001).
In a multicentre, randomised double-blind, placebo control study, Freed et al (2002)
compared the effects of rosiglitazone alone and in combination with atorvastatin on
glycaemic control and lipid metabolism. 243 people with Type 2 diabetes were treated with
rosiglitazone 4mg twice a day in an 8-week open-label period and then were randomised to a
16-week period to continued rosiglitazone plus placebo, or atorvastatin 10mg/day, or
atorvastatin 20mg/day. Eight weeks of rosiglitazone alone treatment resulted in a 5.8%
increase in HDL cholesterol (from 1.01 to 1.06mmol/L) and a 9.0% in LDL cholesterol (from
3.13 to 3.44mmol/L). Baseline HbA1c was similar (7.81.5, 7.91.2%) but after 8 weeks, a
total of 75% of people achieved HbA1c of <8.0% and 38% achieved HbA1c of <7.0% in the
rosiglitazone group.
A total of 297 people with Type 2 diabetes (mean age 58.4 years) were randomised to receive
pioglitazone 30mg/day, or 45mg/day or placebo for 16 weeks in a multicentre study (Herz et
al, 2003). The reduction in HbA1c was 0.8% and 0.9% with pioglitazone (both p<0.001), and
0.2% with placebo (p=0.025), the difference between pioglitazone and placebo being
significant (p<0.001). HDL cholesterol increased by 16% with pioglitazone 30mg/day
(p<0.001) and 20% with pioglitazone 45mg/day (p<0.001), compared with a 9% increase
with placebo (pioglitazone v placebo, p<0.001). For triglycerides, a fall of 16% with
pioglitazone 45mg/day was significantly greater than placebo (p=0.007), whereas a 5%
reduction with pioglitazone 30mg/day did not reach significance. Total cholesterol was
reduced by 4% (p<0.05) and LDL cholesterol by 7% (p<0.05) with pioglitazone 30mg/day,
but not with pioglitazone 45mg/day. Body weight increased slightly in people receiving
pioglitazone (0.35kg, 0.82kg, respectively) compared with a reduction of 1.52kg in people
receiving placebo (p<0.001).
In summary:
Thiazolidinediones have a modestly favourable dose dependent effect in increasing HDL
cholesterol and lowering triglycerides despite an increase in weight
89
Table 10: Effects of acarbose therapy on lipids in people with Type 2 diabetes
Effects on Lipids
Reference
Population studied
Drug
dose
Mean total
cholesterol
(mmol/L)
Before
Coniff, 1995a
(US)
Coniff, 1995b
(US)
Hanefeld,
1991
(Germany)
Hoffmann,
1997
(Germany)
Lam, 1998
(Hong Kong)

22-wk RCT
aged over 30 yrs
acarbose, n=58
acarbose, n=54
acarbose, n=53
placebo, n=64
36-wk RCT
mean age 56 yrs
acarbose, n=67
tolbutamide, n=66
acar+tolb, n=60
placebo, n=62
24-wk RCT
age 43-70 yrs
acarbose, n=47
placebo, n=47
6-mth RCT
age 35-70 yrs
metformin, n=31
acarbose, n=31
placebo, n=32
24-wk RCT
age 35-70 yrs
acarbose n=45
placebo n=44
After
Mean LDL
Cholesterol
(mmol/L)
Before
After
Mean HDL
Cholesterol
(mmol/L)
Before
After
HbA1c
(%)
Mean
Triglycerides
(mmol/L)
Before
After
Before
After
Body Weight
(kg)
Before
Other Factors
After
Lp(a) (mg/dl)
300mg/d
600mg/d
900mg/d
5.60
5.44
5.45
5.38
5.69
5.45
5.42
5.32
2.31
2.14
2.60
2.27
2.42
2.04
2.74
2.58
8.69
8.96
9.54
8.67
8.24
8.56
8.77
9.00
85.9
87.9
84.5
91.3
90.93
87.51
83.80
90.85
19.9
11.8
36.4
25.6
16.75
11.14
35.12
23.52
600mg/d
tolb 0.751.5g/d
5.98
5.70
5.98
5.98
5.78
5.75
6.11
5.85
3.94
3.83
3.73
4.04
3.86
3.73
3.94
3.74
1.01
1.03
1.01
1.06
1.09
1.11
1.14
1.11
2.81
2.24
2.49
2.73
2.33
2.21
2.25
2.41
6.88
6.95
6.73
7.10
6.34
6.02
5.41***
7.14
5.7
5.8
5.8
6.0
2.2
2.1
1.8
1.9
9.30
9.40
8.65
9.32
300mg/d
76.2
78.2
74.7
76.7
LDL/HDL ratio
1.7g/d
300mg/d
5.74
6.30
5.90
5.83
5.41
5.83
300mg/d
-0.09
-0.05
3.59
4.08
3.62
3.64
3.19
3.80
1.61
1.42
1.54
1.61
1.65
1.39
1.41
1.68
1.60
1.28
1.23
1.46
9.7
9.6
9.4
8.7
8.5
9.8
79.0
73.9
74.9
78.5
73.1
75.1
-0.06
-0.06
+0.16
-0.22
9.5
9.4
8.8
9.4
-0.54
+0.42
2.56
3.15
2.63
2.56
2.31
3.01
90
Table 11 Effects of thiazolidinedione therapy on lipids in people with Type 2 diabetes

Effects on Lipids
Reference
Population studied
Drug
dose
Mean total
cholesterol
(mmol/L)
Before
Freed, 2002
(US)
Herz, 2003
(Canada,
Spain)
Rosenblatt,
2001
(US)

24-wk RCT
aged 35-80 yrs
rosiglitazone, n=237, 8 wk
rosiglitazone+atorvastatin,
n=82, 16 wk
rosiglitazone+atorvastatin,
n=79, 16 wk
rosiglitazone+placebo,
n=76, 16 wk
16-wk RCT
mean age 58.4 yrs
pioglitazone, n=99
pioglitazone, n=99
placebo, n=99
16-wk RCT
mean age 54.4 yrs
pioglitazone, n=101
placebo, n=96
Mean LDL
Cholesterol
(mmol/L)
After
Before
Mean HDL
Cholesterol
(mmol/L)
After
Before
After
Mean
Triglycerides
(mmol/L)
Before
After
HbA1c
(%)
Before
After
Body Weight
(kg)
Before
Other Factors
After
FPG (mmol/L)
8mg/d
10mg/d
3.34
9.0%
2.31
1.04
5.8%
1.06
1.86
2.0%
1.51
7.9
7.2
20mg/d
3.44
2.12
1.04
1.09
1.81
1.32
7.6
3.52
3.55
1.14
1.09
1.75
1.79
4%
7%
1.14
1.13
16%
20%
1.91
1.99
5%
16%
1.20
9%
30mg/d
45mg/d
7.1
7.1
8.5
7.5
7.8
7.0
8.7
7.1
7.5
7.6
6.7****
6.7****/
7.5
7.3*
1.72
86.6
84.1
0.35kg
0.82kg
86.3
1.58kg
****/
1.4-1.7kg
8.7
FPG (mmol/L)
30mg/d
5.75
5.72
no
sig.
change
3.33
3.46
no
sig.
change
1.03
1.19***
4.02
3.43***
10.65
10.05
1.35****
2.76
3.16
3.22
10.40
11.16
1.87
0.43
1.02
1.05
91
Summary - Improved blood glucose control and lipids
Metformin, whether used as monotherapy or added to sulphonylurea or insulin therapy

may result in modest improvements in lipids, independent of a reduction in body weight
Sulphonylurea therapy results in a modest improvement in lipid profile, despite the

potential to increase body weight
Insulin therapy in people with Type 2 diabetes who have failed oral hypoglycaemic
therapy has a modestly favourable effect on lipids
Acarbose therapy in people who have failed dietary therapy or maximum sulphonylurea
therapy has little effect on lipid levels which may reflect the more modest improvement in
diabetes control achieved with acarbose compared with other hypoglycaemic agents
Thiazolidinediones have a modestly favourable effect on increasing HDL cholesterol and

lowering triglycerides despite an increase in weight
A reduction in HbA1c of approximately 1.5% is required to have a beneficial effect on

lipids
92

Improved blood glucose control and lipids
Author
Evidence
level of Evidence
Level
Study Type
Quality
Rating
Magnitude
Rating
Relevance
Rating
Cathelineau G (1997)
III-2
Cohort
Medium
HighC+ T+
High
(Adults France)
Coniff RF (1995a)
II
RCT
High
High
High
(Adults US)
Coniff RF (1995b)
II
RCT
High
High
High
(Adults US)
Daileyl GE (2002)
C+L+T+
High
III-2
Cohort
High
High
(Adults US)
DeFronzo RA (1995)
High
II
RCT
High
High C+L+T+
(Adults US)
Derosa G (2003
II
RCT
High
Low
High
(Adults Italy)
Emanuele N (1998)
High
II
RCT
Medium
Medium C+T+
(Adult men - US)
Fanghanel G (1996)
Low
II
RCT
High
High C+L+ H+ T+
(Adults Mexico)
Freed MI (2002)
High
II
RCT
High
High L+ H+ T+
(Adults US)
Giugliano D (1993)
High
II
RCT
High
High C+ H+ T+
(Adults Italy)
Hanefeld M (1991)
High
II
RCT
High
High T+
(Adults Germany)
Hermann LS (1994)
High
II
RCT
High
High C+ L+ H+T+
(Adults Sweden)
Herz M (2003)
High
(Adults Canada,
II
RCT
High
High H+T+
Spain)
Hoffmann J 1997
High
II
RCT
High
High H+ L+
(Adults Germany)
Kudlacek S (1992)
High
III-2
Cohort
Medium
High C+ T+
(Adults Austria)
Lam KSL (1998)
II
RCT
High
High
Medium
(Adults China)
Landstedt-Hallin L
II
RCT
High
High C+ H+ T+
High
(1995)
(Adults Sweden)
Rains SGH (1988)
High
II
RCT
Medium
HighC+ L+
(Adults UK)
Rodier M (1995)
High
II
RCT
High
High H+ T+
(Adults France)
Rosenblatt S (2001)
High
II
RCT
High
High H+ T+
(Adults US)
Wolffenbuttel BHR
III-2
Cohort
Medium
High C+ H+ T+
High
(1996)
(Adults Netherland)
+
the lipids improved as the glycaemic control improved; High = clinically important & statistically significant; Medium =
small clinical importance & statistically significant; Low = no statistically significant effect.
C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T= triglycerides; V= VLDL-Cholesterol.
93
Section 4: Lipids
Issue
What are the effects on lipids of treatment with lipid-modifying agents and hormone
replacement therapy in Type 2 diabetes?
Recommendations
Statins should be used to lower LDL cholesterol when triglycerides are normal or only
slightly elevated. For severe hypercholesterolaemia, a bile acid binding resin or low dose
nicotinic acid may be added.
Fibrates should be used as first line therapy in people with predominantly elevated
triglycerides and low HDL cholesterol with normal to slightly elevated LDL cholesterol
levels. If treatment with a fibrate is not tolerated or if additional triglycerides lowering
effect is required, fish oil can be used but the effect on diabetes control should be
monitored.
Treatment with a statin and fibrate should be considered in people with moderate to marked
elevation of both LDL cholesterol and triglycerides. Because of the increased risk of
myositis, the person should be fully informed and carefully monitored.
Evidence Statements
Fibric acid derivatives (fibrates) are effective in reducing triglycerides and increasing
HDL cholesterol in people with Type 2 diabetes
Evidence level II
Statins are effective in the reducing total and LDL cholesterol in people with Type 2
diabetes
Evidence level II
Nicotinic acid (niacin) is effective in improving lipids in people with Type 2 diabetes
but may have a small adverse effect on blood glucose control
Evidence level II
Bile acid sequestrants (resins) may be effective in lowering total and LDL cholesterol in
people with Type 2 diabetes but data are limited
Evidence level II
Omega 3 fatty acids (-3) are effective in lowering triglycerides in people with Type 2
diabetes but may cause a dose dependent deterioration in blod glucose control
Evidence level II
94
Oestrogen replacement therapy may have a modest beneficial effect on lipids in

postmenopausal women with Type 2 diabetes
Evidence level II
Some combination therapies are effective in reducing lipids in people with Type 2
diabetes but data are limited
95
Background - Effects of lipid-modifying agents and hormone

replacement therapy on lipids in Type 2 diabetes
In people with Type 2 diabetes, there is a cluster of metabolic disturbances that include lipid
abnormalities. At the basis of these abnormalities are insulin resistance and central obesity,
which are associated with abnormal concentrations of several classes of lipoproteins
including high levels of very low density lipoprotein (VLDL) particles and low levels of high
density lipoprotein (HDL) particles. Furthermore, there are often changes in the composition
of lipoproteins. For example, there is a preponderance of small, dense low density lipoprotein
(LDL) particles which are thought to have increased atherogenicity (Barakat et al, 1990)
Lipid abnormalities in Type 2 diabetes are characterised by raised fasting triglycerides and
lowered HDL cholesterol. These two factors are thought to contribute significantly to the
increased risk of coronary heart disease in people with Type 2 diabetes (Laakso et al, 1993;
Laakso, 1996). In addition, people with diabetes have the same prevalence of lipid
abnormalities as the non diabetic population eg increased total cholesterol and increased LDL
cholesterol.
In diabetes, these lipid abnormalities are often exacerbated by poor blood glucose control.
The management of lipid abnormalities in people with Type 2 diabetes is to attempt to
improve blood glucose control with diet, exercise and hypoglycaemic agents (see Sections 2
and 3). However, even with good diabetes control lipid abnormalities often persists.
Because of the specific metabolic abnormalities found in Type 2 diabetes, the results of lipidlowering medication studies in people without diabetes may not be directly applicable to
people with diabetes with lipid abnormalities. The review in this Section focuses on the lipidlowering effects of commonly used therapeutic agents (statins, fibrates, niacin, resins,
hormone replacement therapy (HRT) and -3 fatty acids) from well-designed, randomised
controlled trials in people with Type 2 diabetes (Table 13). There are a number of reviews on
the effects of lipid-lowering agents in the treatment of lipid abnormalities in Type 2 diabetes
(Garg & Grundy, 1997; Haffner, 1998, Colagiuri & Best, 2002).
96
Table 13: Effects of lipid-modifying agents on lipids and lipoproteins in people with Type 2 diabetes
Lipid Modifying Agents
Dose
Fibrates (see Table 14)
Effects on Lipids and Lipoproteins (%)

TCHOL
LDL
HDL
TG
APO-A
APO-B
Glycaemic
control
Gemfibrozil
1200mg/day
6.6-11%
5.2-10%
6.4 -14%
28-50%
2-21%
4.1%
No effect
Bezafibrate
400-600mg/day
8.6-14.2%
6-10.8%
11.4-20%
33-51%
5%-9.6%
30-5%
No effect
Fenofibrate
200mg/day
10-11%
7-11%
6-7%
24-28%
No effect
Simvastatin
20-40 mg/day
24-30%
34-42%
4-9%
9-15%
No effect
Pravastatin
40 mg/day
19-21.2%
27-31.3%
4-8%
6.3-16%
No effect
Lovastatin
20-40 mg/day
18-20%
25-26%
6-14%
15%-2%
No effect
Fluvastatin
40 mg/day
20%
25%
5%
17%
No effect
Atorvastatin
10 mg/day
29-32%
18-43.7%
4.2-16.7%
11-29.7%
No effect
1.53 g/day
4-8%
7-8%
13-29%
15-36%
Raises HbA1c, FBG &

plasma uric acid
82 g/day
18%
28%
5%
7%
FBG 13%
1.8-3.0 g/day
5.9 - 7.9%
1.6% - 5%
1-8.8%
3.4-31%
Mean rise in blood

glucose 0.26 mmol/L
and in HbA1c 0.15%
Statins (see Table 15)
Second-line agents
Nicotinic acid
(see Table 16)
Bile acid sequestrants
(cholestyramine)
-3 fatty acids (fish oil)
(see Table 17)
T Chol (total cholesterol), LDL (low density lipoprotein cholesterol), HDL (high density lipoprotein cholesterol), TG (total plasma triglycerides), Apo-A (Apo lipoprotein-A), Apo-B (Apo lipoprotein B), HbA1c (glycated
haemoglobin), FBG (fasting blood glucose).
() decrease, () increase
97
Evidence - Effects of lipid-modifying agents and hormone replacement

therapy on lipids in Type 2 diabetes
Many studies were identified through the literature search but only studies which included
approximately 50 or more subjects are reviewed in this Section, unless the only relevant data
available were from smaller studies.
Fibric acid derivatives (fibrates) are effective in reducing triglycerides and increasing
HDL cholesterol in people with Type 2 diabetes
Fibrates stimulate the peroxisome proliferator activated receptor-, changing the expression
of a number of enzymes that regulate lipid metabolism including lipoprotein lipase. Fibrates
decrease hepatic production of VLDL particles and enhance their clearance.
The only fibrate currently available in Australia is gemfibrozil, but trials using fenofibrate
and bezafibrate are also reviewed because these other fibrates are widely used throughout the
world (see Table 14).
Gemfibrozil in Type 2 diabetes
There have been a number of randomised placebo controlled trials testing the efficacy and
safety of gemfibrozil in people with diabetes.
The largest of these included 214 people with diabetes randomised to gemfibrozil 600mg
twice daily and 109 to placebo for 20 weeks (Vinik et al, 1993). Triglycerides fell by 28%
from 3.0 to 2.0mmol/L with gemfibrozil, while triglycerides rose by 8% from 3.0 to 3.1
mmol/L in the placebo group (p<0.0001 gemfibrozil v placebo). HDL cholesterol increased
significantly and peaked at 12 weeks by 12.2% in the gemfibrozil group compared with little
change in the placebo group (p<0.001). The reduction in mean total cholesterol was
significant in the gemfibrozil group compared with an increase in the placebo group (p<0.05).
LDL cholesterol rose in both groups (p<0.05) but there was no difference between the
groups.
Frick et al (1987) recruited 4,081 middle-age men with primary dyslipidaemia (non-HDL
cholesterol 5.2mmol/L) in the Helsinki Heart Study. Over the mean follow-up of 5 years,
treatment with gemfibrozil 1200mg/day significantly lowered triglycerides by 43% (from
1.98 to 1.30mmol/L) and increased HDL cholesterol by 10% (from 1.22 to 1.32mmol/L).
Total and LDL cholesterol were also reduced by 11% (6.99 to 6.39mmol/L) and 10% (4.90 to
4.49mmol/L), respectively. There were only minimal changes in lipid levels in the placebo
group. Koskinen et al (1992) reported the lipid results of 135 people with Type 2 diabetes in
the Helsinki Heart Study. Triglycerides level fell by 27% from a baseline of 2.4mmol/L in the
59 people on gemfibrozil and fell by 5% from a baseline of 2.9mmol/L in 76 people on
placebo (no p value reported). HDL cholesterol rose by 6% from a baseline of 1.18mmol/L in
the gemfibrozil group compared with a 1% increase in the placebo group. Total and LDL
cholesterol were reduced to 6.48 mmol/L and 4.66 in the gemfibrozil group, to 7.10 mmol/L
and 4.91 mmol/L, respectively in the placebo group.
Avogaro et al (1999) randomised people with Type 2 diabetes and plasma triglycerides 2.0
mmol/L to gemfibrozil treatment (n=110) or to placebo (n=107). During the 20-week study
period, gemfibrozil significantly decreased plasma triglycerides from 3.6 to 2.4mmol/L
(p<0.001) compared with an increase from 3.6 to 4.3mmo/L (p<0.05) in the placebo group.
HDL cholesterol increased significantly with both gemfibrozil and placebo (both p<0.05). No
98
significant changes in total and LDL cholesterol were observed. The mean HbA1c values were
similar in both groups (7.7 to 8.1% in the gemfibrozil group; 7.7 to 7.7% in the placebo
group, p=0.09 between groups).
In a study of 96 people with Type 2 diabetes and dyslipidaemia (defined as LDL cholesterol
>4.0mmol/L and triglycerides 4.5mmol/L) (Tikkanen et al, 1998), 49 were randomly
assigned to take gemfibrozil (600 mg twice a day) and 47 to take simvastatin (10mg/day for
the first 8 weeks, 20mg/day for the next 8 weeks and 40mg/day for the third 8-week period).
After 24 weeks of gemfibrozil treatment, triglycerides fell by 45% from a baseline of
2.5mmol/L (p<0.01), ranging from about 40% in people with hypercholesterolaemia and
initial triglycerides <2.3 mmol/L to 50% or more in people with combined hyperlipidaemia.
HDL cholesterol increased by 14% from 1.19mmol/L at the end of study (p<0.01).
Gemfibrozil was also effective in reducing total cholesterol by 10% from 7.0mmol/L
(p<0.01) and LDL cholesterol by 6.5% from 4.6mmol/L (p<0.01). In contrast, simvastatin
resulted in a reduction in total cholesterol by 30% from 6.9mmol/L (p<0.01) and LDL
cholesterol by 42% from 4.5 mmol/L(p<0.01). Triglycerides were also reduced by 15% from
2.5mmol/L with simvastatin (p<0.01), but HDL cholesterol did not change significantly
(+4%).
In a 16-week randomised controlled trial of 136 people with Type 2 diabetes (Schweitzer et
al, 2002), treatment with gemfibrozil 1200mg/d (n=66) resulted in a greater reduction in
triglycerides levels compared with treatment with pravastatin 40mg/d (n=70) (-29.6% v 6.3%, p<0.001). In contrast, total and LDL cholesterol were significantly lower with
pravastatin than with gemfibrozil (-21.2% v -6.6%, p<0.001; -31.3% v -5.2%, p<0.001,
respectively). The increment in HDL cholesterol was 6.4% in the pravastatin group and 5.8%
in the gemfibrozil group. During the study period, HbA1c did not change significantly in
either group (7.5 to 7.8% with pravastatin; 7.6 to 8.1% with gemfibrozil, p=0.31).
An increased level of LDL cholesterol with gemfibrozil treatment in some studies could have
an adverse effect in people with Type 2 diabetes who are already at increased risk of
macrovascular disease. However, gemfibrozil treatment has been shown to increase LDL
particle size, potentially rendering these particles less atherogenic (Lahdenpera et al, 1993;
O'Neal et al, 1998). Lahdenpera et al (1993) reported that LDL particle diameter increased
from 2447 to 2515 (p<0.05) whereas it remained unchanged in the placebo group.
ONeal et al (1998) found no significant difference in LDL cholesterol level between
gemfibrozil (from 3.8 to 4.3 mmol/L) and placebo (from 3.5 to 3.9 mmol/L), but a significant
increase in LDL particle diameter was observed in the gemfibrozil group (p<0.02).
Gemfibrozil has also been found to have no significant adverse effects on glycaemic control.
Change in HbA1c was similar in the gemfibrozil group (from 6.8 to 7.2%) and the placebo
group (from 6.5 to 6.9%), with no difference in the percentage changes, 8.6 and 7.2,
respectively (Vinik et al, 1993). Similarly, Vuorinen-Markkola et al (1993) reported HbA1c
increased slightly in both gemfibrozil (8.20.4%, p<0.05) and placebo group (8.00.3%,
p=NS) during 12 weeks treatment period. There were no differences in mean 24h blood
glucose concentration in the two groups (10.40.6 v 11.00.7 mmol/L; 10.00.8 v 9.80.7
mmol/L, respectively).
In summary:
The most consistent effect of gemfibrozil is a significant reduction in triglycerides levels
(approx 30-50%) and an increase in HDL cholesterol (approx 10%).
99
Table 14: Effects of fibrates on lipids in Type 2 diabetes

Effects on Lipids
Reference
Avogaro, 1999
(Italy)
DAIS
investigators,
2001
(Canada, Finland,
Sweden, France)
Elkeles, 1998
(UK)
SENDCAPS
Kirchgassler,
1998
(Germany)
Population
studied
20-wk follow-up RCT
gemfibrozil n=110
placebo n=107
3-yr follow-up RCT
Fenofibrate n=207
Placebo n=211
3-yr follow-up RCT
age: 35-65 yrs
Bezafibrate n=64
Placebo n=64
12-wk cohort study
Fenofibrate
Drug dose
1200mg/d
200mg/d
400mg/d
200mg/d
Inclusion
criteria
(mmol/)
TG 2.0
T-CHO/HDL
4.0
LDL 3.5-4.5
TG 5.2
TG < 8.0
T-CHO
< 8.0
T-CHO/HDL
< 7.2
TG 2.8
LDL 4.1
Total
Cholesterol
(mmol/L)
LDL
Cholesterol
(mmol/L)
Before
After
Before
5.96
5.91
6.20
5.91
5.56
5.58
5.0
5.63
3.38
3.43
5.77
5.60
5.29
5.80
7.8
6.4
After
HDL
Cholesterol
(mmol/L)
VLDL
Cholesterol
(mmol/L)
Before
After
0.85
0.80
1.04
*
0.91
3.14
3.41
1.01
1.05
1.09
1.07
3.66
3.98
3.31
3.94
1.02
0.94
1.04
0.92
5.2
4.0
1.1
1.36
no sig.change
no sig.change
100
After
-

5-yr follow-up RCT
non HDLGemfibrozil (n=59)
1200mg/d
CHO >5.2
7.54
6.48
5.18
4.66
1.18
1.26
Placebo (n=76)
7.54
7.10
5.23
4.91
1.18
1.19
mean age 61 yrs
Ogawa, 2000
16-wk follow-up
(Japan)
Bezafibrate n=174
400mg/d
6.20
5.43
1.20
1.44
Control n=168
6.57
1.21
6.23
1.21
Before/ After comparison* p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001
Koskinen, (1992)
(Finland)
Before
Total
Triglycerides
(mmol/L)
Apo A1
(mg/dl)
Before
After
3.57
3.59
2.42
*
4.29
2.59
2.42
1.84
2.47
2.24
2.09
1.44
2.00
141
128
134
122
131
130
139
155
4.6
3.22
2.42
2.90
1.79
2.75
2.98
3.09
1.47
3.02
Before
Apo B
(mg/dl)
After
Before
After
-
Table 14: Effects of fibrates on lipids in Type 2 diabetes

Effects on Lipids
Reference
Rovellini, 1992
(Italy)
Rustemeijer,
2000
(The
Netherlands)
Schweitzer, 2002
(US)
Tikkanen, 1998
(Finland)
Vinik, 1993
(US)
Population
studied
Drug dose

8-mth follow-up RCT
mean age 65yrs
Bezafibrate
Control, no treatment
aged 40-80 yrs
12-wk follow-up
RCT, crossover
Pravastatin, n=22
Bezafibrate, n=23
mean age 57 yrs RCT
16-wk follow-up
Pravastatin, n=70
Gemfibrozil, n=66
age 35-70yr RCT
24-wk follow-up
Gemfibrozil n=49,
Simvastatin n=47
1200 mg/d
10 40 mg/d

20-wk follow-up RCT
age 36-84 yrs.
Gemfibrozil n=214
1200mg/d
Inclusion
criteria
(mmol/)
Total
Cholesterol
(mmol/L)
LDL
Cholesterol
(mmol/L)
HDL
Cholesterol
(mmol/L)
VLDL
Cholesterol
(mmol/L)
Total
Triglycerides
(mmol/L)
Apo A1
(mg/dl)
Apo B
(mg/dl)
Before
After
Before
After
Before
After
Before
After
Before
After
Before
After
Before
After
7.12
6.76
6.11****
6.73
1.14
1.14
1.27
1.11
3.22
2.85
1.73****
2.89
mmol/l
mmol/l
400mg/d
40mg/d
400mg/d
40mg/d
1200mg/d
T-CHO
5.0-8.0
TG
1.8-5.0
LDL
3.4 to 5.2
TG 4.5
LDL>4.0
TG <4.5
TG
1.7-5.6
6.6
6.7
5.06
5.98
4.03
4.12
2.85
3.87
1.15
1.15
1.25
1.33
1.41
1.43
0.99
0.86
2.95
2.87
2.48
1.79
1.37
1.35
1.43
1.48
6.26
6.14
4.93
5.73
4.10
3.96
2.82
3.75
1.23
1.20
1.30
1.28
0.58
0.71
0.55
0.52
2.06
2.22
1.93
1.56
108.2
103
123.3
126.8
123.2
119.2
98.2
112.7
4.57
4.53
4.27
**
2.65
1.19
1.26
1.35**
1.31**
6.3
**
4.84
**
7.00
6.94
2.54
2.46
1.39
2.08
6.06
5.76*
3.76
3.78
0.96
1.09
**
***
**
3.00
2.02
3.03
3.08
*
5.87
0.96
3.68
Placebo n=109
3.66
6.06
0.97
101
Bezafibrate in Type 2 diabetes

Randomised controlled trials with the fibric acid derivative bezafibrate (not presently
approved for use in Australia) have shown similar effects to gemfibrozil in reducing
triglycerides and increasing HDL cholesterol, but a greater ability to reduce LDL cholesterol
in people with Type 2 diabetes.
The largest and longest study was the St Marys, Ealing, Northwick Park Diabetes
Cardiovascular Disease Prevention (SENDCAP) study (Elkeles et al, 1998) in which lipid
measurements were made in 128 people with Type 2 diabetes before and after 3 years of
treatment with bezafibrate 400mg daily (n=64) or placebo (n=64). Median triglyceride levels
fell by 33% from 2.2 to 1.4mmol/L on bezafibrate and by 5% from 2.1 to 2.0mmol/L on
placebo (p=0.001 for bezafibrate compared with placebo). Median HDL cholesterol rose by
6% (1.02 to 1.04mmol/L) with bezafibrate and fell by 2% (0.94 to 0.92mmol/L) with placebo
(p=0.02). Total cholesterol was lower after 3 years on bezafibrate compared with placebo (5.8
to 5.3 v 5.6 to 5.8mmol/L, p=0.004), but the change in LDL cholesterol between the groups
did not reach significance (3.7 to 3.3 v 4.0 to 3.9mmol/L, p=0.06).
Another study followed 45 people with Type 2 diabetes on bezafibrate 400mg daily for 8
months and compared the effects with a control group of 44 people, but there was no placebo
treatment (Rovellini et al, 1992). Triglycerides levels fell by 51% from 3.2 to 1.7mmol/L in
the treated group (p<0.001) and rose by 2% from 2.9mmol/L in the control group. HDL
cholesterol showed a nonsignificant trend toward an increase from 1.14 to 1.27mmol/L in the
bezafibrate group and did not change in the control group.
The study by Ogawa et al (2000) randomised 342 people with Type 2 diabetes to treatment
with bezafibrate (n=174) or to a control group (n=168). Compared with people in the control
group, people on bezafibrate 400mg/d had significantly lower triglycerides (3.0 to 1.5 v 3.1 to
3.0mmol/L, p<0.01) and total cholesterol (6.2 to 5.4 v 6.2 to 6.6mmol/L, p<0.01) after 16
weeks of treatment. HDL cholesterol was increased significantly in the bezafibrate group
compared with the control group (1.20 to 1.44 v 1.21 to 1.21mmol/L, p<0.01).
In a 12-week randomised, crossover study of 45 people with insulin treated Type 2 diabetes,
Rustemeijer et al (2000) reported that bezafibrate 400mg daily was more effective than
pravastatin 40mg daily in increasing HDL cholesterol (+15.3 v +8.7%, p<0.01) and Apo A1
(+9.6 v +4.3%, p<0.001), and reducing triglycerides (-37.6 v -16.0%, p<0.001). Although
total cholesterol also fell with bezafibrate (p<0.01), this reduction was smaller compared to
that with pravastatin (-10.8 v -23.3%, p<0.01).
No adverse effects of bezafibrate on glycaemic parameters of fasting glucose, HbA1c or
fructosamine have been reported. In the SENDCAP study there was no difference in HbA1c
between the groups treated with bezafibrate (from 9.6 to 10.3%) or placebo (from 9.4 to
10.1%) (p=0.4) (Elkeles et al, 1998). Glycaemic control improved during 8 months
bezafibrate treatment in the study by Rovellini et al (1992) with blood glucose level
decreasing from 9.0 to 7.9mmol/L (p<0.001) and HbA1c from 7.7% at baseline to 7.2% at 8
months (p<0.01), however this study was not blinded. In the study by Ogawa et al (2000),
treatment with bezafibrate was associated with a reduction in HbA1c (7.20.1 to 6.90.1%,
p<0.05) and FPG (8.4 to 7.1 mmol/L, p<0.01). In contrast, these values did not change in the
control group. There was no change in body weight during the study.
Fenofibrate in Type 2 diabetes
The most useful data on the effect of fenofibrate (not presently approved for use in Australia)
on lipid levels in Type 2 diabetes comes from clinical trials of CHD prevention. The Diabetes
and Atherosclerosis Intervention Study (DAIS) followed 207 people on fenofibrate 200mg
daily and 211 people on placebo for at least 3 years (DAIS Investigators, 2001). Triglycerides
102
fell by 28% from 2.6mmol/L with fenofibrate and rose by 1% from 2.4mmol/L with placebo
(p<0.0001), while HDL cholesterol rose by 7% from 1.01mmol/L on fenofibrate and by 2%
from 1.05mmol/L on placebo (p<0.0001). LDL cholesterol fell by 7% from 3.4mmol/L and
total cholesterol by 10% from 5.6mmol/L on fenofibrate and was unchanged on placebo (both
p<0.0001).
These results are very similar to those from two large, open label, before and after studies.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study included a 6
week active run-in period, with 9,795 people with Type 2 diabetes on fenofibrate 200mg
daily. Triglycerides fell by 24% and HDL cholesterol rose by 6% with fenofibrate. LDL
cholesterol fell by 11% and total cholesterol also fell by 11% over 6 weeks. All changes were
highly significant (personal communication from the FIELD study investigators, 2001).
Another open label study with the same dose of fenofibrate for 3 months in 1,379 people with
Type 2 diabetes demonstrated a 30% reduction of triglycerides from 4.6mmol/L and a 24%
increase of HDL cholesterol from 1.1mmol/L. LDL cholesterol fell by 23% from 5.2mmol/L
and total cholesterol by 18% from 7.8mmol/L (Kirchgassler et al, 1998). As with bezafibrate,
fenofibrate seems to be more effective than gemfibrozil in lowering total and LDL
cholesterol.
Statins are effective in the reducing total and LDL cholesterol in people with Type 2
diabetes
Statins inhibit the hepatic enzyme HMGCoA (3-hydroxy-3-methylglutaryl Coenzyme A)
reductase which is rate limiting in the production of cholesterol. A lower cholesterol level
within the hepatocyte causes upregulation of LDL receptors and enhanced clearance of LDL
particles from plasma. Statins have become by far the most widely used class of lipid
modifying agents, achieving substantial reductions in total and LDL cholesterol
concentrations. Statins also have minor to moderate effects in reducing triglycerides and
increasing HDL cholesterol, but are less effective than fibrates in this regard.
Placebo controlled or comparative studies of the lipid modifying effects of statins have been
performed in people with Type 2 diabetes using pravastatin, simvastatin, fluvastatin,
lovastatin and atorvastatin (see Table 15). In addition, lipid changes with statin therapy in
people with Type 2 diabetes have been reported from clinical trials and indicate that the
effects are the same as in non-diabetic subjects.
Pravastatin in Type 2 diabetes
Major randomised controlled trials showing reduction of cardiovascular events with
pravastatin have all used 40mg daily. Treatment with pravastatin 40mg daily over 5 years
was tested in a subgroup analysis of the 586 people with clinically diagnosed Type 2 diabetes
in the secondary prevention Cholesterol and Recurrent Events (CARE) trial. Pravastatin
reduced baseline mean total cholesterol of 5.3mmol/L by 19% and mean LDL cholesterol of
3.5mmol/L by 27% compared with placebo (Goldberg et al, 1998). In the non-diabetic group
total cholesterol was reduced by 20% and LDL cholesterol by 28%. Mean baseline
triglyceride levels of 1.9mmol/L fell by 13% in the diabetic group and mean HDL cholesterol
of 0.97mmol/L rose by 4%. In the non-diabetic group triglycerides levels fell by 14% and
HDL cholesterol rose by 5%.
A randomised, double-blind crossover study of 45 people with insulin treated Type 2 diabetes
(Rustemeijer et al, 2000) showed that pravastatin 40mg/day was more effective in reducing
total cholesterol (-23.3 v -10.8%, p<0.001), LDL cholesterol (-29.2 v -6.0%, p<0.001), and
LDL-ApoB (-25.7 v -9.4%, p<0.001) compared with bezafibrate 400mg/day over a 12-week
treatment period. In contrast, bezafibrate was superior in increasing HDL cholesterol (+15.3 v
+8.7%, p<0.01) and Apo A1 (+9.6 v +4.3%, p<0.001), and reducing triglycerides (-37.6 v
16.0%, p<0.001). Pravastatin treatment was associated with a significant increase in HbA1c
level (8.1 to 8.6%, p<0.001) while bezafibrate treatment was accompanied by a significant
103
decrease in HbA1c level (8.3 to 7.9%, p<0.01). No changes in body weight were observed in
either treatment period.
In a 16-week randomised controlled trial of 136 people with Type 2 diabetes (Schweitzer et
al, 2002), total and LDL cholesterol were significantly lower with pravastatin 40mg/day
(n=70) than with gemfibrozil 1200mg/day (n=66) (-21.2% v -6.6%, p<0.001; -31.3% v 5.2%, p<0.001, respectively). In contrast, gemfibrozil had a greater lowering effect on
triglyceride levels (-29.6% v -6.3%, p<0.001). The increment in HDL cholesterol was 6.4%
in the pravastatin group and 5.8% in the gemfibrozil group. In addition, pravastatin reduced
Apo B concentration to a significantly greater extent than gemfibrozil (-19.3% v -4.1%,
p<0.001). During the study period, HbA1c did not change significantly in either group (7.5 to
7.8% with pravastatin; 7.6 to 8.1% with gemfibrozil, p=0.31).
Simvastatin in Type 2 diabetes
The dose of simvastatin used in major clinical trials with cardiovascular events as outcomes
has been 20 to 40mg daily. In a subgroup analysis of the 202 people with clinically diagnosed
Type 2 diabetes in the secondary prevention Scandinavian Simvastatin Survival Study (4S),
treatment with simvastatin 20 to 40mg daily over 5 years reduced baseline mean total
cholesterol of 6.7mmol/L by 27% and mean LDL cholesterol of 4.8mmol/L by 36%
compared with baseline (Pyorala et al, 1997). In the non-diabetic group total cholesterol was
reduced by 24% and LDL cholesterol by 34%. Mean baseline triglycerides levels of 1.7
mmol/L fell by 11% in the diabetic group and mean HDL cholesterol of 1.12mmol/L rose by
7%. In the non-diabetic group triglycerides level fell by 9% and HDL cholesterol rose by 8%.
In a subsequent analysis of data from the 4S trial which included an additional 281 people
diagnosed with Type 2 diabetes on the basis of fasting blood glucose 7.0 mmol/L, lipid and
lipoprotein changes were again not different between diabetic and non-diabetic groups
(Haffner et al, 1999).
In another placebo controlled trial 28 people were randomised to treatment with simvastatin
for 24 weeks and 29 people to placebo (Farrer et al, 1994). Simvastatin dose was titrated from
10 up to 40mg daily (mean dose at completion was 29mg). On active treatment total
cholesterol fell by 28% from 7.8 to 5.6mmol/L (p<0.001) and LDL cholesterol by 38% from
5.5 to 3.4mmol/L (p<0.001). Triglycerides levels fell by 15% from 2.5 to 2.2mmol/L
(p<0.05), while HDL cholesterol rose by 9% from 1.16 to 1.23mmol/L (p<0.05). Between
group differences for total, LDL cholesterol and triglycerides were significant (p<0.0010.01). No changes in HbA1c, FPG were observed with simvastatin treatment.
104
Table 15: Effects of statins on lipids in Type 2 diabetes

Effects on Lipids and Lipoproteins
Reference
Athyros, 2002a
(Greece)
Population

age 44-69 yrs, RCT
24-wk follow-up
Atorvastatin, n=40
Fenofibrate, n=40
Drug
Dose
(mg/d)
20
200
Inclusion
Criteria
(mmol/L)
T-CHO
>5.7
LDL >3.4
TG
2.3-4.5
In combination, n=40
Total
Cholesterrol
(mmol/L)
LDL
Cholesterol
(mmol/L)
Before
After
Before
After
Before
After
6.53
4.51**
4.17
2.51**
0.90
0.98**
**
6.55
5.52**
6.60
4.12**
**
n=6,605
age 45-73 yrs, RCT
Placebo
Lovastatin
20-40
T-CHO
4.65-6.82
TG 4.52
3.62**
4.22
3.31**
**
5.85
5.71
5.90
4.75**
Farrer, 1994
(UK)
10-40
T-CHO
>6.5
TG <5.0
8.1
7.8
8.0
5.6****
Freed, 2002
(US)
8mg/d
10mg/d
20mg/d
0.91
1.11**
5.6
5.5
Before
After
Total
Triglycerides
(mmol/L)
4.04
2.96**
After
Before
After
3.14
2.20**
124
127
124
132
124
138
5.5
3.4****
3.18
1.89**
3.14
1.57**
3.34
**
0.97
1.02**
1.88
1.78
1.17
1.23*
1.84
1.61**
3.44
2.9
2.5
3.5
2.2**
135
130
140
149.5
3.52
180
180
1.04
1.06
1.04
1.86
3.55
1.09
1.81
1.32
1.75
1.79
1.04
1.09
**
1.51
-
Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison p<0.05, p<0.01, p<0.005, p<0.001 T-CHO = Total cholesterol; LDL = LDL cholesterol; TG = Triglycerides;
IFG = Impaired fasting glucose
105
178
129.6
**
2.31
2.12
After
Before
**
1.18
1.16
Apo B
(mg/dl)
**
**
0.96
0.96
Apo A1
(mg/dl)
Before
**

24-wk RCT
aged 35-80 yrs
rosiglitazone+atorvast
atin, n=82, 16 wk
rosiglitazone+atorvast
atin, n=79, 16 wk
rosiglitazone+placebo
n=76, 16 wk
1.04**
**
3.98
3.89
VLDL
Cholesterol
(mmol/L)
0.90
**
n=57; Type 2 diabetes

age 25-70 yrs RCT
9-mth follow-up
Placebo
Simvastatin
**
4.22
**
Downs, 1998
(US)
AFCAPS
TexCAPS
HDL
Cholesterol
(mmol/L)

Reference
Gavish, 2000
(Israel)
Gentile, 2000
(Italy)
Goldberg, 1990
(US)
Goldberg, 1998
(US)
CARE
Haffner, 1999
(Scandinavia)
Population

age 49-70 yrs
21-mth follow-up
first 6 mths
Simvastatin, n=100
Bezafibrate, n=48
then 12 mths
in combination, n=148
age 50-65 yrs
24-wk follow-up RCT
Atorvastatin, n=84
Simvastatin, n=78
Pravastatin, n=81
Lovastatin n=80
Placebo, n=86
n=102, Type 2 diabetes
age 18-70 yrs
24-wk follow-up RCT
Lovastatin n=50
Gemfibrozil n=52
n=586, age 21-75 yrs
Type 2 diabetes
5-yr follow-up RCT
Pravastatin v
Placebo
n=1,161 age 35-70 yrs
Type 2 diabetes+IFG
5.4-yr follow-up RCT
Simvastatin
Placebo
Drug
Dose
(mg/d)
Inclusion
Criteria
(mmol/L)
20
40
10
10
20
20
20-40
2600
40
up to 40
LDL >4.6
TG 4.5
LDL 4.14
TG <4.52
T-CHO <6.22
LDL
2.98-4.51
TG <3.96
T-CHO
5.5-8.0
TG 2.5
Total
Cholesterrol
(mmol/L)
LDL
Cholesterol
(mmol/L)
HDL
Cholesterol
(mmol/L)
Before
After
Before
After
Before
After
6.9
7.0
5.4**
6.7**
4.5
4.6
3.1**
4.4**
0.9
0.8
0.9
1.0**
7.0
5.4**
4.5
3.2**
0.8
1.0**
29%
21%
16%
18%
1%
7.04
7.10
5.61**
6.61**
37%
26%
23%
21%
1%
5.02
4.97
3.67**
4.88
VLDL
Cholesterol
(mmol/L)
Before
7.4%
7.1%
3.2%
7.2%
0.5%
1.09
1.08
1.22**
1.28**
After
Before
After
3.8
5.2
3.5
3.2**
4.3
2.5**
24%
14%
12%
11%
1%
0.64**
0.55**
0.93
1.02
Total
Triglycerides
(mmol/L)
2.29
2.45
2.15
1.46**
1.85
1.85
1.61
1.85
1.65
1.65
1.54
1.72
5.33
5.33
4.32
5.33
3.52
3.52
2.57
3.52
0.97
0.97
1.01
0.97
6.74
6.74
4.90
6.87
4.86
4.86
3.10
5.05
1.13
1.13
1.21
1.10
Apo A1
(mg/dl)
Before
After
Apo B
(mg/dl)
Before
106
After

Reference
Population
Drug
Dose
(mg/d)
Inclusion
Criteria
(mmol/L)
Total
Cholesterrol
(mmol/L)
Before
Knopp, 1994b
(US & Canada)
Pyorala, 1997
(Scandinavia)
4S
Rustemeijer,
2000
(The
Netherlands)

age 40-70 yrs, RCT
20-wk follow-up
Placebo at 6 wk
Fluvastatin at 6 wk
Placebo at 12 wk
Fluvastatin at 12 wk
aged 35-70 yrs
5.4-yr follow-up RCT
Placebo
Simvastatin
aged 40-80 yrs
12-wk follow-up
RCT, crossover
Pravastatin, n=22
Bezafibrate, n=23
20
220
after 8wk
diet therapy
T-CHO
>5.2
LDL
3.4-7.8
TG >
2.3-11.3
T-CHO
5.5-8.0
TG 2.5
20-40
40
T-CHO
5.0-8.0
TG
1.8-5.0
7.33
6.16
7.38
5.93
Before
After
4.38
3.60
4.53
3.42
HDL
Cholesterol
(mmol/L)
Before
After
VLDL
Cholesterol
(mmol/L)
Before
0.98
1.06
1.04
1.09
After
1.94
1.40
1.81
1.40
6.72
6.71
6.6
4.90
5.06
4.80
4.81
4.03
6.7
400
After
LDL
Cholesterol
(mmol/L)
5.98
3.08
2.85
1.13
1.12
Total
Triglycerides
(mmol/L)
Before
After
Apo A1
(mg/dl)
Before
4.14
3.18
3.66
3.27
1.78
1.69
After
3.87
After
mmol/l
mmol/l
1.43
1.50
1.15
1.25
1.41
0.99
2.95
2.48
1.37
1.15
1.33
1.43
0.86
2.87
1.79
1.35
1.48
4.12
Before
1.20
Apo B
(mg/dl)
Schweitzer,
2002
(US)
SoedamahMuthu, 2003
(UK)

mean age 57 yrs
Pravastatin
Gemfibrozil
aged 40-75 yrs
6-mth RCT
Atorvastatin
Placebo
40
LDL
3.4 to 5.2
TG 4.5
1200
10
LDL 3.9
TG 5.0
6.26
4.93
4.10
2.82
1.23
1.30
0.58
0.55
2.06
1.93
108.2
123.3
0.71
0.52
2.22
1.56
103
126.8
1.85
1.50**
6.14
5.73
3.96
3.75
1.20
1.28
5.49
3.61**
3.48
1.85**
1.20
1.39
**
5.22
5.22
**
3.16
2.95
**
1.23
1.22
1.65
1.70
107

Reference
The DALI
Study Group,
2001
(The
Netherlands)
Tikkanen, 1998
(Finland)
Wagner, 2003
(Spain)
Population

aged 45-75 yrs
30-wk RCT
Atorvastatin, n=73
Atorvastatin, n=72
Placebo, n=72
age 35-70 yrs
24-wk follow-up
Simvastatin
Gemfibrozil
age 35-70 yrs
24-wk follow-up
Atorvastatin 12 wk
Gemfibrozil 12 wk
in combination 12wk
Drug
Dose
(mg/d)
10
80
10-40
2600
10-20
900-1200
Inclusion
Criteria
(mmol/L)
T-CHO
4.0-8.0
TG
1.5-6.0
LDL >4.0
TG <4.5
Total
Cholesterrol
(mmol/L)
LDL
Cholesterol
(mmol/L)
HDL
Cholesterol
(mmol/L)
Before
After
Before
After
Before
After
5.9
6.0
6.0
4.1
3.6
6.0
3.7
3.7
3.8
2.2
1.7
3.6
1.05
1.03
1.05
1.10
1.09
1.04
6.94
7.00
4.84**
6.30**
4.53
4.57
2.65**
4.27**
1.26
1.19
1.31**
1.35**
VLDL
Cholesterol
(mmol/L)
Before
After
Total
Triglycerides
(mmol/L)
Before
2.54
2.85
2.62
2.46
2.54
After
Apo A1
(mg/dl)
Before
After
1.84
1.78
2.88
2.08**
1.39***
Apo B
(mg/dl)
Before
After
122
124
127
84
74
125
135
134
137
138
134
139
124
122
125
93****
115****
95****
LDL >2.6
TG <4.5
3.94
3.81
3.83
2.56****
3.68**
2.75****
1.19
1.19
1.19
1.24**
1.24*
1.24*
1.83
1.89
2.14
1.62****
1.28****
1.32****
108
The effects of simvastatin on the lipid profile in people with Type 2 diabetes have been
compared directly with those of gemfibrozil in a double blind trial over 24 weeks (Tikkanen
et al, 1998). Simvastatin was started at 10mg daily in 47 people and increased to 20mg after 8
weeks and 40mg after 16 weeks, whereas gemfibrozil was given as 600mg twice daily to 49
people for 24 weeks. After 24 weeks simvastatin reduced total cholesterol by 30% from the
baseline level of 6.9mmol/L compared with a 10% reduction with gemfibrozil (both p<0.01).
The reduction of LDL cholesterol from 4.5mmol/L was 42% with simvastatin compared with
7% with gemfibrozil (both p<0.01). The statin effects on total and LDL cholesterol were
significantly greater than the fibrate effects (both p<0.01). In contrast reduction of
triglyceride levels from 2.5mmol/L with simvastatin was 15% and with gemfibrozil 45%
(both p<0.01), while the rise in HDL cholesterol from 1.26mmol/L was 4% with simvastatin
(p=NS) and 14% with gemfibrozil (p<0.01). The fibrate effects on triglycerides and HDL
cholesterol were significantly greater than the statin effects (both p<0.01).
Lovostatin in Type 2 diabetes
Lovastatin (not presently approved for use in Australia) was used in the AFCAPS/TexCAPS
primary prevention trial (Downs et al, 1998). Among 6,605 participants aged 45 to 73 years
(diabetes not specified) who were randomly assigned to lovastatin 20-40mg/day (n=3,304) or
placeob (n=3,301), the mean total cholesterol was 5.7mmol/L, LDL cholesterol 3.9mmol/L,
and HDL cholesterol 0.94mmol/L for men and 1.03mmol/L for women and triglycerides
were 1.8mmol/L at baseline. At one year, lovastatin significantly reduced total and LDL
cholesterol compared with placebo (-18 v +0.9%, p<0.001; -25 v +1.5%, p<0.001,
respectively). Triglycerides fell by 15% with lovastatin and rose by 1.7% with placebo
(p<0.001). Lovastatin resulted in a 6% increase in HDL cholesterol comparing with a 2%
increase with placebo(p<0.001).
A double blind placebo controlled trial has compared lovastatin 20 to 40 mg daily with
gemfibrozil 600mg twice daily over 24 weeks in 102 people with Type 2 diabetes (Goldberg
et al, 1990). From a mean baseline level of 7.1mmol/L total cholesterol fell by 20% on
lovastatin (n=50; p<0.01) and by 7% on gemfibrozil (n=52; p<0.01), while LDL cholesterol
fell from 5.0mmol/L by 26% on lovastatin (p<0.01) and by 1% on gemfibrozil (p=NS).
Triglycerides fell from 2.3mmol/L by 36% on gemfibrozil (p<0.05), but rose by 2% on
lovastatin (p=NS), while HDL cholesterol rose from 1.08mmol/L by 21% on gemfibrozil and
14% on lovastatin (p<0.01). Lovastatin was more effective in reducing total and LDL
cholesterol than gemfibrozil (both p<0.01), whereas gemfibrozil lowered triglycerides more
than lovastatin (p<0.05).
Fluvastatin in Type 2 diabetes
A relatively large double blind placebo controlled trial in people with Type 2 diabetes and
significantly elevated levels of both cholesterol and triglycerides has shown significant
changes in lipid and lipoprotein levels with fluvastatin 20mg daily for 6 weeks, then 40mg
daily for 6 weeks (Knopp et al, 1994b). Baseline total cholesterol of 7.3mmol/L fell by 20%
(p<0.001) at the end of the study on fluvastatin (n=30) compared with placebo (n=29).
Baseline LDL cholesterol of 4.5mmol/L fell by 25% (p<0.001) and baseline triglycerides of
3.9mmol/L by 17% (p<0.01). HDL cholesterol was 1.02mmol/L at baseline and rose by 5%
with fluvastatin (p<0.10).
Atorvastatin in Type 2 diabetes
In a 6-month study, Soedamah-Muthu et al (2003) compared the effect of atorvastatin 10
mg/day with placebo among 122 people with Type 2 diabetes, who had a history of previous
myocardial infarction and modestly increased lipids (mean LDL 3.2mmol/L and median
triglycerides 1.8mmol/L). Over 6 months, the median changes in total cholesterol and LDL
109
cholesterol were significantly greater in the atorvastatin group than in the placebo group (-1.8
v -0.2mmol/L, p<0.001; -1.5 v -0.3mmol/L, p<0.001, respectively). Triglycerides were also
reduced significantly with atovastatin treatment (-0.55 v -0.05mmol/L, p<0.001). There were
no significant differences in HbA1c (p=0.4) and BMI (p=0.4) between the two groups during
the study period.
In the DALI study (The Diabetes Atorvastatin Lipid Intervention Study) (The DALI Study
Group, 2001), 217 people aged 45-75 years with Type 2 diabetes were randomised to receive
atorvastatin 10mg/day (n=73), atorvastatin 80mg/d (n=72), or placebo (n=72) for 30 weeks.
Treatment with atorvastatin 10 and 80mg produced a significant reduction in triglycerides
levels (-25%, -35%, respectively, both p<0.001), while both had a similar effect on HDL
cholesterol (+6.0% v +5.2%, respectively), but without difference between the two groups.
Atorvastatin 80mg was more effective than atorvastatin 10mg in lowering total cholesterol (39%, p<0.001 v -30%, p<0.001), LDL cholesterol (-52%, p<0.001 v -41%, p<0.001), and
Apo B (-40%, p<0.001 v -31%, p<0.001) (all p<0.005). During the 30 weeks of treatment,
atorvastatin 80mg was associated with a slight increase in HbA1c (from 8.4 to 8.6%, p=0.06),
whereas a slight decrease in HbA1c was observed in both atorvastatin 10mg and placebo
group (p<0.05 at week 30).
In an open-label, randomised trial, Gentile et al (2000) compared once daily atorvastatin 10
mg with simvastatin 10mg, pravastatin 20mg, lovastatin 10mg, and placebo in 409 people
with Type 2 diabetes and moderate elevated LDL cholesterol (>4.2mmol/L). During 24
weeks of treatment, atorvastatin produced greater reduction in total cholesterol (-29%) and
LDL cholesterol (-37%) than simvastatin (-21%, p<0.05; -26%, p<0.05, respectively),
pravastatin (-16%, p<0.01; -23%, p<0.01), lovastatin (-18%, p<0.05; -21%, p<0.01), and
placebo (+1%, p<0.01; -1%, p<0.01). Similarly, atorvastatin was more effective in reducing
triglyceride levels (-24%) than simvastatin (-14%, p<0.05), pravastatin (-12%, p<0.05),
lovastatin (-11%, p<0.05), and placebo (-1%, p<0.01). However, with regard to the effect of
increasing HDL cholesterol, atorvastatin did not differ from other statins, except for
pravastatin which had a smaller increment in HDL cholesterol than atorvastatin (+3.2% v
+7.4%, p<0.05). These results could reflect the medication doses used in the study and their
equivalence.
Wagner et al (2003) compared atorvastatin 10-20mg/day with gemfibrozil 900-1200mg/day
in 44 people with Type 2 diabetes and elevated lipids (LDL cholesterol >2.6mmol/L and
triglycerides <4.5mmol/L) in a randomised control trial. After 12 weeks of treatment, LDL
cholesterol was significantly lower with atorvastatin (3.9 to 2.6mmol/L, p<0.0001 v 3.8 to 3.7
mmol/L, p<0.01), whereas gemfibrozil lowered triglycerides more effectively (1.8 to 1.6
mmol/L v 1.9 to 1.3mmol/L, p<0.001). HDL cholesterol increased from 1.19 to 1.24mmol/L
on both treatments (p<0.05). Mean LDL particle size increased only after treatment with
gemfibrozil (from 25.590.06 to 25.690.06 nm, p<0.05). Apo B was reduced from 124 to 93
mg/dl with atorvastatin and from 122 to 115 mg/dl with gemfibrozil (both p<0.0001).
Glycaemic control remained stable with gemfibrozil (HbA1c from 7.2 to 7.3%), while HbA1c
rose from 7.0 to 7.4% (p<0.05) after treatment with atorvastatin.
In a multicentre, randomised double-blind, placebo control study, Freed et al (2002)
compared the effects of rosiglitazone alone and in combination with atorvastatin on
glycaemic control and lipids. 243 people with Type 2 diabetes were treated with rosiglitazone
4mg twice a day during the first 8 weeks. During the 8 weeks of rosiglitazone treatment there
was 5.8% increase in total HDL cholesterol whereas LDL cholesterol increased by 9.0%. All
subjects were then randomised to a 16-week period of combined rosiglitazone with
atorvastatin 10mg/day, 20mg/day, or placebo. With atorvastain added, there was a significant
reduction in LDL cholesterol (-31.5%, -38.8%, respectively) compared with rosiglitazone
plus placebo (p<0.0001). Triglycerides fell by 18.5% (p<0.001) and 27.2% (p<0.0001),
respectively. Total HDL cholesterol further increased by 4.8%, and HDL3 cholesterol by
5.2% with the combination therapy (p<0.001). Over the 24-week, glycaemic control
110
improved with HbA1c decreasing from 7.9 to 7.2%, 7.6 to 7.1%, and 7.8 to 7.0%,
respectively. Body weight increases ranged from 1.4 to 1.7kg during this period.
Nicotinic acid (niacin) is effective in improving lipids in people with Type 2 diabetes but
may have a small adverse effect on blood glucose control
Studies which have examined the effect of nicotinic acid (niacin) on lipid levels in people
with Type 2 diabetes are shown in Table 16.
The effect of niacin on lipid and lipoprotein levels was studied in a prospective, randomised
placebo-controlled trial which involved 468 subjects, including 125 with diabetes (type not
specified) (Elam et al, 2000). After a 12 week run-in period with niacin 100mg, 500mg, and
then 1000mg daily, 64 people with diabetes were randomly assigned to niacin 3000mg/d and
61 to placebo for a further 48 weeks. Treatment with niacin significantly reduced LDL
cholesterol by 8% and triglycerides by 23%, while HDL cholesterol increased significantly
by 29% (p<0.001 for all compared with placebo). With regard to glycaemic control, HbA1c
was unchanged in the niacin group compared with a reduction in HbA1c of 0.3% in the
placebo group (p=0.04).
Grundy et al (2002) assessed the effect of extended-release (ER) niacin 1000-1500mg/day in
146 people with Type 2 diabetes, including 69 people who were also treated with statins, in a
randomised, placebo controlled trial. The dose of ER niacin was gradually titrated to 10001500mg in the first 4 weeks. During 16 weeks, HDL cholesterol increased in a dosedependent manner, with a 13-19% increase in the 1000mg niacin group and 22-24% increase
in the 1500mg niacin group compared with little change in the placebo group (both p<0.05).
There was also a dose-related reduction in triglycerides levels with a 15-20% decrease in the
1000mg niacin group and a 28-36% decrease in the 1500mg niacin group, but only the latter
was significantly different from the decrease of 5-8% in the placebo group (p<0.05). The
reduction in total and LDL cholesterol was only observed in the 1500mg niacin group
(compared with placebo, p<0.05). Changes in HbA1c over the study period were small in all
treatment groups, with -0.02% in the placebo group, +0.07% in the 1000mg niacin group, and
+0.29% in the 1500mg niacin group, but the difference between placebo and the 1500mg
niacin group was significant (p=0.048).
The effects on the lipid profile of lower doses of nicotinic acid have been studied in
combination with pravastatin and are reported in the section below on combination therapy in
people with Type 2 diabetes.
111
Table 16: Effects of nicotonic acid (niacin) on lipids in Type 2 diabetes
Reference
Elam, 2000
(US)
Population studied

mean age 67 yrs
48-wk follow-up RCT
Niacin n=64
Drug
dose
3000mg/d
Inclusi
on
criteria
(mmol/
L)
Effects on Lipids
Total
Cholesterol
(mmol/L)
5.36
LDL
Cholesterol
(mmol/L)
5.13***
3.44
3.16***
HDL
Cholesterol
(mmol/L)
0.98
1.27
VLDL
Cholesterol
(mmol/L)
Total
Triglycerides
(mmol/L)
1.99
1.54****
Apo A 1
(mg/dl)
Apo B
(mg/dl)
5.62
2.27
1.01
Placebo n=61
3.57
1.01
2.37
5.70
3.60
LDL
3.36
aged 21 yrs
HDL
Grundy, 2002
16-wk follow-up
2.26
3.14
1.21
1.01
2.86
2.72
_4%
1000mg/d
(US)
1.03
ER niacin n=45
1.88
2.93
1.34
1.06
2.59
2.75
-6%
1500mg/d
or
ER niacin n=52
2.79
3.03
1.13
1.09
2.74
2.51
+4%
TG 2.20
Placebo, n=49
Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison p<0.05, p<0.01, p<0.005, p<0.001; TG = Triglycerides; T-CHO = Total cholesterol; HDL = HDL cholesterol
112
Bile acid sequestrants (resins) may be effective in lowering total and LDL cholesterol in
people with Type 2 diabetes but data are limited
Studies which have examined the effect of bile acid sequestrants (resins) on lipid levels in
people with Type 2 diabetes are shown in Table 17.
Bile acid sequestrants (resins) bind bile acids in the intestinal tract and interrupt the
enterohepatic pathway. Increased hepatic synthesis of bile acids reduces intracellular
cholesterol levels and upregulates LDL receptor expression, increasing plasma clearance of
LDL cholesterol. Bile acid sequestrants are effective in lowering LDL cholesterol levels in
people without diabetes and have additive effects to statins, which prevent the compensatory
increase in hepatic cholesterol synthesis that occurs with resins.
Only one well controlled study of resin therapy has been reported in people with Type 2
diabetes. In a randomised, double blind, placebo controlled, crossover study 21 people with
Type 2 diabetes took 8g cholestyramine twice daily for 6 weeks (Garg & Grundy, 1994b). All
participants had fasting triglyceride levels below 3.4mmol/L. Compared with placebo, total
cholesterol was 18% lower on cholestyramine (5.9 v 4.9mmol/L, p<0.001) and LDL
cholesterol was 28% lower (4.1 v 3.0mmol/L, p<0.001). However, triglycerides levels rose
by 7% on cholestyramine (from 1.9 to 2.1mmol/L) compared with placebo (p=0.02). There
was no significant change in HDL cholesterol which was 1.02mmol/L on placebo and 5%
higher on cholestyramine (p=NS). There was also a 13% reduction in mean plasma glucose
compared with placebo (6.5 v 7.6mmol/L, p=0.003), but no difference in HbA1c (8.3 v 8.8%,
p=0.17) was observed. Constipation was the main side effect and two subjects discontinued
the study because of cholestyramine intolerance.
Since cholestyramine may increase triglycerides, its use should be restricted to people with
normal triglycerides. Also since it is not absorbed from the intestinal tract into the systemic
circulation, cholestyramine can be used in people with moderate to severe renal failure or
hepatic dysfunction or who are intolerant of statin therapy
Omega3 fatty acids (-3) are effective in lowering triglycerides in people with Type 2
diabetes but may cause a dose dependent deterioration in blood glucose control
There is considerable epidemiological evidence that eating fish is associated with lower risk
of coronary heart disease (CHD). A recent secondary prevention trial has also shown that -3
polyunsaturated fatty acids in the form of fish oil capsules reduce CHD risk, although a
subgroup analysis of people with diabetes (15% of the 11,324 participants) has not been
reported (GISSI, 1999). The two main polyunsaturated long-chain -3 fatty acids in fish oil
are eicosapentaenoic acid (EPA; n-3, C20:5) and docosahexaenoic acid (DHA; n-3, C22:6).
Protection from CHD is thought to be mediated through the effects these fatty acids have on
lipid metabolism, platelet aggregation and coagulation factors
There have been at least 15 controlled trials and many uncontrolled trials of fish oil therapy in
Type 2 diabetes and two systematic reviews have been reported (Friedberg et al, 1998;
Montori et al, 2000). The meta-analysis by Friedberg et al (1998) analysed data from 7
controlled trials and 7 uncontrolled trials of people with Type 2 diabetes. Total cholesterol
fell by 1% from the mean baseline level of 5.8mmol/L (p=NS), while LDL cholesterol rose
by 5% from 3.7mmol/L (p<0.05). Mean triglycerides levels at baseline were 2.6mmol/L and
fell by 31% on fish oil (p<0.05). HDL cholesterol fell by 1% from the mean baseline level of
1.01mmol/L (p=NS). Fasting blood glucose rose by 5% from the mean baseline level of 9.1
mmol/L (p=0.06) and HbA1c rose by a relative change of 2% from 8.8% (p=NS). The dose of
113
fish oil varied between studies, but the controlled trials generally used about 1.8g of EPA and
1.2g of DHA. There was a direct relationship between dose and effects on triglycerides and
blood glucose control. For every 1g per day increase in EPA or DHA, triglycerides levels fell
by 0.36 and 0.47mmol/L (both p<0.05) and HbA1c rose by absolute levels of 0.38 and 0.6%
respectively (both p<0.05).
The meta-analysis by Montori et al (2000) considered only randomised controlled trials and
included data from 18 studies. Doses of fish oil ranged from 3 to 18g daily (1.08-5.2g EPA
and 0.3-4.8g DHA). There was a significant effect of fish oil in lowering triglycerides (-0.56
mmol/L [95% CI -0.71 to -0.41]) and the effect was more evident (-0.73mmol/L [CI -0.95 to
-0.51]) in trials that recruited only hypertriglyceridaemic subjects. LDL cholesterol rose
significantly with fish oil (0.21mmol/L [CI 0.02 to 0.41]) and this increase was greater in
trials that used the highest doses of fish oil (0.51mmol/L [CI 0.18 to 0.84]) and that recruited
subjects with baseline hypertriglyceridaemia (0.60mmol/L [CI 0.16 to 1.04]). Fish oil had no
significant effects on total cholesterol (0.007mmol/L [CI -0.13 to 0.15]) and HDL cholesterol
(0.02mmol/L [CI 0.01 to 0.05]). There was no significant difference in fasting glucose or
HbA1c. Mean weighted difference for fasting glucose was 0.26 mmol/L (CI -0.08 to 0.60) and
for HbA1c 0.15% (CI -0.08 to 0.37).
A randomised crossover study has compared the lipid and lipoprotein effects of fish oil
(2.89g EPA and 1.78g DHA daily) with gemfibrozil (900mg daily) over 2 week treatment
periods (Fasching et al, 1996). In 10 people with Type 2 diabetes, total cholesterol fell by
13% with gemfibrozil (from 6.5 to 5.6mmol/L, p<0.01) and fell by 6% with fish oil (from 6.6
to 6.2mmol/L, p<0.05). LDL cholesterol also fell from 4.7 to 4.0mmol/L, and from 4.9 to 4.8
mmol/L, respectively. Triglycerides fell by 39% on gemfibrozil (from 2.2 to 1.4mmol/L,
p<0.001) and by 18% on fish oil (from 2.3 to 1.9mmol/L, p<0.01). The effects of gemfibrozil
on cholesterol and triglycerides were greater than fish oil (both p<0.05).
Oestrogen replacement therapy may have a modest beneficial effect on lipids in
postmenopausal women with Type 2 diabetes
Since many women with diabetes take HRT for a variety of reasons, the effects of HRT on
lipid and lipoprotein levels in postmenopausal women with Type 2 diabetes are relevant to
their cardiovascular risk management (Table 18).
The Heart and Estrogen/progestin Replacement Study (HERS) (Hulley et al, 1998)
randomised 2,763 women with coronary disease, including 18% with diabetes, aged less than
80 years to be treated with 0.625mg conjugated equine oestrogen plus 2.5mg
medroxyprogesterone acetate (n=1,380) or placebo (n=1,383). At the end of the first year,
LDL cholesterol decreased by 14% (3.8 to 3.2mmol/L) in the hormone group and by 3% (3.8
to 3.6mmol/L) in the placebo group (p<0.001). HDL cholesterol increased from 1.29 to 1.40
mmol/L in the hormone group but decreased from 1.29 to 1.27mmol/L in the placebo group
(p<0.001). Mean triglycerdies rose by 10% and 2%, respectively in the hormone group and
placebo group.
In the Womens Health Initiative study (Manson et al, 2003), 16,608 postmenopausal women
aged 50-79years including 2.4% with previous CHD (number with diabetes not specified),
were randomly assigned to conjugated equine estrogen 0.625mg/day plus
medroxyprogesterone acetate 2.5mg/day (n=8,506) or to placebo (n=8,102). The 2 groups
were comparable at baseline except that more women in the placebo group had a history of
coronary revascularisation (1.5 v 1.1%, p=0.04). At one year, women in the hormone group
had lower levels of total and LDL cholesterol (-5.4%, -12.7%, respectively), and higher levels
114
of HDL cholesterol (+7.3%) and triglycerides (+6%) than women in the placebo group (all
p<0.05).
There have been a number of studies specifically in women with Type 2 diabetes. Forty
postmenopausal women with Type 2 diabetes were randomised to treatment with unopposed
oestrogen therapy, given as 17--oestradiol 2mg daily for 6 weeks, or to placebo (Brussaard
et al, 1997). Compared with placebo, 17oestradiol significantly reduced total cholesterol
(-5% v 1%, p=0.04) and LDL cholesterol (-14% v 2%, p=0.0001) over the 6 week treatment
period. HDL cholesterol significantly increased in the oestradiol group compared with the
placebo group (23% v 3%, p=0.0002). Triglycerides levels did not change significantly with
oestradiol (1.74 to 1.79mmol/L, p=NS). HbA1c at baseline was 8.7% and fell by 7% on
oestrogen (p=0.03).
Manning et al (2001) used a crossover design to compare combined HRT (oestrogen 0.625
mg plus medroxyprogesterone 2.5mg daily) with placebo among 61 women with Type 2
diabetes (mean age 64 years). After 6 months, total cholesterol was 7% lower and LDL
cholesterol was 12% lower with HRT therapy than with placebo (5.8 v 6.3mmol/L, p<0.05;
3.6 v 4.1mmol/L, p<0.05, respectively). Lp(a) decreased significantly during HRT treatment
(149.4 v 173.4U/L, p<0.05). There was a nonsignificant trend of an increase in HDL
cholesterol with HRT therapy (1.19 v 1.09mmol/L). HbA1c remained stable in both treatment
periods.
Perera et al (2001) in a randomised placebo-controlled trial in 43 women with Type 2
diabetes were treated with 80g estreadiol patches in combination with oral norethisterone
1mg daily or identical placebos for 6 months. Total cholesterol and triglycerides were
reduced by 8% and 22%, respectively in those receiving HRT compared with placebos (both
p<0.05). There was also a trend to reduced HDL cholesterol in the HRT group (-8% v +1%,
p=0.06). No changes in LDL and VLDL cholesterol were observed. HbA1c was unchanged in
the HRT group, whereas HbA1c increased slightly in the placebo group (from 6.4 to 6.8%),
but this did not differ between the two groups.
Data from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial showed
raloxifene, an oestrogen-receptor modulator, improved lipid profiles in women with Type 2
diabetes (Barrett-Connor et al, 2003). 202 women were randomised to receive raloxifene 60
mg/day (n=108) or placebo (n=94) in this 3-year study. At 36 months, raloxifene treatment
significantly reduced total cholesterol and LDL cholesterol compared with placebo (both
p<0.004). The median change in triglycerides (+0.8% v -3.6%, p=NS) and HDL cholesterol
(+3.5% v +4.4%, p=NS) did not differ among women treated with raloxifene or placebo.
Glycaemic control was comparable in both groups (median change in HbA1c: -0.54% v 4.03%, p=NS) over the study period.
These results show that oestrogen therapy in postmenopausal women with Type 2 diabetes
has a modest effect in reducing total and LDL cholesterol and, overall, little effect on HDL
cholesterol and triglycerides.
115
Table 17: Effects of -3 fatty acid (fish oils) on lipids in Type 2 diabetes
Effects on lipids
Reference
Fasching, 1996
(Austria)
Friedberg, 1998
GISSI, 1999
Population studied

mean age 61yrs
12-wk follow-up
RCT crossover
Fish oil for 2 wk
Gemfibrozil for 2 wk
with 8 wk wash-out
n=14 studies of Type 2
diabetes
Systematic Review
Fish oil supplements
n=11,324
42-mth follow-up
14.8% Type 2 diabetes
Fish oil, n=2,836
Vitamin E, n=2,830
Fish oil+Vit E, n=2,830
Control, n=2,828
Drug
dose
(g/d)
4.6
900mg
1.821.6
Inclusion
Criteria
Type 2b
Type 4
Hyperlipidaemia
Total
Cholesterol
(mmol/L)
LDL
Cholesterol
(mmol/L)
HDL
Cholesterol
(mmol/L)
Before
After
Before
After
6.60
6.49
6.21
5.64
4.86
4.68
4.78
3.98
Before
After
Before
0.75
0.93
After
0.49
0.47
5.8
1.0
300mg
VLDL
Cholesterol
(mmol/L)
5.73
3.70
3.90
1.01
Total
Triglycerides
(mmol/L)
Before
After
1.89
1.35
2.30
2.22
1.00
2.60
change from
baseline to 6 mths
change from
baseline to 6 mths
change from
baseline to 6 mths
change from
baseline to 6 mths
7.9%
7.1%
8.9%
7.1%
9.9%
7.2%
10.8%
7.4%
8.8%
9.4%
8.9%
9.2%
3.4%
2.9%
0.9%
1.4%
mean change
from baseline
mean change
from baseline
mean change
from baseline
0.007
CI (-0.13, 0.15)
0.21*
CI (0.02-0.41)
0.02
CI (0.01-0.05)
1.79
Apo A1
(mg/dl)
Apo B
(mg/dl)
Before
After
Before
Afterr
141
139
136
136
155
151
139
128
fish oil v control
Montori, 2000
n=18 studies
Systematic review
Type 2 diabetes
Fish oil supplements
3-18
Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison p<0.05, p<0.01, p<0.005, p<0.001;
116
mean change
from baseline
-0.56*
CI(-0.71, -0.41)
Table 18: Effects of hormone replacement therapy on lipids in Type 2 diabetes
Reference
Barrett-Connor,
2003
(US)
Brussaard, 1997
(Belgium)
Hulley, 1998
(US)
Manning, 2001
(New Zealand)
Manson, 2003
(multicentres)
Population studied

mean age 68 yrs
3-yr follow-up RCT
raloxifene,n=108
placebo,n=94
mean age 60 yrs
RCT 6-wk follow-up
17 -estradiol n=20
placebo n=20
n=2,763
18% Type 2 diabetes
4.1-yr follow-up
estrogen
+medroyprogesterone v
placebo
mean age 64 yrs
12-mth crossover RCT
estrogen
placebo
n=16,608
aged 50-79 yrs
5.2-yr follow-up
estrogen
placebo
Drug
dose
(mg/day)
Inclusion
criteria
(mmol/L)
60
Effects on lipids
Total
Cholesterol
(mmol/L)
LDL
Cholesterol
(mmol/L)
Before
After
mean change
from baseline
Before
After
mean change
from baseline
-12.5%
-3%
-16%
-4%
HDL
Cholesterol
(mmol/L)
Before
After
mean change
from baseline
VLDL
Cholesterol
(mmol/L)
Before
After
+3.5%
+4.4%
Total
Triglyceride
(mmol/L)
HbA1c
(%)
Before
After
mean change
from baseline
Before
After
mean change
from baseline
+0.8%
-3.6%
-0.54%
-4.03%
0.625
2.5
4.97*
5.32
5.25
5.28
TG >3.4
3.30
3.36
2.86****
3.42
1.20
1.20
1.46****
1.24
3.75
3.23
1.29
1.40
3.62
3.75
0.625
2.5
0.625
2.5
5.80
3.60
0.62
0.60
1.74
1.53
1.79
1.61
1.90
2.04
1.86
1.93
8.0*
7.8
8.7
8.1
1.27
1.29
1.19
0.70
6.29
4.09
1.09
difference in mean
% change from
baseline to year 1
between gps
difference in mean
% change from
baseline to year 1
between gps
difference in mean
% change from
baseline to year 1
between gps
-5.4%
-12.7%
+7.3%
Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison p<0.05, p<0.01, p<0.005, p<0.001
117
0.69
0.64
2.40
7.6
0.70
2.31
7.6
difference in mean
% change from
baseline to year 1
between gps
+6.9%
Table 18: Effects of hormone replacement therapy on lipids in Type 2 diabetes
Reference
Perera, 2001
(UK)
Population studied

mean age 62 yrs
6-mth RCT
estradiol patches
+ norethisterone v.
identical placebos
Drug
dose
(mg/day)
80g
1
Inclusion
criteria
(mmol/L)
Effects on lipids
Total
Cholesterol
(mmol/L)
LDL
Cholesterol
(mmol/L)
HDL
Cholesterol
(mmol/L)
VLDL
Cholesterol
(mmol/L)
Total
Triglyceride
(mmol/L)
HbA1c
(%)
Before
After
Before
After
Before
After
Before
After
Before
After
Before
After
5.60
5.13*
3.66
3.37
1.26
1.16
0.70
0.70
1.78
1.38*
6.6
6.6
5.23
5.12
3.46
3.26
1.14
1.15
0.60
0.53
1.42
1.42
6.4
6.8
Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison p<0.05, p<0.01, p<0.005, p<0.001
118
Some combination therapies are effective in reducing lipids in people with Type 2
diabetes but data are limited
The specific lipid abnormality of Type 2 diabetes (elevated triglycerides and low HDL
cholesterol) is often combined with elevated total and LDL cholesterol, which has the same
prevalence in people with Type 2 diabetes as in the overall population. Correction of these
multiple lipid abnormalities is often not possible with a single lipid modifying agent and in
clinical practice combination therapy with more than one agent may be used. Despite the
potential benefit, only a few studies have been carried out using combination therapy in
people with Type 2 diabetes.
Combination therapy with statin plus fibrate
Gavish et al (2000) performed an open 21-month trial in which 48 people with Type 2
diabetes received slow release bezafibrate 400mg/day and 100 received simvastatin
20mg/day for 6 months following which all subjects received both medications for one year.
All subjects received only diet and oral hypoglycaemic agents in the first 3 months. The
effects of the combination therapy were significantly greater than either simvastatin or
bezafibrate alone, with a 42% reduction in plasma triglycerides (4.3 to 2.5mmol/L, p<0.01),
23% reduction in total cholesterol (7.0 to 5.4mmol/L, p<0.01) and 29% reduction in LDL
cholesterol (4.5 to 3.2mmol/L, p<0.01), whilst HDL cholesterol increased by 25% (0.8 to 1.0
mmol/L, p<0.01). Lp(a) was also reduced by 19% from 3228 to 2624mg/dl (p<0.01). More
importantly, cardiovascular events were significantly reduced from 6% with statin and 12%
with fibrate to less than 2% during the combination treatment (p values not stated). The
change in plasma creatinine phosphokinase (CPK) was greater with combination therapy
from 7433 to 11387IU/L compared with 8848IU/L with simvastatin alone and 7624
IU/L with bezafibrate alone, but all changes were within the acceptable normal range for
CPK.
The effect of a combination of atorvastatin 20mg/day and micronised fenofibrate 200mg/day
(n=40) on lipids was compared to each drug alone (n=40 for each group) in 120 people with
Type 2 diabetes who were free of coronary artery disease at study entry (Athyros et al,
2002a). The combination therapy reduced total cholesterol by 37%, LDL cholesterol by 46%,
and triglycerides by 50%; whereas it increased HDL cholesterol by 22% (p<0.0001 for all
compared with baseline). All these changes were significantly greater than those of
monotherapies (all p<0.05), and more people on combined therapy reached the ADA (2001)
recommended LDL cholesterol goal of <2.6mmol/L (97.5% for combination therapy, 80%
with atorvastatin, 5% with fenofibrate, p<0.05), the desirable triglyceride levels of <2.26
mmol/L (100% v 75%, 92.5%, respectively, p<0.05), and the optimal HDL cholesterol goal
of >1.2mmol/L (60% v 7.5%, 30%, respectively, p<0.05). Moreover, the combined therapy
reduced the 10-year probability for myocardial infarction from 21.6% to 4.2% (p<0.0001)
compared with 7.5% with atorvastatin and 10.9% with fenofibrate (combined compared with
monotherapies, p<0.05). No significant adverse events were recorded. CPK was increased
with combined therapy at a higher level than with both monotherapies, but it still remained
within the normal range.
One component of the study by Wagner et al (2003) reported that the low dose combination
of atorvastatin 10mg and gemfibrozil 900mg in 44 people with Type 2 diabetes significantly
reduced LDL cholesterol by 26.5% (from 3.8 to 2.8mmol/L, p<0.0001), triglycerides by
24.1% (from 2.1 to 1.3 mmol/L, p<0.0001) and Apo B by 21.8% (125 to 95mg/dl, p<0.0001)
during 12 weeks of treatment. HDL cholesterol increased from 1.19 to 1.24mmol/L (p<0.05).
Mean LDL particle size was also decreased with combined treatment (from 25.510.06 to
25.680.06nm, p<0.05). Glycaemic control improved, with a reduction in HbA1c from 7.4 to
7.3% (p<0.05) and no change in body weight occurred after treatment. There was no an
119
elevation in liver enzymes greater than 3 times the upper normal limit and in CPK greater
than 10 times the upper normal limit during the study period.
Combination therapy with statin plus low-dose nicotinic acid
Because of its potential beneficial effect on HDL cholesterol, nicotinic acid is potentially
useful in Type 2 diabetes. However, high doses can worsen blood glucose control and can
cause significant side effects.
Flushing with nicotinic acid occurs so frequently that a double blind trial is not feasible.
There have been two randomised trials of combination therapy with pravastatin and nicotinic
acid. In the first study 11 people with Type 2 diabetes were included in a trial of pravastatin
40mg daily (n=6) or nicotinic acid 1,500mg daily (n=5) for 12 weeks, followed by
combination therapy with pravastatin 20mg daily plus nicotinic acid 1,000mg daily in all
participants (Tsalamandris et al, 1994). Baseline total cholesterol in people taking nicotinic
acid first was 8.1mmol/L and in people taking pravastatin first 7.3mmol/L, LDL cholesterol
was 5.7 and 5.2mmol/L, triglycerides were 6.7 and 5.5mmol/L and HDL cholesterol was 0.97
and 0.83mmol/L. On combination therapy total cholesterol fell by 26%, LDL cholesterol by
32%, triglycerides by 38% and HDL cholesterol rose by 33% (p values not given). HbA1c
rose from 7.4 to 7.9% (p=NS), but there was no effect on fasting glucose.
Another open label study included 14 people with Type 2 diabetes and 2 with Type 1
diabetes, using pravastatin 20mg daily as sole therapy for 4 weeks. Nicotinic acid was then
added, titrating up to 1,500mg daily over 2 weeks and continuing both pravastatin and
nicotinic acid for another 4 weeks (Gardner et al, 1997). Baseline total cholesterol was 7.7
mmol/L and fell by 21% with pravastatin (p<0.05) and by 27% with combination therapy
(p<0.05). LDL cholesterol was 5.3mmol/L at baseline and fell by 23% (p<0.05) and by 33%
(p<0.05 compared with both baseline and pravastatin alone). Triglycerides levels at baseline
were 2.1mmol/L and fell by 13% and 22% (both p=NS). HDL cholesterol was 1.14mmol/L at
baseline, did not change with pravastatin, but rose by 14% with combination therapy (p=NS).
Fasting glucose was 11.8 mmol/L at baseline, rose by 3% with pravastatin and fell by 11%
with combination therapy.
The following study demonstrated that combined intensive lipid lowering therapy improved
overall lipid profile in people with diabetes (Kanters et al, 1999). In order to reach the NCEP
II recommended lipid targets (triglycerides <1.7mmol/L, LDL cholesterol <2.6mmol/L, and
HDL cholesterol >0.9 mmol/L for men and >1.1 mmol/L for women), a stepped medication
strategy was used, in which simvastatin 20 mg daily or gemfibrozil 600mg twice daily was
given first, then followed by the combination of the two and finally the combination plus
acipimox 500-1500mg daily. During 30 weeks, the lipid targets were reached in 42 out of 59
people (71%) with Type 2 diabetes, with total cholesterol decreasing by 1.7mmol/L, LDL
cholesterol by 1.3mmol/L, and triglycerides by 1.1mmol/L. Mean HbA1c did not change
during the study. Five people dropped out because of side effects including flushing and
headache, myalgia and gastrointestinal disturbance.
The LDL particle size before and after lipid-lowering treatment with the same stepped
medication strategy described above was examined in 50 people with Type 2 diabetes
(Niemeijer-Kanters et al, 2001). At baseline, 24 people were characterised by the more
atherogenic LDL subclass pattern B. After 30 weeks of treatment, a shift towards normal
LDL particle size (pattern A) was observed in 17 people, with an increase in LDL particle
diameter (from 2535 to 2666, p<0.001) observed only in this group, while 7 people still
showed LDL subclass pattern B. Overall, reductions in total cholesterol of 1.4 to 1.5mmol/L
(p<0.001), LDL cholesterol of 0.6 to 0.8mmol/L (p<0.001), and triglycerides of 0.6 to
1.6mmol/L (p<0.001) were observed in people with LDL subclass pattern A or B at the end
of study, whereas HDL cholesterol rose by 0.3 to 0.4mmol/L (p<0.001), with a significant
increase in HDL3 cholesterol (p<0.001).
120
Summary Effects of lipid-modifying agents and hormone replacement

therapy on lipids
Fibrates reduce plasma triglycerides by approximately 30-50% in people with Type 2

diabetes
Fibrates generally increase HDL cholesterol by approximately 10% in people with Type
2 diabetes
The effect of gemfibrozil on LDL cholesterol in people with Type 2 diabetes is variable.
Fibrates have no adverse effects on glycaemic parameters
The primary effect of statins in people with Type 2 diabetes is to lower LDL cholesterol
Statins reduce total cholesterol by between 20 and 30% and the LDL cholesterol by
between 25 and 45% in people with Type 2 diabetes
The triglyceride-lowering effect of statins varies between 6 and 30% and the HDL
raising effect between 4 and 17%
Statins do not affect glycaemic control in people with Type 2 diabetes
Nicotinic acid improves the lipid profile in people with Type 2 diabetes by lowering
total and LDL cholesterol and triglycerides and increases HDL cholesterol
Nicotinic acid in high doses may cause a modest deterioration in blood glucose control
There are limited data on the effectiveness of bile acid sequestrants in Type 2 diabetes
-3 fatty acids given as fish oil supplements lower triglycerides by between 5 and 30%,
increase LDL cholesterol levels by 5% and HDL cholesterol by 1-9% and have little
effect on total cholesterol levels
-3 fatty acids (fish oil) may cause a dose dependent deterioration in blood glucose
control increase fasting
Oestrogen therapy in postmenopausal women with Type 2 diabetes increases HDL
cholesterol by 5 to 20%, reduces LDL cholesterol by about 10% and increases
triglyceride levels by about 5%
Combined therapy with a statin and a fibrate is effective in people with Type 2 diabetes,
although data are limited
Care must be taken with combination therapy to fully inform and monitor patients
because of the increased risk of myositis in people treated with a statin plus a fibrate
121

Effects of lipid-lowering agents and hormone replacement therapy on lipids in
Type 2 diabetes
Author
Evidence
Level of Evidence
Level
Study Type
Athyros VG (2002a)
(Adults Greece)
Avogaro A (1999)
(Adults Italy)
Barrett-Connor E (2003)
(Adult women US)
Brussard HE (1997a)
(Adult women The
Netherlands)
DAIS Investigators (2001)
(Adults Canada, Finland,
Sweden, France)
Down JR (1998)
(Adults US)
Elam MB (2000)
(Adults US)
Elkeles RS (1998)
(Adults UK)
Farrer M (1994)
(Adults UK)
Fasching P (1996)
(Adults Austria)
Freed MI (2002)
(Adults US)
Frick MH (1987)
(Adult men Finland)
Friedberg CE (1998)
Quality
Rating
Magnitude
Rating
Relevance
Rating
High C+L+ H+ T+
High
II
RCT
High
II
RCT
High
High
II
RCT
High
High C+L+
High
II
RCT
High
High C+L+ H+
High
II
RCT
High
High C+L+ H+ T+
High
II
RCT
High
High C+L+ H+ T+
High
II
RCT
High
High L+ H+ T+
High
C+ H+ T+
High
High
H+ T+
High
II
RCT
High
II
RCT
High
High C+L+ H+ T+
High
II
RCT
Medium
High L+ T+
High
L+ H+ T+
High
II
RCT
High
II
RCT
Medium
High +
Low
Meta-analysis
High
High L- T+
High
High
Gardner SF (1997)
III-2
Cohort
Medium
High L+
High
(Adults US)
Garg A (1994b)
C+L+ TII
RCT
High
High
High
(Adults US)
Gavish D (2000)
III-2
Cohort
High
High C+L+ T+ H+
Medium
(Adults Israel)
Gentile S (2000)
High
II
RCT
High
High C+L+ H+ T+
(Adults Italy)
GISSI (1999)
+
II
RCT
High
High
High
(Adults Italy)
Goldberg R (1990)
II
RCT
High
High+
High
(Adults US)
Goldberg R (1998)
II
RCT
High
High+
High
(Adults US)
Grundy SM (2002)
II
RCT
High
High H+ T+
High
(Adults US)
Haffner SM (1999)
High
II
RCT
Medium
High+
(Adults Danmark, Finland,
Iceland, Norway, Sweden)
Hulley S (1998)
Low
II
RCT
High
Low
(Adult women US)
Kanters SDJM (1999)
+
III-2
Cohort
High
High
High
Kirchgassler KU (1998)
III-2
Cohort
Medium
High+
High
(Adults Germany)
Knopp RH (1994b)
High
II
RCT
High
High C+L+ H+ T+
(Adults US)
Koskinen P (1992)
II
RCT
High
High+
High
(Adult men Finland)
Lahdenpera S (1993)
II
RCT
High
High L- H+ T+
High
(Adults Finland)
+
lipid modifying agents improve lipid levels; High = clinically important & statistically significant; Medium = small clinical
importance & statistically significant; Low = no statistically significant effect.
122

Evidence
Author
Level of Evidence
Level
Type
Manning PJ (2001)
(Adult women New Zealand)
Manson JE (2003)
(Women multicentres)
Montori VM (2000)
Quality
Rating
Magnitude
Rating
Relevance
Rating
II
RCT
High
High C+L+
High
II
RCT
High
Low
High
Meta-analysis
High
High L- T+
High
Niemeijer-Kanters SDJM
High
III-2
Cohort
High
High C+L+ H+ T+
(2001)
Ogawa S (2000)
Low
II
RCT
Medium
High C+ H+ T+
(Adults Japan)
ONeal DN (1998)
High
II
RCT
High
High C+ T+
(Adults Australia)
Perera M (2001)
II
RCT
High
High C+ T+
High
(Adults UK)
Petersen M (2002)
FO+
High
II
RCT
High
High
(Adults Denmark)
Pyorala K (1997)
II
RCT
High
High+
High
(Adults Scandinavia)
Rovellini A (1992)
III-2
Cohort
Medium
High C+ T+
High
(Adults Italy)
Rustemeijer C (2000)
II
RCT
High
High C+ L+ T+ H+
High
Schweitzer M (2002)
II
RCT
High
High C+ L+ T+
High
(Adults US)
Soedamah-Muthu SS (2003)
II
RCT
High
High C+ L+ T+
High
(Adults UK)
The DALI Study Group
High
II
RCT
High
High C+ L+ H+ T+
(2001)
Tikkanen MJ (1998)
High
II
RCT
High
High C+ L+ H+ T+
(Adults Finland)
Tsalamandris C (1994)
C+L+ H+ T+
High
III-2
Cohort
High
High
(Adults Australia)
Vinik AI (1993)
High
II
RCT
High
High C+ H+ T+
(Adults US)
Vuorinen-Markkola H (1993)
High
II
RCT
Medium
High H+ T+
(Adults Finland)
Wagner AM (2003)
High
II
RCT
High
High L+ H+ T+
(Adults Spain)
lipid modifying agents improve lipid levels; High = clinically important & statistically significant; Medium = small clinical
123
Section 5: Lipids
Issue
Does treatment with lipid modifying agents or hormone replacement therapy improve
outcomes in Type 2 diabetes?
Recommendations
People with Type 2 diabetes who have an LDL cholesterol >2.5mmol/L after interventions
to modify lifestyle and improve blood glucose control, should be considered for statin
therapy
People with Type 2 diabetes who have triglycerides >2.0mmol/L after interventions to
modify lifestyle and improve blood glucose control, should be considered for fibrate
therapy
Evidence Statements
Statins can prevent coronary heart disease in people with Type 2 diabetes
Evidence level II
Statins can prevent coronary heart disease in people with impaired fasting glucose
(IFG)
Evidence level II
Statins can prevent stroke in people with Type 2 diabetes

Evidence level II
Fibrates may prevent coronary heart disease in people with Type 2 diabetes
Evidence level II
There are no data on the effect of -3 polyunsaturated fatty acids (fish oil) and the risk
of cardiovascular disease specifically in people with Type 2 diabetes
Evidence level II
There is no evidence that hormone replacement therapy reduces the risk of coronary
heart disease in postmenopausal women with Type 2 diabetes
Evidence level II
Lipid modifying therapy in Type 2 diabetes is considered to be cost effective

Evidence level III
The primary target in people with Type 2 diabetes is an LDL cholesterol of 2.5mmol/L
Evidence level II
124
Background - Effects of lipid modifying agents on outcomes in Type 2

diabetes
Cardiovascular disease, particularly coronary heart disease (CHD), is the most common cause
of morbidity and mortality in Type 2 diabetes (Laakso, 1997). For men with Type 2 diabetes
the mortality from CHD is 2-4 times higher than in non-diabetic men and the relative risk is
even greater for women with Type 2 diabetes (Stamler et al, 1993). This increased prevalence
of CVD is addressed in detail in the Prevention and Detection of Macrovascular Disease in
Type 2 Diabetes guideline.
The common CVD risk factors (lipids, blood pressure, smoking and increasing age) are also
operative in people with Type 2 diabetes (Turner et al, 1998). LDL cholesterol level remains
an important predictor of CVD risk in Type 2 diabetes, but levels are similar to the nondiabetic population and therefore LDL cholesterol alone does not explain the excessive CVD
in this group (see Section 1 of this guideline). The increase in CHD is also associated with
elevated triglycerides and reduced HDL cholesterol levels, the specific form of lipid
abnormality frequently found in Type 2 diabetes. These lipid abnormalities are also
associated with qualitative changes in LDL cholesterol, particularly particle size and
composition, which is thought to render the particles more atherogenic (Barakat et al, 1990).
Many studies in Type 2 diabetes have shown that lipid abnormalities can be corrected by
lipid modifying interventions, but data on altering outcomes are more limited. The earlier
large prospective studies included only small cohorts of people with Type 2 diabetes and
these were mainly secondary prevention studies in people with pre-existing CHD. However
recent data have become available on prevention studies (primary or secondary) with statins
involving significant numbers of people with diabetes (Steiner, 2000; Colagiuri & Best,
2002). The results of similar studies with fibric acid derivatives or fibrates will become
available in 2005.
With the convincing data of benefit of statin therapy from the Heart Protection Study in
people with diabetes (Heart Protection Study Collaborative Group, 2003), a central issue
considered in this Section is how should lipid modifying agents be used in people with Type
2 diabetes.
The aim of the management of people with Type 2 diabetes is to prevent or reduce morbidity
and premature mortality from macrovascular and microvascular complications. In addition to
treatment of the diabetes, this requires treatment of other modifiable risk factors such as
blood pressure, lipids and smoking.
It is widely accepted that blood pressure and lipid lowering therapy should be used (unless
contraindicated) in the management of all people with Type 2 diabetes who have had a
previous cardiac or cerebrovascular event. However the use of these therapies in people who
have not had a previous macrovascular event (ie primary prevention) is not universally
agreed.
Published guidelines have used the following approaches to lipid lowering therapy for
primary prevention of CVD in people with diabetes:
intervention based on blood lipid levels alone (NCEP 2001, NCEP 2002; ADA 2004;
NHF 2001)
intervention based on blood lipid levels and assessment of overall cardiovascular risk
(UK NICE guidelines 2002, European Guidelines on Cardiovascular Disease Prevention
125
in Clinical Practice, 2003). However it should be noted that the European Guidelines on
Cardiovascular Disease Prevention in Clinical Practice classify all people with Type 2
diabetes as being at high risk and suggest blood lipid lowering therapy in those with lipid
levels above target.
Absolute risk assessment and the prediction of future vascular events
The concept of risk factors for vascular disease is universally accepted based on
epidemiological studies showing an association of particular risk factors and cardiovascular
events and intervention studies demonstrating that reducing risk factors results in a reduction
in CVD events.
In recent years there has been an increasing focus on using a combination of risk factors
rather than single risk factors to predict the likelihood of a future vascular event. The concept
of using absolute risk assessment to inform clinical decision making in the primary
prevention of vascular disease is widely accepted (Jackson, 2000a). Absolute risk assessment
allows identification of individuals in whom the largest number of vascular events will occur.
Most methods for calculating absolute risk are based on data derived from the Framingham
study (Anderson et al, 1991). However the applicability of the Framingham equations to
predict CHD in people with diabetes has been questioned because of the low prevalence of
diabetes in the Framingham study. Yeo and Yeo (2001) compared mean values for age, sex,
systolic blood pressure, smoking habit, diabetes status, total cholesterol and HDL cholesterol
to estimate predicted CHD events and mortality using the Framingham equations for subjects
participating in the UKPDS (UKPDS 33) with actual event rates observed during the study.
The Framingham estimate for annual CHD events was 1.6% and 0.2% for mortality
compared with UKPDS observed event rates of 2.7% and 1.0% respectively, a 40% and 80%
respectively underestimate by the Framingham equations. By comparison the Framingham
estimates correlated closely with observed event rates in the non-diabetic WOSCOPS
population. Recently a specific risk assessment tool has been developed based on the UKPDS
which may more accurately define risk in people with diabetes (Stevens et al, 2001).
There is no universal agreement on the level of risk for intervening, a decision which is not
only influenced by the risk level but also by available resources (British Cardiac Society,
British Hyperlipidaemia Association, British Hypertension Society, British Diabetic
Association, 2000).
In Australia, the National Vascular Disease Prevention Alliance (an alliance of the National
Heart Foundation, Diabetes Australia, National Stroke Foundation and the Australian Kidney
Foundation) is working with the Department of Health and Ageing to develop a policy and
tool for absolute risk assessment for Australia on which to base interventions to reduce CVD
risk factors.
Approach to use of Lipid Lowering Therapy
Two approaches have been used in clinical studies of lipid lowering therapy:
fixed dose of a medication
adjusting the dose of medication to achieve a target lipid level
Most outcomes studies have used a fixed dose of medication whereas most guidelines
advocate adjusting therapy to achieve a target lipid level (mostly LDL cholesterol).
Until the absolute risk work described above is completed, the position adopted in both the
Lipid Control and Blood Pressure Control Guidelines is that interventions with lipid and
blood pressure lowering therapy in people with Type 2 diabetes who have not had a previous
macrovascular event should be based on lipid and blood pressure levels exceeding target
levels.
126
Evidence - Effects of lipid modifying agents and hormone replacement

therapy on outcomes in Type 2 diabetes
A recent meta-analysis has examined the cardiovascular benefit of lowering cholesterol,
blood pressure and blood glucose in people with Type 2 diabetes. This study was reported
before the release of the Heart Protection Study (HPS Collaborative Group, 2002a) findings
and combined primary and secondary prevention studies and treatment with statins and
fibrates (Huang, 2001). The lipid lowering studies showed significantly reduced combined
cardiac events (risk rate 0.77, 95% CI 0.62-0.96) for secondary prevention (3 studies) but no
significant effect in primary prevention studies (2 studies). Of individual cardiac events only
the reduction in myocardial infarction in secondary prevention studies was significant. The
benefit was comparable to blood pressure lowering and greater than for blood glucose
lowering.
Statins can prevent coronary heart disease in people with Type 2 diabetes
There is evidence from well designed studies that reducing LDL cholesterol with statins
decreases the risk of CHD (Table 19). These large double blind, placebo controlled trials
have been performed predominantly in non-diabetic populations but some have included
substantial numbers of people with diabetes. Those studies which included subgroup analyses
of people with diabetes are reviewed below. Where there is no information in people with
diabetes, studies in the non-diabetic population are described.
Secondary Prevention
Improvement in clinical outcomes
The 4S (Scandinavian Simvastatin Survival Study) included 4,444 people aged 35-70 years
with total cholesterol between 5.5 and 8.0mmol/L (mean 6.75mmol/L) and triglycerides 2.5
mmol/L who were randomised to treatment with simvastatin or placebo and were followed
for an average period of 5.4 years (Scandinavian Simvastatin Survival Study Group (4S),
1994). Simvastatin was commenced at a dose of 20mg daily and was titrated to 40mg to
achieve a target total cholesterol of 3.0-5.2mmol/l. At 1 year 72% achieved the target
cholesterol with 37% of participants taking simvastatin 40mg. Over the course of the study,
the mean changes from baseline in the simvastatin group were reductions of 25% for total
cholesterol, 35% for LDL cholesterol and 10% for triglycerides, with an increase of 8% for
HDL cholesterol. The risk of major coronary events in the simvastatin treated group was
reduced by 34% (p<0.00001).
There have been two published analyses of the diabetic subgroup in the 4S study (Pyorala et
al, 1997; Haffner et al, 1999). Of the 4,444 subjects, 202 had a clinical history of diabetes.
Over the 5.4-year follow-up, simvastatin treatment significantly reduced the risk of major
CHD events (RR 0.45 [0.27-0.74], p=0.002) and of any atherosclerotic event (RR 0.63 [0.430.92], p=0.018). Total mortality was decreased by 43% (RR 0.57 [0.30-1.08]), but this did
not achieve statistical significance (p=0.087) (Pyorala et al, 1997). A subgroup analysis of
people with diabetes in the 4S study by Haffner et al (1999) included a further 281 subjects
who were defined as having diabetes on the basis of fasting glucose 7.0mmol/L (total with
diabetes 483). Lipid and lipoprotein changes with treatment in the diabetic subgroup were
similar to the non-diabetic group. Treatment with simvastatin reduced major CHD events by
42% (RR 0.58 [CI 0.41-0.80], p=0.001) and revascularisation by 48% (RR 0.52 [CI 0.320.82], p=0.005). These were not significantly different from a 32% reduction (RR 0.68 [CI
0.59-0.79], p<0.001) and a 33% reduction (RR 0.67 [CI 0.55-0.80], p<0.001) in the cohort
with normal glucose tolerance. Total mortality was reduced by 21% with simvastatin, but this
127
was not significant (RR 0.79 [CI 0.49-1.27], p=0.34). The corresponding figure in
nondiabetic cohort was 28% (RR 0.72 [CI 0.57-0.90], p=0.005).
The CARE study (Cholesterol And Recurrent Events) (Sacks et al, 1996) included 4,159
people with mean cholesterol levels of 5.4mmol/L and LDL cholesterol 3.0 to 4.5mmol/L.
Participants were randomised to placebo or pravastatin 40mg/day and had a median followup period of 5.0 years. Pravastatin lowered total cholesterol by 20%, LDL cholesterol by
32%, triglycerides by 14% and raised HDL cholesterol by 5% (p<0.001 for all comparisons).
Myocardial infarction or CHD death was reduced by 24% (p<0.003) in the group on
pravastatin and there was also a 31% reduction (p<0.03) in the risk of stroke.
The CARE study included 586 people with a clinical history of diabetes (Goldberg et al,
1998). Average cholesterol levels, response to pravastatin and risk reduction of end points
were similar to the non-diabetic group. In people with diabetes there was a significant
reduction in total coronary events (CHD death, nonfatal MI, revascularisation procedures)
(25%, p=0.05) and in revascularisation procedures (32%, p=0.04). However because of the
higher event rates, people with diabetes experienced a greater absolute risk reduction in total
coronary events compared with people without diabetes (8.1% v 5.2%).
The LIPID study (Long-term Intervention with Pravastatin in Ischaemic Disease) (LIPID
Study Group, 1998) followed 9,014 subjects for an average of 6.1 years. Initial cholesterol
levels, the response to pravastatin 40mg daily and the reduction of cardiovascular events were
similar to CARE. Overall, there was a 22% reduction in total mortality (CI 13-31%, p<0.001)
and a 24% reduction in CHD death (CI 12-35%, p<0.001). The risk of myocardial infarction
decreased by 29% (CI 18-38%, p<0.001) and the risk of stroke by 19% (CI 0-34%, p=0.048)
in the pravastatin group.
In the LIPID study there were 1,077 subjects with diabetes (Keech et al, 2003). The risk of a
major CHD event in these 1,077 subjects with diabetes was 61% higher than the non-diabetic
group. There was a 19% reduction in myocardial infarction or CHD death in the group with
diabetes (absolute risk reduced from 23.4 to 19.6%, p=0.11) compared with a 24% reduction
among all patients (absolute risk reduced from 15.9 to 12.3%, p<0.001).
The Heart Protection Study (HPS) was a primary and secondary prevention study of
simvastatin 40mg daily and anti-oxidant vitamin therapy (vitamin E 600mg, vitamin C 250
mg, beta-carotene 20mg daily) in a 22 factorial design (HPS Collaborative Group, 2002a;
HPS Collaborative Group, 2002b). HPS included 20,536 people aged 40-80 years with total
cholesterol >3.5mmol/L and a substantial 5 year risk of death because of a past history of
coronary disease or occlusive disease of non-coronary arteries, or diabetes or treated
hypertension (Heart Protection Study Collaborative Group, 2002a). In the 10,269 people
assigned to treatment with simvastatin 40mg daily, the risk of a major vascular event (CHD,
stroke or revascularisation) was 19.8% compared with 25.2% in the 10,267 people on placebo
(24% relative risk reduction, p<0.00001). The study failed to show any effect of antioxidant
vitamin therapy for the whole cohort or any subcategory (Heart Protection Study
Collaborative Group, 2002b).
The Heart Protection Study included 5,963 people with diabetes of whom 1,981 had had a
previous CHD event. Overall there was a highly significant 13% reduction in all cause
mortality (14.9 v 12.9%, p< 0.0003) due to an 18% reduction in coronary death (p<0.0005).
The incidence of a first major vascular event was reduced by 22% in people with diabetes
treated with simvastatin compared with placebo (p <0.0001). Simvastatin therapy reduced the
incidence of a first major vascular event by 11% (325/972 v 381/1009) compared with
placebo (OR 0.89 [CI 0.75-1.05]), however this was not significant (HPS Collaborative
128
Group, 2002a). In the 2,912 people with diabetes and no diagnosed vascular disease at
baseline, there was a 33% reduction in first major vascular event (p=0.0003) (HPS
Collaborative Group, 2003).
In the PROSPER study (Shepherd et al, 2002), 5,804 elderly people (aged 70-82 years, 623
with diabetes) with previous cardiovascular disease were randomised to pravastatin 40
mg/day or placebo for an average of 3.2 years. LDL cholesterol was 34% lower in the
pravastatin group than in the placebo group. Pravastatin resulted in a 15% reduction in the
incidence of the combined primary endpoint (HR 0.85, CI 0.74-0.97; p=0.014), 19%
reduction in CHD death or nonfatal myocardial infarction (HR 0.81, CI 0.69-0.94, p=0.006)
and 24% reduction in mortality from CHD (HR 0.76, CI 0.58-0.99, p=0.043). Fatal or
nonfatal stroke was not affected (HR 1.03, CI 0.81-1.31, p=0.8). With regard to baseline LDL
cholesterol levels, the incidence of primary endpoint was significantly reduced in people with
LDL >4.11mmol/L (HR 0.77, CI 0.60-0.98) compared with people with LDL <3.41mmol/L
(HR 0.88, CI 0.80-1.10) and LDL 3.41-4.11mmol/L (HR 0.88, CI 0.70-1.10). Among people
with diabetes (n=623) the incidence of primary endpoint was higher (HR 1.27, CI 0.90-1.80)
compared with people without diabetes (HR 0.79, CI 0.59-0.91) (between groups p=0.015).
In the GREACE study (Athyros et al, 2002b), 1,600 people (19.6% with diabetes) with a
prior myocardial infarction or stenosis of >70% of at least one coronary artery were randomly
assigned to treatment with atorvastatin (10-80mg/day) group or to usual care. The mean
atorvastatin dosage was 24mg/day and 14% of people in the usual care group received lipidlowering treatment during the entire study (statins 12%, fibrates 2%). Treatment with
atorvastatin lowered total cholesterol by 36% (6.66 to 4.27mmol/L), LDL cholesterol by 46%
(4.66 to 2.57mmol/L) and increased HDL cholesterol by 7% (1.01 to 1.09mmol/L) compared
with the changes in the usual care group (-4% [6.60 to 6.35mmol/L], p<0.0001; -5% [4.63 to
4.38mmol/L], p<0.0001; and +2% [1.01 to 1.04mmol/L], p=0.003, respectively). After 3
years, 97% people in the atorvastatin group compared with only 3% people in the usual group
achieved the NCEP recommended LDL cholesterol target of <2.6 mmol/L. Overall,
atorvastatin significantly reduced risk of total mortality (RR 0.57, CI 0.39-0.78; p=0.0021),
CHD mortality (RR 0.53, CI 0.29-0.74, p=0.0017), coronary morbidity (RR 0.46, CI 0.250.71; p<0.0001) and stroke (RR 0.53, CI 0.30-0.82; p=0.034). People with diabetes also
benefited from atorvastatin therapy with a 58% reduction in all cardiac events (p<0.0001).
Hoogwerf et al (1999) reported the effects of aggressive and moderate lipid lowering therapy
on the clinical outcomes in the subset of people with Type 2 diabetes who had had a CABG
procedure 1 to 11 years previously in he Post CABG Trial. Of the 116 people with diabetes,
63 were randomly assigned to aggressive lipid lowering using lovastatin (dosage not stated)
to achieve an LDL cholesterol of 1.55-2.20mmol/L, while 53 were assigned to moderate lipid
lowering using lovastatin to achieve an LDL cholesterol goal of 3.36-3.62mmol/L. Overall
the outcomes in people with and without diabetes were similar. Over the 4-year period, there
was a general reduction in RR for clinical events associated with aggressive lipid lowering
therapy, with a 47% reduction in combined endpoint (14.9 v 26.2%, RR 0.53 [CI 0.18-1.60]),
a 33% reduction in death (6.5 v 9.6%, RR 0.67 [CI 0.12-3.75]) and a 60% reduction in MI
(4.8 v 11.6%, RR 0.40 [CI 0.07-2.47]), but none of these reached statistical significance. Also
fewer people treated with aggressive lipid lowering therapy had a PTCA during the study
period (4.9 v 7.9%, RR 0.61 [CI 0.09-4.39]), but again this did not reach significance.
In a 24-month multicentre, randomised controlled trial, Cannon et al (2004) compared the
effects of pravastatin 40mg/day with atorvastatin 80mg/day in 4,162 people (mean age 58
years, 17.6% with diabetes) who had experienced an acute myocardial infarction or unstable
angina within the proceeding 10 days. At baseline, the lipid levels were comparable between
129
the two groups. During the follow-up, the median LDL cholesterol level achieved was
2.46mmol/L (interquartile rage 2.04-2.92mmol/L) in the pravastatin group and 1.60mmol/L
(interquartile range 1.29-2.04mmol/L) in the atorvastatin group (atorvastatin v pravastatin,
p<0.001). The median HDL cholesterol level rose by 8.1% in the pravastatin group and 6.5%
in the atorvastatin group (p<0.001). Overall, high-dose atorvastatin therapy resulted in a 16%
reduction (CI 5-26) in the rate of primary endpoint compared with standard-dose pravastatin
therapy (22.4 v 26.3%, p<0.001). The benefit appeared to be greater among people with a
baseline LDL cholesterol of 3.24mmol/L, with a 34% reduction, compared with a 7%
reduction in the event rate among those with a baseline LDL cholesterol of <3.24mmol/L
(p<0.02). Among 734 people with diabetes, the 2-year event rates were reduced from 34.6%
in the pravastatin group to 28.8% in the atorvastatin group (no p value reported but not
significant from Figure 5) compared with a significant reduction from 24.6% with pravastatin
to 21.0% with atorvastatin in the 3,428 people without diabetes.
The following 2 studies specifically examined statin treatment in people with hypertension
and included a mix of people with and without a previous CVD event. The ALLHAT study
was primarily designed to compare the effectiveness of different blood pressure lowering
medications - chlorthalidone, amlodipine, lisinopril and doxazocin in people aged 55 years
and older with hypertension and at least one additional CHD risk factor (ALLHAT
Collaborative Research Group, 2002a). ALLHAT-LLT was a substudy of ALLHAT which
included 10,355 people (mean age 66 years), of whom 3,638 had Type 2 diabetes, with LDL
cholesterol of 3.1-4.9mmol/L in those without CHD and 2.6-3.3mmol/L in those with CHD
and fasting triglycerides less than 3.9mmol/L not receiving lipid lowering medication at the
beginning of the study. People in ALLHAT-LLT were randomised to open-label treatment
with pravastatin 40mg/day (n=5,170) or to receive usual care (n=5,185). Over a mean 4.8
year follow-up, the study failed to show a difference in all-cause mortality or CHD events
between pravastatin and controls, a result which was observed for the total cohort and for the
diabetic population (ALLHAT Collaborative Research Group, 2002b). The 6-year mortality
rate was 14.9% for pravastatin and 15.3% for usual care, with a RR of 0.99 (CI 0.89-1.11,
p=0.88) and the numbers of CVD deaths were similar in both groups (295 v 300) (RR 0.99,
CI 0.84-1.16, p=0.91). CHD events (fatal CHD plus nonfatal MI) were somewhat lower in
the pravastatin group than in the usual care group (380 v 421), but this did not reach
significance (RR 0.91, CI 0.79-1.04, p=0.16). Possible explanations for this lack of difference
include the modest differential reduction in LDL cholesterol (approximately 17%), the openlabel study design, or the decreased benefit of lipid lowering therapy in people with well
controlled hypertension.
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a randomised CHD primary
prevention study comparing conventional (-blocker diuretic) and more contemporary
(CCB ACEI) blood pressure lowering therapy in 10,305 adults aged 40-79 years with
hypertension. In addition, the study population was required to have at least 3 other risk
factors for cardiovascular disease. The study included a 22 factorial design comparing
additional treatment with atorvastatin 10mg/day in people with a total cholesterol of 6.5
mmol/L. The study population included 2,532 people with diabetes (24.3% in the atorvastatin
treatment group and 24.8% in the placebo group) (Sever et al, 2003). The lipid lowering part
of the study was discontinued after 3.3 years follow-up because cardiovascular outcomes
were significantly higher in the placebo group although the blood pressure was 138/80
mg/Hg for both groups. The hazard ratios were 0.73 (0.56-0.96, p=0.02) for fatal and nonfatal stroke, 0.79 (0.69-0.90, p=0.0005) for CVD and 0.71 (0.59-0.86, p=0.0005) for coronary
events. However analysis of the diabetic subgroup did not show a significant difference in the
primary endpoint of non-fatal MI plus fatal CHD. The authors speculate that this might be the
result of the low number of absolute events among people with diabetes resulting in
inadequate power to demonstrate a difference and the increased usage of statins in the
diabetes placebo group (14%) compared with the non-diabetic placebo group (8%). However
130
the possibility remains that lipid lowering therapy is not as effective in people with diabetes
who have well controlled blood pressure.
Improvement in angiographic outcomes
Hoogwerf et al (1999) reported the effects of aggressive and moderate lipid lowering therapy
on the angiographic outcomes in the subgroup of people with Type 2 diabetes who had had a
CABG procedure 1 to 11 years previously in the Post CABG Trial. Of the 116 people with
diabetes, 63 were randomly assigned to aggressive lipid lowering using lovastatin (dosage not
stated) to achieve an LDL cholesterol of 1.55-2.20mmol/L, while 53 were assigned to
moderate lipid lowering using lovastatin to achieve an LDL cholesterol goal of 3.363.62mmol/L. Among people with diabetes, the RRs for substantial progression and occlusion
in saphenous vein grafts were lower with aggressive lipid lowering compared with moderate
lipid lowering (RR 0.49 [CI 0.20-1.19], RR 0.54 [CI 0.15-2.02], respectively), although these
were not significant. The corresponding figures in people without diabetes were 0.60 (CI
0.46-0.79) and 0.61 (CI 0.41-0.92), respectively. The mean change in minimum lumen
diameter was -0.277 mm with aggressive therapy and -0.315 mm with moderate therapy in
the diabetic group, -0.194 mm and -0.389 mm, respectively in the non-diabetic group. There
were no statistically significant differences for all angiographic outcomes between people
with and without diabetes. As reviewed earlier in this Section clinical outcomes were similar
in the 2 groups.
The SCAT Study (Teo et al, 2000) randomised 460 subjects, 70% with a previous myocardial
infarction, to simvastatin 10mg/day or to placebo during an average follow-up of 47.8
months. Changes in coronary angiographic measurement between simvastatain and placebo
were as follows: mean diameter -0.070.20 v -0.140.20 mm (p=0.004), minimum diameter 0.0970.17 v -0.160.20 mm (p=0.0001), and percent diameter stenosis 1.67 v 3.83%
(p=0.0003). Among 11% subjects with diabetes, the differences for the above measurements
were also significant between simvastatin and placebo - p=0.031; p=0.025; and p=0.02,
respectively. With regard to clinical events, there were no differences between the two groups
in cardiac death, myocardial infarction, stroke, and the combined endpoint (all p>0.05).
However, fewer subjects in the simvastatin group needed revascularisation procedures
compared with the placebo group (13 v 28, p=0.02).
The Canadian Coronary Atherosclerosis Intervention Trial (Waters et al, 1994) examined the
effect of lovastatin 20-80mg/day on the progression of coronary atherosclerosis. LDL
cholesterol was decreased by 21% from 6.47 to 5.08mmol/L in the lovastatin group (n=165)
compared with a reduction of 1.4% in the placebo group (n=166) (between groups p<0.001).
The mean lovastatin dose was 36mg/day during the 2-year study period. Lovastatin treatment
was significantly associated with less worsening of all coronary lesions measured by the
minimum lumen diameter (MLD) (0.050.13 v 0.090.16mm, p=0.010) and less new
coronary lesions developed (23 v 49, p=0.001). Progression of lesions (worsening in MLD
0.04 mm) occurred in 33% of people in the lovastatin group compared with 50% in the
placebo group (p=0.003). However, among 14% people with diabetes, the worsening in MLD
of coronary lesions was not significant between the two treatment groups (0.08 v 0.11 mm,
p=0.43).
Primary Prevention
Prior to the Heart Protection Study there were little data
prevention of CVD in diabetes. Of the 20,536 participants
3,982 had diabetes and no previous CHD event. There was
first major vascular event in the simvastatin treated group
131
on statin therapy for primary

in the Heart Protection Study,
a significant 26% reduction in
(p<0.001) (HPS Collaborative
Group, 2002a). In the 2,912 people with diabetes and no diagnosed vascular disease at
baseline, there was a 33% reduction in first major vascular event (p=0.0003) (HPS
Collaborative Group, 2003). There was no effect with anti-oxidant vitamin supplements (HPS
Collaborative Group, 2002b).
The CARDS (Collaborative Atorvastatin Diabetes Study) (www.cardstrial.org, 2004)
randomised 2,838 people (mean age 61 years) with Type 2 diabetes but no history of
coronary, cerebrovascular or severe peripheral vascular disease to atorvastatin (10 mg/day)
(n=1,428) or placebo (n=1,410). At baseline the median LDL cholesterol level in both groups
was 3.1 mmol/L. After a mean follow-up of 4.5 years, LDL cholesterol was reduced by 40%
to 1.9 mmol/L (p<0.0001) and total cholesterol by 26% (from 5.4 to 4.0 mmol/L, p<0.0001)
in the atorvastatin group ccompared with little changes in the placebo group. 80% of subjects
in the atorvastatin group achieved LDL cholesterol target level of <2.6 mmol/L, while the
corresponding figure in the placebo group was only about 25%. Atorvastatin treatment
resulted in a 37% risk reduction in combined primary endpoint (CI 17-52, p=0.001), a 32%
risk reduction in any CVD endpoint (CI 15-45, p=0.001), and a 48% risk reduction in stroke
(CI 11-69). All cause mortality was also reduced by 27% (CI -1, 48) with atorvastatin but this
was not significant (p=0.059).
WOSCOPS (West of Scotland Coronary Prevention Study) was a primary prevention study in
6,595 men with mean cholesterol 7.0mmol/L (Shepherd et al, 1995). After an average followup period of 4.9 years there was a 31% reduction (p<0.001) of nonfatal myocardial infarction
or death from CHD in the group randomised to pravastatin 40mg daily compared with
placebo. Another primary prevention study, the AFCAPS/TexCAPS (Airforce/Texas
Coronary Atherosclerosis Prevention Study) recruited 5,608 men and 997 women with mean
cholesterol 5.71mmol/L, mean LDL cholesterol 3.89mmol/L and mean HDL cholesterol 0.94
mmol/L in men and 1.03mmol/L in women. Participants were randomised to either lovastatin
20-40mg daily or placebo. After an average follow-up period of 5.2 years there was a 37%
reduction (p<0.001) of acute major coronary events in the lovastatin treated group (Downs et
al, 1998). These two primary prevention studies provide only limited data relevant to diabetes
because of the small numbers of people with Type 2 diabetes included. In WOSCOPS only
about 1% of people had diabetes (76 in total) and a separate analysis of the subgroup with
diabetes was not performed (Shepherd et al, 1995). Of the AFCAPS/TexCAPS study
participants, 2.3% had a clinical history of diabetes (155 in total). The 43% risk reduction of
acute major coronary events in the diabetic group was not significantly different from the
36% reduction for the total cohort (Downs et al, 1998).
132
Table 19: Effects of lipid modifying agents on risk of cardiovascular disease

Study
No.
Proportion
with
diabetes
Description
Followup
Blood lipid effects
Main results
Before
After
AFCAPS/
TexCAPS
Downs, 1998
6,605
2.3%
RCT
Age 45-73 yr
Lovastatin 40mg/day v placebo
T-CHO 4.65-6.82mmol/L
LDL 3.36-4.91mmol/L
HDL 1.16mmol/L for men
1.22mmol/Lfor women
TG 4.52 mmol/L
5.2 yrs
All subjects
Lovastatin gp:
T-CHO 5.71
LDL
3.89
HDL
0.94 (men)
1.03 (women)
TG
1.78
All subjects
Lovastatin gp:
T-CHO 4.75
LDL
2.96
HDL
1.00 (men)
1.11 (women)
TG
1.61
ALLHAT-LLT
The ALLHAT
Collaborative
Research Group,
10,355
35%
4.8 yrs
All subjects
Pravastatin gp
T-CHO
5.77
LDL
3.77
HDL
1.23
TG
1.70
All subjects
Pravastatin gp
T-CHO
4.77
LDL
2.70
HDL
1.26
TG
1.64
10,305
24.6%
RCT - 22 factorial design

14% history of CHD, 100%
hypertension, mean age 66 yrs
randomised to:
pravastatin or usual care
pravastatin started at 20mg/day and
increased to 40mg/day to achieve a
25% decrease in LDL cholesterol
After first 1,000 subjects recruited
everyone randomised to pravastatin
received 40mg/day
RCT - 22 factorial design
9.7% with a previous stroke or TIA
5% with PVD
100% with hypertension
Age 40-79 yr
T-CHO 6.5mmol/L
TG <4.5mmol/L
Atorvastatin 10mg/day v
Placebo
3.3 yrs
All subjects
Atorvastatin gp:
T-CHO
5.48
LDL
3.44
HDL
1.31
TG
1.66
All subjects
Atorvastatin gp:
T-CHO
4.18
LDL
2.28
HDL
1.30
TG
1.32
2002b
ASCOT
Sever, 2003
T-CHO = Total cholesterol; HDL = HDL cholesterol; LDL = LDL cholesterol; TG = Triglycerides. MLD = minimum lumen diameter. IMT = intima-media thickness
133
RR Lovastatin v placebo
First acute major coronary event 0.63
(0.50-0.79), p<0.001
MI 0.60 (0.43-0.83), p=0.002
Unstable angina 0.68 (0.49-0.95), p=0.02
Revascularization 0.67 (0.52-0.85),
p=0.001
Coronary events 0.75 (0.61-0.92), p=0.006
CVD events 0.75 (0.62-0.91), p=0.003
RR Pravastatin v usual care:
Overall:
All-cause mortality: 14.9 v 15.3%, p=NS
CVD deaths: 6.9 v 7.1%, p=NS
CHD events: 9.3 v 10.4%, p=NS
RRs in people with diabetes:
All-cause mortality: 1.03, p=NS
CHD death & MI: 0.89, p=NS
HR Atorvastatin v placebo:
Nonfatal MI plus fatal CHD: 0.64 (0.500.83), p=0.0005
Total coronary events: 0.71 (0.59-0.86),
p=0.0005
Total CVD events: 0.79 (0.69-0.90),
p=0.0005
Fatal or nonfatal stroke: 0.73 (0.56-0.96),
p=0.024
In people with diabetes, no significant
benefits for above endpoints

Study
No.
Proportion
with
diabetes
Description
Followup
Blood lipid effects
Main results
Before
After
BIP Study
The BIP Study
Group, 2000
3,090
10%
RCT
Previous MI or stable angina,
Age 45-74 yr
T-CHO 4.7-6.5mmol/L
LDL4.7mmol/L
HDL 1.17mmol/L
TG <3.9mmol/L
Bezafibrate 400mg/day v placebo
6.2 yrs
All subjects
Bezafibrate gp:
T-CHO
5.49
LDL
3.83
HDL
0.90
TG
1.64
All subjects
Bezafibrate gp:
T-CHO
(no data)
LDL
(no data)
HDL
1.06
TG
1.30
RRR Bezafibrate v placebo:

Primary endpoint, 9.4%, p=NS
Non-fatal MI, 12.8%, p=NS
Secondary endpoint, 4.9%, p=NS
All endpoints combined, 6.6%, p=NS
TG 2.2mmol/L 39% reduction in primary
endpoint (p<0.02)
No separate analysis for diabetic group
CARE Trial
Sacks, 1996
4,159
14.5%
RCT
100% previous MI
Age 21-75 yr
T-CHO <6.21mmol/L
TG <4.0mmol/L
Pravastatin 40mg/day v placebo
5 yrs
All subjects
Pravastatin gp:
T-CHO
5.41
LDL
3.60
HDL
1.00
TG
1.76
All subjects
Pravastatin gp:
T-CHO
4.33
LDL
2.59
HDL
1.05
TG
1.51
CARE Trial
Goldberg, 1998
4,159
14% in
pravastatin
15% in
placebo group
RCT
100% previous MI
Age 21-75 yr
T-CHO <6.21mmol/L
TG <4.0mmol/L
pravastatin 40mg/day v placebo
5 yrs
Diabetic cohort
Pravastatin gp:
T-CHO
5.33
LDL
3.52
HDL
0.97
TG
1.85
Diabetic cohort
Pravastatin gp:
T-CHO
4.32
LDL
2.57
HDL
1.01
TG
1.61
2,838
100%
RCT
Mean age 61 yr
LDL4.14mmol/L
TG6.78mmol/L
atorvastatin 10mg/day v placebo
4.5 yrs
Atorvastatin gp:
T-CHO
5.40
LDL
3.10
HDL
1.30
TG
1.70
Atorvastatin gp:
T-CHO
4.00
LDL
1.90
HDL
1.32
TG
1.30
RRR in pravastatin group

Death from CHD: 20% (-5, 39), p=NS
Nonfatal MI: 23% (4-39), p=0.02
Fatal MI: 37% (-5, 62), p=NS
Risk reduction of coronary events
with diabetes: 25% (0-43), p=0.05
without diabetes: 23% (11-33), p<0.001
RRRs in people with diabetes in
pravastatin group
Coronary events: 25% (p=0.05)
Revascularisation: 32% (p=0.04)
CHD death: 3% (p=NS)
Fatal MI: 46% (p=NS)
Nonfatal MI: 18% (p=NS)
Total MI: 23% (p=NS)
Stroke: 14% (p=NS)
RRRs in atorvastatin group
combined
primary
endpoint:
37%
(p=0.001)
any CVD endpoint: 32% (p=0.001)
acute coronary events: 36%
stroke: 48%
all-cause mortality: 27% (p=NS)
Subgroup analysis
of people with
diabetes
CARDS Study
2004
134

Study
CCAIT
Canadian
Coronary
Atherosclerosis
Intervention Trial
Waters, 1994
DAIS
Investigators, 2001
DART
Burr, 1989
No.
331
418
2,033 men
Proportion
with
diabetes
Description
14%
100%
Nil
Followup
Blood lipid effects

Before
After
RCT
Mean age 53 yr
54% had a previous MI
18% had a previous angioplasty
T-CHO 5.70-7.78mmol/L
All received intensive dietary
counselling
Lovastatin 20mg/day, up to 80mg/day
to achieve LDL of <3.36mmol/L v
placebo
2 yrs
All subjects
Lovastatin gp:
T-CHO
6.47
LDL
4.48
HDL
1.07
TG
2.19
All subjects
Lovastatin gp:
T-CHO
5.08
LDL
3.16
HDL
1.12
TG
1.95
RCT
Type 2 diabetes, half had a history of
CAD
Age 40-65 yr
T-CHO/HDL 4mmol/L
LDL 3.5-4.5mmol/L
TG 5.2mmol/L
Fenofibrate 200mg/day v placebo
4 yrs
RCT
All had previous MI
Age <70 yr
Given dietary advice to reduce fat
intake, increase fibre and increase fish
consumption
v no dietary advice
2 yrs
All had diabetes

Fenofibrate gp:
T-CHO
5.56
LDL
3.38
HDL
1.01
TG
2.59
Main results
All had diabetes

Fenofibrate gp:
T-CHO
5.00
LDL
3.14
HDL
1.09
TG
1.84
(estimated from
chart)
All subjects
Adjusted fat advice v none
T-CHO 6.29 v 6.55mmol/L, p=NS
HDL 1.04 v 1.05mmol/L, p=NS
135
Lovastatin v placebo
worsening in MLD of all lesions:
0.050.13 v 0.090.16 mm, p=0.01
progression of worsening in lumen
diameter 0.04mm: 33 v 50%, p=0.003
new coronary lesions developed: 23 v 49,
p=0.001
In people with diabetes:
worsening in MLD of all lesions: 0.08 v
0.11 mm, p=NS
Fenofibrate v placebo:
40% less progression in MLD ,p=0.029;
42% less percentage diameter stenosis
p=0.02;
No difference in clinical outcomes
bar
RRs in different groups:

adjusted fat 1.0 (0.77-1.30) all deaths
0.91 (0.71-1.15) IHD events
adjusted fish 0.71 (0.54-0.93, p<0.05) all
deaths
0.84 (0.66-1.07) IHD events
adjusted fibre 1.27 (0.99-1.65) all deaths
1.23 (0.95-1.53) IHD events

Study
No.
Proportion
with
diabetes
Description
Followup
Blood lipid effects

Before
Main results
After
GISSI
Prevenzione
Trial
1999
11,324
14.8%
RCT
Gruppo Italiano per lo Studio della
Supravvivenza nellInfarto
Miocardico Prevenzione Trial
Age limits not defined
4 groups:
-3 PUFA (850mg/day)
vitamin E (300mg/day)
n-3 PUFA + vitamin E
control
42 months
All subjects
% change from baseline to 6 months:
n-3; Vit E; both; control
T-CHO: 7.9; 7.1; 8.9; 7.1%; p=0.039
LDL: 9.9; 7.2; 10.8; 7.4%; p=0.002
HDL: 8.8; 9.4; 8.9; 9.2%; p=0.0001
TG: 3.4; 2.9; 0.9; 1.4%; p=0.0001
GREACE
The GREek
Atorvastatin and
Coronary-heartdisease Evaluation
Athyros, 2002b
1,600
19.6%
Randomised, open-label
All prior MI or >70% occlusion of
one coronary artery
Age <75 yr
LDL >2.6mmol/L
TG <4.5mmol/L
Atorvastatin 10mg/d, up to 80mg/d to
achieve LDL of 2.6mmol/L v
Usual care
3 yrs
All subjects
Atorvastatin gp:
T-CHO
6.66
LDL
4.66
HDL
1.01
TG
2.08
All subjects
Atorvastatin gp:
T-CHO
4.27
LDL
2.57
HDL
1.09
TG
1.45
RR of -3 PUFA
Death, MI or stroke: 0.85 (0.74-0.98);
CVD death, MI or stroke: 0.80 (0.68-0.95)
All fatal events: 0.80 (0.67-0.94)
RR of vitamin E
CVD death, MI or stroke:
0.88 (0.75-1.04)
All fatal events: 0.86 (0.72-1.02)
RR of -3 PUFA+Vitamin E
CVD death, MI or stroke: 0.88 (0.75-1.03)
All fatal events:0.80 (0.67-0.95)
No separate results for people with diabetes
RRs Atorvastatin v usual care:
Total death: 0.57 (0.39-0.78), p=0.002
CHD death: 0.53 (0.29-0.74), p=0.0017
Coronary morbidity: 0.46 (0.25-0.71),
p=0.0001
Stroke: 0.53 (0.30-0.82), p=0.034
All cardiac events: RR 0.42, p<0.0001
136

Study
No.
Proportion
with
diabetes
Description
Followup
Blood lipid effects
Main results
Before
After
All subjects
Simvastatin gp:
T-CHO
5.1
LDL
2.7
HDL
1.08
TG
1.9
Heart Protection
Study, 2002a
20,536
19.4%
RCT 2x2 factorial design

Age 40-80 yr
T-CHO 3.5mmol/L
simvastatin 40mg/day v placebo
5 yrs
All subjects
Simvastatin gp:
T-CHO
5.9
LDL
3.4
HDL
1.06
TG
2.1
Heart Protection
Study, 2002b
20,536
19.4%

Age 40-80 yrs
T-CHO 3.5mmol/L
Vitamin E 600mg/day
Vitamin C 250mg/day
-carotene 20mg/day
v placebo
5 yrs
All subjects
Average lipids levels during follow-up (supplement
v placebo; difference)
T-CHO: 4.89 v 4.74, 0.15 mmol/L (p=0.024)
LDL: 2.82 v 2.74, 0.08 mmol/L(p=0.019)
HDL: 1.10 v 1.13, -0.03 mmol/L(p=0.007)
TG: 2.13 v 1.92, 0.21 mmol/L(p=0.027)
137
With simvastatin:
RRs in mortality:
Vascular 0.83 (0.75-0.91), p<0.0001
Non-vascular 0.95 (0.85-1.07), p=NS
All-cause 0.87 (0.81-0.94), p=0.0003
RRs of major event
Coronary
events
0.73
(0.67-0.79),
p<0.0001
Stroke 0.75 (0.66-0.85), p<0.0001
Revascularisation
0.76 (0.70-0.83), p<0.0001
Any major vascular events 0.76 (0.720.81), p<0.0001
In people with diabetes & prior MI:
RR for first major vascular event 0.76
(0.71-0.82), p<0.0001
RRs in mortality:
Vascular 1.05 (0.95-1.15), p=NS
Non-vascular 1.04 (0.92-1.17), p= NS
All-cause 1.04 (0.97-1.12), p= NS
RRs in major event
Coronary 1.02 (0.94-1.11), p=NS
Stroke 0.99 (0.87-1.12), p=NS
Revascularisation 0.98 (0.90-1.06), p=NS
Any major vascular event 1.00 (0.94-1.06),
p=NS
In people with diabetes & prior MI:
RR for first major vascular event 1.01
(0.95-1.08), p=NS

Study
No.
Proportion
with
diabetes
Description
Followup
Blood lipid effects
Main results
Before
After
Heart Protection
Study, 2003
5,963
100%

19% with previous MI
14% with other CHD
18% other vascular disease
Age 40-80 yr
T-CHO 3.5mmol/L
simvastatin 40mg/day v placebo
5 yrs
Diabetic cohort
Simvastatin gp:
T-CHO
5.7
LDL
3.2
HDL
1.06
TG
2.3
Diabetic cohort
Simvastatin gp:
T-CHO
4.6
LDL
2.3
HDL
1.07
TG
2.0
Helsinki Heart
Study
Frick, 1987
4,081 men
2.6%
RCT
Age 40-55 yr
non-HDL 5.2mmol/L
Gemfibrozil 1200mg/day v placebo
5 yrs
All subjects
Gemfibrozil gp:
T-CHO
6.99
LDL
4.90
HDL
1.22
TG
1.98
All subjects
Gemfibrozil gp:
T-CHO
6.39
LDL
4.49
HDL
1.32
TG
1.30
Helsinki Heart
Study
Koskinen, 1992
4,081 men
3.3%
known
diabetes &
FPG
7mmol/L
RCT
Age 40-55 yr
Lifestyle changes were recommended
to both groups.
5 yrs
Diabetic cohort
Gemfibrozil gp:
T-CHO
7.54
LDL
5.18
HDL
1.18
TG
2.42
Diabetic cohort
Gemfibrozil gp:
T-CHO
6.48
LDL
4.66
HDL
1.26
TG
1.79
138
For simvastatin group:

Major coronary events: RR 0.73 (0.670.79), p<0.0001
Stroke: RR 0.75 (0.66-0.85), p<0.0001
Revascularisation: RR 0.76 (0.70-0.83),
p<0.0001
Any major vascular event: RR 0.76 (0.720.81), p<0.0001
In people with prior CHD:
OR 0.89 (0.75-1.05), p=NS
In people with other CVD:
OR 0.78 (0.60-1.00), p=NS
In people without CVD:
OR 0.69 (0.55-0.87), p<0.01
Gemfibrozil v placebo:
Cardiac endpoints: 27.3 v 41.4 per 1000,
Overall reduction in cardiac endpoints in
Gemfibrozil gp: 34.0% (8.2-52.6), p<0.02
Nonfatal MI: 21.9 v 35.0 per 1000, 37%
reduction, p<0.02
Total mortality: 21.9 v 20.7 per 1000,
p=NS
No separate results for people with diabetes
Diabetes v without diabetes:
MI or cardiac death: 7.4 v 3.3%, p<0.02
Gemfibrizol v placebo in diabetes:
CHD events 3.4 v 10.5%, p=NS

Study
HERS
Hulley, 1998
LIPID Study
Group, 1998
No.
2,763
women
9,014
Proportion
with
diabetes
Description
18.5%
9%
Followup
Blood lipid effects
Main results
Before
After
RCT
Heart and Oestrogen/progestin
Replacement Study
17% had a Q-wave MI
45% had PTCA & 41.5% had CABG
Age 55 yr
TG <3.4mmol/L
Oestrogen 0.625mg/day +
progesterone 2.5mg/day
v placebo
4.1 yrs
All subjects
Estrogen-progestin gp:
T-CHO
LDL
3.75
HDL
1.29
TG
1.90
All subjects
at 1 year
T-CHO
LDL
HDL
TG
RCT
All had previous MI or unstable
angina
Age 31-75 yr
T-CHO 4.0-7.0mmol/L
TG <5.0mmol/L
6.1 yrs
All subjects
Pravastatin gp:
T-CHO
5.64
LDL
3.88
HDL
0.93
TG
1.60
All subjects
Pravastatin gp:
T-CHO
4.62
LDL
2.91
HDL
0.98
TG
1.42
RRR in pravastatin group

Mortality 22% (13-31), p<0.001
Death from CHD 24% (12-35), p<0.001
Death from CVD 25% (13-35), p<0.001
MI 29% (18-38), p<0.001
Any stroke 19% (0-34), p=0.048
In combined coronary endpoint:
Diabetes 19% (-10, 41), p= NS
Nondiabetes 25% (15-33), p<0.001
6.1 yrs
All subjects
Pravastatin gp:
T-CHO
5.65
LDL
3.89
HDL
0.93
TG
1.50
All subjects
Pravastatin gp:
T-CHO
4.59
LDL
2.84
HDL
0.97
TG
1.41
RRRs in pravastatin group:

Stroke from any cause: 19% (0-34), p=0.05
Nonhaemorrhagic stroke: 23% (5-38),
p=0.02
Haemorrhagic stroke: 0.2 v 0.4%, p=NS
3.23
1.40
2.04

LIPID
White, 2000
9,014
9%
All with a previous MI or unstable

angina
Age 31-75 yrs
T-CHO 4.0-7.0mmol/L
RCT
Relative hazard (RH) treatment group

primary CHD events: 0.99 (0.80-1.22),
p=NS
CHD death: 1.24 (0.87-1.75), p=NS
nonfatal MI: 0.91 (0.71-1.17), p=NS
RH at Year 4-5 compared to Year 1
primary CHD events: 0.67 (0.43-1.04),
p=0.009
CHD death: 0.95 (0.49-1.84), p=NS
nonfatal MI: 0.58 (0.34-1.02), p=0.01
No separate results for people with
diabetes

overall risk of stroke: 27% (-17, 54), p=NS
139

Study
LIPID
Keech, 2003
No.
9,014
Proportion
with
diabetes
Description
8.7% known
diabetes
3.3%
undiagnosed
diabetes
10.4% IFG
Post-CABG Trial
Hoogwerf, 1999
Post-CABG Trial
Knatterud, 2000
1,351
1,351
8.6%
8.6%
Followup
Blood lipid effects

Before
After
RCT
All with a previous MI or unstable
angina
Age 31-75 yr
T-CHO 4.0-7.0mmol/L
TG <5.0 mmol/L
6.1 yrs
Age 21-74 yr
All had CABG
No lipid inclusion criteria
RCT 22 factorial design
aggressive v moderate lipid

lowering with lovastatin
aggressive: to achieve LDL 1.55-2.20
moderate: to achieve LDL 3.36-3.62
warfarin v placebo
Mean age 60.9 yr
All had previous CABG
LDL 3.4-3.6mmol/L
TG3.4 mmol/L
RCT 22 factorial design
aggressive v moderate lipidlowering with lovastatin (40-80

mg/d v 2.5-5 mg/d)
aggressive: to achieve LDL 1.6-2.2
moderate: to achieve LDL 3.4-3.6
warfarin v placebo
4 yrs
Diabetic cohort:
Pravastatin gp:
T-CHO
5.56
LDL
3.70
HDL
0.86
TG
1.90
IFG cohort:
T-CHO
5.62
LDL
3.80
HDL
0.90
TG
1.72
Diabetic cohort
T-CHO
5.82
LDL
3.93
HDL
0.93
TG
2.09
Diabetic cohort:
Pravastatin gp:
T-CHO
4.45
LDL
2.66
HDL
0.90
TG
1.54
IFG cohort:
T-CHO
4.66
LDL
2.85
HDL
0.95
TG
1.56
Diabetic cohort
Aggressive treatment
LDL
2.49
All subjects:
T-CHO
LDL
HDL
TG
All subjects:
Aggressive treatment
LDL
2.41
7.5 yrs
5.83
4.01
1.01
1.79
Main results
Moderate treatment
LDL
3.49
Moderate treatment
LDL
3.49
140
RRRs Pravastatin v placebo:

in people with diabetes:
major CHD event: 24%, p<0.001
any CVD event: 21%, p<0.008
stroke: 39%, p=0.02
in people with IFG:
major CHD event: 19%, p=NS
any CVD event: 26%, p=0.003
stroke: 42%, p=NS
Aggressive v moderate treatment
RRs in people with diabetes:
Combined endpoint: 0.53 (0.18-1.60)
Death: 0.67 (0.12-3.75)
MI: 0.40 (0.07-2.47)
CABG: 1.14 (0.16-8.19)
PTCA: 0.61 (0.09-4.39)
Aggressive v moderate treatment

CVD death or nonfatal MI: 15.1 v 20.3%,
p=0.03
Composite clinical endpoint: 30.6 v 40.2%,
p=0.001

Study
No.
Proportion
with
diabetes
Description
Followup
Blood lipid effects
Main results
Before
After
PPP
The Prospective
Pravastatin
Pooling Project
Byington, 2001
19,768
7.3%
Data from CARE, LIPID, &

WOSCOPS
Mean age 58 yr
Pravachol 40mg/day v placebo
5 yrs
All subjects
Pravastatin gp
T-CHO
5.83
LDL
4.01
HDL
1.01
TG
1.79
All subjects
Pravastatin gp
T-CHO
no data
LDL
no data
HDL
no data
TG
no data
HRs Pravastatin v placebo:

across all 3 trials
Total stroke: 0.80 (0.68-0.93), p=0.01
Nonfatal stroke: 0.76 (0.64-0.90)
CARE & LIPID:
Total stroke: 0.78 (0.65-0.93), p=0.01
Nonfatal stroke: 0.75 (0.62-0.90)
In people with diabetes
Total stroke: HR approximately 0.74 (not
significant)
PROSPER
Shepherd, 2002
5,804
10.7%
RCT
Aged 70-82 yr with previous vascular
disease (CHD, cerebrovascular
disease, or PVD)
T-CHO 4.0-9.0mmol/L
TG <6.0mmol/L
3.2 yrs
All subjects
T-CHO
5.7
LDL
3.8
HDL
1.30
TG
1.5
All subjects
T-CHO
LDL
2.5
HDL
1.37
TG
1.3
HRs Pravastatin v placebo:

Primary endpoints: 0.85 (0.74-0.97),
p=0.014
CHD death or nonfatal MI: 0.81 (0.690.94), p=0.006
Nonfatal MI: 0.86 (0.72-1.03), p=NS
CHD death: 0.76 (0.58-0.99), p=0.043
Fatal or nonfatal stroke: 1.03 (0.81-1.31),
p=NS
TIA: 0.75 (0.55-1.00), p=0.051
Primary endpoint: 0.78 (0.66-0.93) for
CVD+; 0.94 (0.77-1.15) for CVDIn people with diabetes:
Primary endpoint: 1.27 (0.90-1.80), p=NS
Pravastatin 40mg/day v
placebo
141

Study
No.
Proportion
with
diabetes
Description
Followup
Blood lipid effects
4.8%
Main results
Before
After
RCT
All with angina or previous MI
Age 35-70 yr
T-CHO 5.5-8.0mmol/L
TG <2.5mmol/L
Simvastatin 20-40mg/day v placebo
5.4 yrs
All subjects
Simvastatin
T-CHO
LDL
HDL
TG
All subjects
Simvastatin
T-CHO
LDL
HDL
TG
Scandinavian
Simvastatin
Survival Study
(4S), 1994
4,444
Scandinavian
Simvastatin
Survival Study
(4S)
Pyorala, 1997
4,444
4.8%
RCT
Type 2 diabetes (n=202) &
nondiabetic (n=4,242)
Age 35-70 yr
T-CHO 5.5-8.0mmol/L
TG <2.5mmol/L
Simvastatin 20-40mg/day v
placebo
5.4 yrs
Simvastatin-treated
diabetic cohort
T-CHO
6.72
LDL
4.80
HDL
1.13
TG
1.69
Simvastatin-treated
diabetic cohort
T-CHO
4.90
LDL
3.10
HDL
1.21
TG
1.54
Scandinavian
Simvastatin
Survival Study
(4S)
Haffner, 1999
4,398
11% diabetes
-4.6% known
diabetes (202)
-6.4% newly
diagnosed
(281)
15.4% IFG
RCT
All with angina pectoris or previous
MI
Age 35-70 yr
T-CHO 5.5-8.0mmol/L
TG <2.5mmol/L
Simvastatin 20-40mg/day v placebo
5.4 yrs
Diabetic cohort
Simvastatin gp:
T-CHO
6.74
LDL
4.86
HDL
1.13
TG
1.65
Diabetic cohort
Reductions similar to
Pyorala study
6.74
4.87
1.19
1.49
142
5.06
3.17
1.29
1.34
RRs in simvastatin-treated group

mortality 0.70 (0.58-0.85), p=0.0003
all coronary deaths 0.58 (0.46-0.73), no p
value
all cardiovascular deaths 0.65 (0.52-0.80),
no p value
major coronary events 0.66 (0.59-0.75),
p<0.00001
any coronary events 0.73 (0.67-0.81),
p<0.00001
37% reduction (p<0.00001) in risk of
needing myocardial revascularisation.
No separate data for people with diabetes
RR in simvastatin-treated diabetic cohort:
Total mortality 0.57, p=0.087
CHD mortality 0.64, p=0.24
Major CHD events (CHD death or nonfatal
MI) 0.45, p=0.002
any CHD events 0.61, p=0.015
any atherosclerotic events 0.63, p=0.018
RRs in simvastatin-treated diabetic
cohort:
major coronary events 0.58, p=0.001
total mortality 0.79, p=NS
coronary mortality 0.72, p=NS
revascularizations 0.52, p=0.005
RRs in IFG subjects:
major coronary events 0.62, p=0.003
total mortality 0.57, p=0.02
coronary mortality 0.45, p=0.007
revascularizations 0.57, p=0.009

Study
Proportion
with
diabetes
Description
460
11%
SENDCAPS
Elkeles, 1998
164
100%
TIMI
Thrombolysis in
Myocardial
Infarction Study
Cannon, 2004
4,162
18%
SCAT
Simvastatin/Enala
pril
Coronary
Atherosclerosis
Trial
No.
Teo, 2000
Followup
Blood lipid effects
Main results
Before
After
RCT, 22 factorial design

Mean age 61 yr
54% had an angina
70% had a previous MI
T-CHO 4.1-6.2mmol/L
HDL <2.2mmol/L
TG <4.0mmol/L
Simvastatin 10mg/day v placebo
Enalapril 5mg/day v placebo
47.8
months
All subjects
Simvastatin gp:
T-CHO
5.23
LDL
3.39
HDL
0.99
TG
1.85
All subjects
Simvastatin gp:
T-CHO
4.13
LDL
2.33
HDL
1.07
TG
1.62
RCT
Age 35-65 yr
At least one of the following:
T-CHO 5.2mmol/L
or T-CHO/HDL 4.7
or TG 1.8mmol/L
or HDL 1.1mmol/L
Bezafibrate 400mg/day v placebo
RCT 2x2 factorial desig n
Mean age 58 yr
50.2% had hypertension
18.5% had a prior MI
T-CHO 6.21mmol/L
Pravastatin 40 mg/d
Atorvastatin 80 mg/d
3 yrs
All had diabetes

Bezafibrate gp:
T-CHO
5.77
LDL
3.66
HDL
1.02
TG
2.24
All had diabetes

Bezafibrate gp:
T-CHO
5.29
LDL
3.31
HDL
1.04
TG
1.44
24 months
All subjects
Pravastatin gp:
T-CHO
4.66
LDL
2.75
HDL
1.01
TG
1.74
Atorvastatin gp:
T-CHO
4.69
LDL
2.75
HDL
0.98
TG
1.79
All subjects
Pravastatin gp:
T-CHO
no data
LDL
2.46
HDL
1.09
TG
no data
Atorvastatin gp:
T-CHO
no data
LDL
1.60
HDL
1.04
TG
no data
143
Simvastatin v placebo:
reduction in mean diameter: -0.070.20 v 0.140.20 mm, p=0.004
reduction in minimum diameter:
-0.090.17 v -0.160.20 mm, p=0.0001
increase in % diameter stenosis:
1.67 v 3.83%, p=0.0003
In people with diabetes, the above three
measurements were significant for
simvastatin v placebo, with p=0.031;
p=0.025; and p=0.02, respectively
for clinical events:
cardiac death: 3 v 2%, p=NS
MI: 5 v 4%, p=NS
stroke: 2 v 3%, p=NS
combined endpoints: 11 v 9%, p=NS
any revascularisation: 6 v 12%, p=0.021
Bezafibrate v placebo:
confirmed MI: 1.5 v 4.0%, p=NS
probable ischaemia: 6.5 v 19.5%, p=0.03
definite CHD events: 7.4 v 22.6%, p=0.01
Atorvastatin v pravastatin:
combined primary endpoint: 16% (5-26),
p=0.005
need for revascularisation: 14%, p=0.04
recurrent unstable angina: 29%, p=0.02
in people with diabetes:
the 2-yr event rate: 28.8 v 34.6%, no p
value reported

Study
No.
Proportion
with
diabetes
Description
Followup
Blood lipid effects
Main results
Before
After
VA-HIT
Rubins, 1999
2,531
25%
RCT
All with CHD
Mean age 64 yr
LDL 3.6mmol/L
HDL 1.0mmol/L
TG 3.4mmol/L
5.1 yrs
All subjects
Gemfibrizol gp:
T-CHO
4.5
LDL
2.9
HDL
0.82
TG
1.8
All subjects
Gemfibrozil gp:
T-CHO
4.4
LDL
2.9
HDL
0.89
TG
1.3
VA-HIT
Rubins, 2002
2,531
24.8% known
DM
5.6%
undiagnosed
DM
12.8% IFG
5.1 yrs
Diabetic cohort
Gemfibrizol gp:
T-CHO
4.45
LDL
2.81
HDL
0.80
TG
1.88
Diabetic cohort
Gemfibrizol gp:
T-CHO
no data
LDL
2.81
HDL
0.84
TG
1.54
WOSCOPS
Shepherd, 1995
6,595
1.15%
RCT
All with CHD
Mean age 64 yr
LDL 3.6 mmol/L
HDL 1.0 mmol/L
TG 3.4 mmol/L
Gemfibrozil 1200 mg/day v placebo
RCT
Age 45-64 yr
T-CHO 6.5mmol/L
LDL 4.0mmol/L
4.9 yrs
All subjects
Pravastatin gp:
T-CHO
7.04
LDL
4.97
HDL
1.14
TG
1.83
All subjects
Pravastatin gp:
T-CHO
5.63
LDL
3.68
HDL
1.20
TG
1.61
144
RRRs Gemfibrozil v placebo:

Primary event: 22% (7-35), p=0.006
Combined outcome (death from CHD,
nonfatal MI & stroke: 24% (11-36),
p<0.001
Nonfatal MI: 23% (4-38), p=0.02
Death from CHD: 22% (-2, 41), p=NS
Death from any cause: 11% (-8, 27), p=NS
Confirmed stroke: 25% (-6, 47), p=NS
Combined outcome: 24% (-0.1, 43),
p=0.05
HRs Gemfibrozil v placebo in diabetic
cohort:
Composite endpoint: 0.68 (0.53-0.88),
p=0.004
CHD death: 0.59 (0.39-0.91), p=0.02
Stroke: 0.60 (0.37-0.99), p=0.046
RRRs Pravastatin v placebo:
Coronary events 31% (17-43), p<0.001
Nonfatal MI 31% (15-45), p<0.001
Death from CHD 28% (-10, 52), p=NS
Death from all cardiovascular causes 32%
(3-53), p=0.033
Total mortality 22% (0-40), p=0.051
No data for people with diabetes
Statins can prevent coronary heart disease in people with impaired fasting glucose
(IFG)
Impaired Fasting Glucose (IFG) is a relatively new category of glucose intolerance where
FPG is 6.1mmol/L but <7.0mmol/L (The Expert Committee on the Diagnosis and
Classification of Diabetes Mellitus, 1997). The glucose level of 6.1mmol/L was chosen
because above this level the first phase insulin secretory response to intravenous glucose is
lost and there is increased risk of microvascular and macrovascular complications. This
category is in addition to Impaired Glucose Tolerance (IGT) as defined by the oral glucose
tolerance test and the correlation between these two groups of abnormal glucose metabolism
short of diabetes is imperfect (Gomez-Perez et al, 1998). The new category of IFG identifies
a population with impaired glucose metabolism at increased CHD risk (Goldberg, 1998).
Data from the 4S, CARE and LIPID studies show increased risk of CHD event occurrence in
this category (Haffner et al, 1999, Goldberg et al, 1998, Keech et al, 2003).
A post hoc analysis of data from 4S on CHD risk in 678 people with IFG at study entry has
been performed (Haffner et al, 1999). The relative reduction in risk for major coronary events
with simvastatin treatment in this group was 38% (p<0.003) compared with 32% reduction
(p<0.001) in the 1631 people with normal fasting glucose (6.0mmol/L). Because the relative
risk of major coronary events for the IFG group was 1.15 (based on the placebo group data),
the potential benefit from treatment is greater for the IFG group.
A similar outcome was observed in people with IFG treated with pravastatin in the CARE
study (Goldberg et al, 1998). In the 3,553 people who did not have diabetes, 342 had IFG.
The reduction of nonfatal myocardial infarction and CHD death in this group was 23%
compared with a 28% reduction in the 3,104 subjects with normal fasting glucose (p=NS).
Again, the relative risk for CHD events was greater in the IFG group at 1.41, indicating
potentially greater benefit from treatment in this group.
In the LIPID study, people with IFG had a 23% higher risk of a major CHD event than
people with normal fasting glucose (Keech et al, 2003). In this group pravastatin reduced the
risk of CHD death or nonfatal myocardial infarction by 36% from an absolute risk of 17.8 to
11.8% (p<0.009).
There has not been any analysis of subjects with IFG to indicate a benefit from treatment with
statins for primary prevention or with fibrates for either primary or secondary prevention.
Similarly there have been no published data on the use of statins to prevent coronary heart
disease in people with IGT.
Statins can prevent stroke in people with Type 2 diabetes
Blauw et al (1997) performed a meta-analysis to evaluate the effect of statins including
simvastatin, pravastatin and lovastatin in preventing stroke. Thirteen randomised controlled
trials of statins which had reported data of cerebrovascular accidents were identified. A total
of 20,438 subjects aged 55-68 years were included in this analysis, with 0.1 to 15% of
individual study populations having diabetes in 10 trials. During a mean of 2.8 years followup, 181 strokes were observed in people randomised to treatment with statins and 261 strokes
in people randomised to placebo. The overall risk reduction of 31% (OR 0.69, CI 0.57-0.83)
was significant (p<0.001). No separate analysis was performed for people with diabetes.
A meta-analysis by Law et al (2003) showed lowering LDL cholesterol reduced the risk of
stroke. Results from 58 randomised controlled trials of cholesterol lowering by fibrates,
145
statin, niacin, or resins showed that stroke risk was reduced by 20% (CI 14-26) (p<0.001),
mainly due to a 28% reduction (CI 20-35) (p<0.001) in thromboembolic stroke, while
haemorrhagic stroke was only reduced by 3% (CI -35, 47). Moreover, the reduction was more
apparent in people with known vascular disease at study entry (22% reduction [CI 16-28];
p<0.001) than in people without known vascular disease (6% reduction [CI -22 to 14]).
Overall, a 1mmol/L reduction in LDL cholesterol level decreased all stroke by 10% and a
1.8mmol/L reduction decreased all stroke by 17%.
Of 20,356 participants in the Heart Protection Study (HPS Collaborative Group, 2004), 3,280
had pre-existing cerebrovascular disease. Over the 5-year treatment period, simvastatin
resulted in a 25% reduction in the incidence rate of first nonfatal or fatal stroke (4.3% in
simvastatin group v 5.7% in placebo group, RR 0.75 [CI 0.66-0.85], p<0.0001), mainly due
to a 30% reduction in ischaemic stroke (2.8% v 4.0%, RR 0.70 [CI 0.60-0.81], p<0.0001)
with no apparent effect on haemorrhagic stroke (0.5% v 0.5%, RR 0.95 [CI 0.65-1.40],
p=0.8). Among people with preexisting cerebrovascular disease there was no reduction in the
stroke rate (RR 0.95 [CI 0.65-1.40], p=0.8). In contrast, a significant 34% reduction was
observed among those without previous cerebrovascular disease (RR 0.66 [CI 0.57-0.76],
p<0.0001). In the diabetic subgroup (n=5,963), the incidence of first stroke was 5.0% in
people treated with simvastatin compared with 6.5% in people treated with placebo (RR 0.76
[CI 0.61-0.93], p=0.01). The 24% risk reduction (CI 6-39) was similar to a 26% reduction (CI
14-36) in people without diabetes (4.0% v 5.4%, RR 0.74 [CI 0.64-0.86], p=0.0002).
White et al (2000) reported that treatment with pravastatin 40mg/day reduced the risk of
stroke from any cause by 19% (CI 0-34%, p=0.05) and the risk of nonhaemorrhagic stroke by
23% (CI 5-38%, p=0.02) among participants in the LIPID Study. There was no difference in
haemorrhagic stroke between people treated with pravastatin and placebo (0.2 v 0.4%,
p=NS). In people with diabetes the risk of stroke was reduced from 9.9 to 6.3% (relative risk
reduction 39%, CI 7-61%, p=0.02) (Keech et al 2003).
Byington et al (2001) performed a combined analysis of data from the WOSCOPS, CARE
and LIPID studies in which 19,768 people including 7.3% with diabetes (mean age 58 years),
were randomly assigned to pravastatin 40mg/day or placebo. Overall 598 people had a stroke
during 5 years of follow-up. The beneficial effect of pravastatin on total stroke and nonfatal
stroke was observed across all 3 trials, with a 20% (HR 0.80, CI 0.68-0.93; p=0.01) and a
24% redution (HR 0.76, CI 0.64-0.90), respectively. When the 2 secondary prevention trials
(CARE, LIPID) were combined, there was a 22% reduction in total stroke (HR 0.78, CI 0.650.93; p=0.001) and a 25% reduction in nonfatal stroke (HR 0.75, CI 0.62-0.90). The risk
reduction was similar in people with diabetes (HR approximately 0.74 extrapolated from
Figure 3) but this was not significant.
Fibrates may prevent coronary heart disease in people with Type 2 diabetes
The main medications used for lowering triglycerides and increasing HDL cholesterol are
fibric acid derivatives or fibrates and placebo-controlled studies have provided some
evidence of benefit.
The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) (Rubins et al,
1999) studied 2,531 men with established CHD, HDL cholesterol 1.0mmol/L and LDL
cholesterol 3.6mmol/L. The mean LDL cholesterol level was 2.9mmol/L and mean
triglycerides 1.8mmol/L. People randomised to treatment with gemfibrozil 600mg twice daily
had a 31% reduction in triglycerides (1.3mmol/L v 1.9mmol/L, p<0.001), a 6% increase in
HDL cholesterol (0.9mmol/L v 0.8mmol/L, p<0.001), but no change in LDL cholesterol at
one year (2.9mmol/L for both groups) compared with those on placebo. After follow up for a
median of 5.1 years, the group assigned to gemfibrozil (71% in each treatment group were
still taking their assigned medication) had shown a 22% decrease in the primary endpoint of
146
nonfatal myocardial infarction or CHD death (p<0.006). Gemfibrozil treatment was also
associated with a 25% reduction in the risk of stroke (p=0.10).
Rubins et al (2002) conducted a subgroup analysis of people with diabetes from the VA-HIT
study and showed that people with known diabetes (n=627) and people with newly diagnosed
diabetes (n=142) had a significantly higher risk of CVD (known diabetes HR 1.87 [CI 1.442.43], p=0.001; new diabetes HR 1.72 [CI 1.10-2.68], p=0.02) compared with people with
normal fasting glucose. People with diabetes benefited more from treatment with gemfibrozil
than those without diabetes, with a 32% reduction in composite clinical endpoint (HR 0.68
[CI 0.53-0.88], p=0.004) compared with an 18% reduction (HR 0.82 [CI 0.67-1.02], p=0.07)
in people without diabetes. There was also a 41% reduction in CHD death (HR 0.59 [CI 0.390.91], p=0.02) and a 40% reduction in the risk of stroke (HR 0.60 [CI 0.37-0.99], p=0.046) in
the diabetic population.
A multivariable analysis of the entire VA-HIT cohort by Robins et al (2001) showed
concentrations of HDL cholesterol were inversely related to CHD events. Of the 3 major
lipids (HDL cholesterol, LDL cholesterol and triglycerides) measured at baseline and during
treatment, only the increase in HDL cholesterol predicted a lower risk of CHD events. With
every 0.13 mmol/L increase in HDL cholesterol the risk of a CHD events was reduced by
11% (RR 0.89, CI 0.81-0.98, p=0.02). Neither triglycerides nor LDL cholesterol levels
predicted CHD events.
Conducted in Canada, Finland, France and Sweden, the Diabetes Atherosclerosis Intervention
Study (DAIS) randomised 418 people with diabetes (27% women), aged 40 to 65 years, to
treatment with fenofibrate 200mg daily or placebo for an average of 4 years (DAIS, 2001). At
baseline, mean HbA1c was 7.5%, LDL cholesterol was 3.43mmol/L, HDL cholesterol was
1.03mmol/L, triglycerides were 2.42mmol/L and 48% had prior clinical evidence of CHD.
There was a significant improvement in total, LDL and HDL cholesterol and triglycerides (p
for all < 0.001) in those treated with fenofibrate compared with placebo. Primarily an
angiographic study, the DAIS results showed that compared with placebo, fenofibrate
treatment was associated with 40% less progression in MLD [(mean (standard error) (-0.06
(0.016) v -0.10 (0.016), p=0.029)], 42% less progression in percentage diameter stenosis
(2.11 (0.594) v 3.65 (0.608)%, p=0.02). There was also a 23% reduction in combined clinical
endpoints, however this was not significant.
The Bezafibrate Infarction Prevention (BIP) study randomised 3,090 people with established
CHD, HDL cholesterol 1.17mmol/L, triglycerides 3.3mmol/L and LDL cholesterol 4.7
mmol/L to bezafibrate 400mg daily or placebo (BIP Study, 2000). On treatment, HDL
cholesterol increased by 18% and triglycerides decreased by 21%. After a mean period of 6.2
years (76% were still taking study medication) there was a non significant 7.3% (p=0.26)
reduction in the primary endpoint of nonfatal myocardial infarction or CHD death. However,
in a post hoc analysis of the subgroup with triglycerides 2.2mmol/L, the reduction in the
primary endpoint was 39% (p<0.02). In the BIP study 309 subjects (10% of the total cohort)
had diabetes, but a separate analysis of the diabetic subgroup has not yet been reported.
Primary Prevention
The largest study using fibric acid derivatives to date is the Helsinki Heart Study (Frick et al,
1987). This double blind, primary prevention study randomised 4,081 asymptomatic men
aged 40 to 55 years, with non-HDL cholesterol level 5.2mmol/L, to treatment with
gemfibrozil 600mg twice daily or placebo. Despite a total dropout rate of 30% over the 5 year
followup period, there was a reduction of 34% (p<0.02) in the principal endpoints of
nonfatal myocardial infarction and cardiac death in the group assigned to active treatment.
147
Although there was a 26% lower mortality from CHD in the group on gemfibrozil, there were
slightly more deaths overall in the gemfibrozil than the placebo group (45 v 42). A post hoc
analysis of the Helsinki Heart Study (Manninen et al, 1989) showed that the reduction of
CHD from gemfibrozil treatment was greatest in subjects with HDL cholesterol in the lower
tertile (<1.08mmol/L) or triglycerides in the upper tertile (>2.08mmol/L). The 34% reduction
of CHD was greater than expected from the 10% reduction of total cholesterol and in the
subgroup of 1,131 people with LDL cholesterol 4.5mmol/L and triglycerides >2.0mmol/L
there was a 43% reduction in CHD events (p<0.02) with only a 7.5% reduction in LDL
cholesterol level for gemfibrozil compared with placebo treatment. Some of the benefit from
gemfibrozil treatment was attributed to the 15% increase of HDL cholesterol and 38%
reduction of triglycerides compared with placebo.
The Helsinki Heart Study included 135 people with diabetes who had lower HDL cholesterol
(1.18 v 1.26mmol/L; p<0.001) and higher triglycerides (2.69 v 2.05mmol/L; p<0001)
compared with non-diabetic subjects (Koskinen et al, 1992). Gemfibrozil treatment compared
with placebo was associated with a non significant 67% reduction of nonfatal myocardial
infarction and CHD death (p=0.19).
The St Marys, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention
(SENDCAP) study was a primary prevention, double blind study which examined the effect
of bezafibrate 400mg daily on cardiovascular outcome in 164 people with Type 2 diabetes
(Elkeles et al, 1998), with follow up for 3 to 5 years. Inclusion criteria were one of cholesterol 5.2mmol/L, triglycerides 1.8mmol/L, HDL cholesterol 1.1mmol/L or total to
HDL cholesterol ratio 4.7. Median LDL cholesterol was 3.82mmol/L, median HDL
cholesterol 0.98mmol/L and median triglycerides 2.17mmol/L. Over 3 years, bezafibrate
treatment compared with placebo was associated with a 37% reduction of triglycerides
(p=0.001), 8% increase of HDL cholesterol (p=0.02) and 10% reduction of LDL cholesterol
(p=NS). Bezafibrate treatment had no effect on progression of carotid or femoral arterial
disease measured by ultrasound, but there was a 67% reduction (p=0.01) in the incidence of
definite CHD events, defined as documented myocardial infarction or ECG change of
probable ischaemia on Minnesota coding.
Studies of fibrates currently in progress in Type 2 diabetes
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has recruited
over 8,000 people with Type 2 diabetes aged 50 to 75 years in Australia, New Zealand and
Finland. Entry criteria are total cholesterol between 3.0 and 6.5mmol/L, and either
triglycerides >1.0mmol/L or total cholesterol to HDL cholesterol ratio 4.0. Randomised to
treatment with fenofibrate 200mg or placebo, participants will be followed for at least 5
years, with the primary endpoint being CHD mortality. Although mainly a primary
prevention study, about 20% of subjects have evidence of pre-existing CVD. The study will
conclude in 2005.
There are no data on the effect of -3 polyunsaturated fatty acids (fish oil) and the risk
of cardiovascular disease specifically in people with Type 2 diabetes
The -3 polyunsaturated fatty acids of fish oil have anti-atherogenic, anti-thrombotic and
anti-arrhythmic effects (Simopoulos, 1997). A benefit for dietary supplementation with fish
and/or fish oil capsules in survivors of a myocardial infarct has been found in two studies
(Burr et al, 1989; GISSI, 1999). The Gruppo Italiano per lo Studio della Sopravvivenza
nellInfarto Miocardico (GISSI)-Prevenzione trial was a randomised, open-label, secondary
prevention trial with 11,324 people. They were assigned in a 2x2 factorial design to treatment
with 850-882mg eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), 300mg
148
vitamin E, both, or neither within three months of myocardial infarction (GISSI, 1999). After
six months there was a small reduction of triglycerides in the group on fish oil (3.4%) and the
group on fish oil and vitamin E (0.9%), compared with those not on fish oil, but no difference
in other lipid parameters. Four way analysis of the primary endpoint of non-fatal myocardial
infarction, CHD death and non-fatal stroke after follow up for 42 months showed reduction
by 20% on fish oil (p<0.008), compared with 12% on vitamin E (p=NS). At the end of the
study 28.5% of people on fish oil and 26.2% on vitamin E had permanently discontinued the
medication. Of the total cohort 10,683 subjects (14.8%) were classified as having diabetes,
but there has not been a separate analysis of this group. Evidence for benefit in diabetic
subjects is therefore indirect and based on one secondary prevention study at this stage.
Burr et al (1989) randomised 2,033 men who were recovering from a myocardial infarction to
receive or not to receive advice on reducing fat in the diet, increasing fish intake and
increasing the ratio of polyunsaturated fat to saturated fat in the diet. In the Diet and
Reinfarction Trial (DART) those who were given the dietary advice to increase fish intake
had a 29% (CI 0.54-0.92, p<0.05) reduction in 2 year all cause mortality compared to those
who were not given the advice.
heart disease in postmenopausal women with Type 2 diabetes
Observational studies in postmenopausal women without diabetes show that use of hormone
replacement therapy (HRT) is associated with a 50% reduction in the risk of coronary artery
disease (Stampfer et al, 1991). Several mechanisms have been proposed for this potential
cardioprotective effect of HRT including improved lipid profiles, improved vasodilatory
properties, improved insulin sensitivity and effects on clotting factors (Sattar et al, 1996).
However, clinical trial data do not support these observational data. The Heart and
Estrogen/progestin Replacement Study (HERS) was a randomised, double blinded, placebocontrolled trial in which 2,763 women with coronary disease aged less than 80 years were
treated with 0.625mg conjugated equine oestrogen plus 2.5mg medroxyprogesterone acetate
or placebo for an average of 4.1 years. HRT was not associated with a reduction in primary
CHD event (MI or CHD death), with a relative hazard (RH) of 0.99 (CI 0.80-1.22, p=0.91)
despite a net 11% lower LDL cholesterol level (p<0.001) and a 10% higher HDL cholesterol
level (p<0.001) compared with placebo. More women in the HRT group than in the placebo
group experienced venous thromboembolic events (34 v 12, RH 2.89 [CI 1.50-5.58],
p=0.002), and the RH remained elevated over a 4-year period in the HRT group (Hulley et al,
1998). In the HERS trial 19% of subjects had diabetes treated with oral medication or insulin,
but there has not been a separate analysis of the diabetic group.
The Womens Health Initiative study (Manson et al, 2003) also found that combined
hormone therapy did not have cardiac protective effect. Of 16,608 postmenopausal women
aged 50-79years including 2.4% with previous CHD (number with diabetes not specified),
8,506 were randomly assigned to conjugated equine estrogen 0.625mg/day plus
medroxyprogesterone acetate 2.5mg/day and 8,102 to placebo. The 2 groups were
comparable at baseline except that more women in the placebo group had a history of
coronary revascularisation (1.5 v 1.1%, p=0.04). At one year, women in the hormone group
had lower levels of total and LDL cholesterol (-5.4%, -12.7%, respectively), and higher levels
of HDL cholesterol (+7.3%) and triglycerides (+6.9%) than women in the placebo group (all
p<0.05). However, after a mean follow-up of 5.2 years, combined hormone therapy was
associated with increased risk for CHD (adjusted HR 1.24 [0.97-1.60]), nonfatal MI (adjusted
HR 1.28 [0.97-1.70]), and death due to CHD (adjusted HR 1.10 [0.65-1.89]). The absolute
rates of CHD were 39 cases per 10,000 person-year in the hormone group compared to 33
149
cases per 10,000 person-year in the placebo group. Among women with diabetes, the risk of
CHD was 45% higher in the hormone group (adjusted HR 1.45 [0.84-2.49]). The absolute
rates of CHD were 124 and 112 cases per 10,000 person-year, respectively. The authors
concluded that hormone therapy should not be prescribed for the prevention of cardiovascular
disease.
A similar lack of beneficial effects was reported in a case-control study of women with
treated diabetes who had had a MI (n=212) compared with controls without prior MI
(n=122). Relative to never users of oestrogen, the risk of MI was lower for current oestrogen
users (RR 0.51 [CI 0.22-1.15]) and the risk of MI tended to decline with each additional year
of use (RR 0.78 [CI 0.56-1.08]), but these differences were not significant (Kaplan et al,
1998).
Lipid modifying therapy in Type 2 diabetes is considered to be cost effective
Analyses of the long-term costs and benefits of treatment for lipid abnormalities in people
with diabetes have generally assessed the role of statin therapy as most of the major
cardiovascular outcome trials have used statins. Based on the results of the 4S trial, which
was a secondary prevention study of simvastatin therapy, savings from reduced
hospitalisation of the diabetic group offset 67 to 76% of the drug cost (Jonsson et al, 1999).
Using 1995-1997 Swedish costs, each life-year gained was estimated to cost from 1,600
Euros (based on clinical history of diabetes) to 3,200 Euros (based on a fasting glucose 7.0
mmol/L). Cholesterol reduction in people with diabetes and pre-existing CHD remained
highly cost-effective when analyses were based on drug and hospitalisation costs in 10 other
European countries. Cost-effectiveness of secondary prevention therapy in people with
diabetes has also been analysed based on US costs, using a model of risk from the Lipid
Research Clinics Program Prevalence and Follow-up Cohort, validated by comparison with
data from 4S (Grover et al, 2000). Costs per year of life saved were estimated in 1996 US
dollars for men and women as 4,000 with pretreatment LDL cholesterol of 5.46mmol/L to
8,000 with pretreatment LDL cholesterol of 3.85mmol/L.
Estimates of the cost-effectiveness of primary prevention therapy were also made based on
the Lipid Research Clinics model (Grover et al, 2000). For men with pretreatment LDL
cholesterol of 5.46mmol/L, costs in 1996 US dollars per year of life saved range from 4,000
for 60 year olds to 10,000 for 70 year olds; for women the range was about 9,000 to 15,000.
At the lower LDL cholesterol level of 3.85mmol/L, the cost per year of life saved ranged
from $7,000 to $15,000 for men and from $24,000 and $40,000 for women. The same group
has extended their analysis to compare cost-effectiveness in Canada, France, Germany, Italy,
Spain and the UK (Grover et al, 2001). Regardless of the health care costs in these countries,
the cost-effectiveness of simvastatin in people with diabetes without CHD was similar to that
in people with CHD, but without diabetes.
The WOSCOPS trial was a primary prevention study of pravastatin treatment in men with
mean total cholesterol 7.0mmol/L. An economic benefit analysis based on results of the
WOSCOPS trial indicated that for the 40% of men at highest risk, which is likely to include
all those with Type 2 diabetes, the cost per year of life gained was 5,601 based on 1996
costs. If the survival curves are discounted at 6% per year as recommended by the Treasury,
the cost per year of life gained rises to 13,995 (Caro et al, 1997).
Brandle et al (2003) performed an analysis to assess the cost and cost effectiveness of statin
therapy for primary prevention of major coronary events in people with diabetes in the U.S,
especially in the population with LDL cholesterol level of 2.6-3.3 mmol/L. Cost was
estimated from a health system perspective and treatment effectiveness from the diabetic
subgroup of the HPS and UKPDS. Based on data from the NHANES III, it is estimated that
150
3.0 million people with diabetes and without CHD have an LDL cholesterol of 2.6-3.3
mmol/L and 5.9 million with an LDL cholesterol of >3.3 mmol/L. Treatment of LDL
cholesterol of 2.6-3.3 mmol/L to achieve LDL cholesterol <2.6 mmol/L cost $US600 to
$US1,000 per person per year depending on the statin prescribed, while the annual cost in
people with LDL cholesterol >3.3 mmol/L ranges from $US700 to $US2,100. It was
estimated that statin therapy could prevent approximately 71,000 major coronary events per
year in people with diabetes and LDL cholesterol level 2.6 mmol/L. Annual incremental
cost per person, defined as the cost of statin treatment plus the cost of major coronary events
treated with statin minus the cost of major coronary events without statin treatment, ranged
from $US480 to $US950 in the subgroup with LDL cholesterol between 2.6 and 3.3 mmol/L
and from $US590 to $US1,920 in the subgroup with LDL cholesterol >3.3 mmol/L,
respectively.
Glasziou et al (2002) evaluated the cost-effectiveness of pravastatin in the LIPID trial in
which people had a history of unstable angina or previous myocardial infarction and with an
average cholesterol level were randomised to take pravastatin 40mg daily or matching
placebo. During a mean follow-up of 6 years, the all-cause mortality was 11.0% in the
pravastatin group compared with 14.1% in the placebo group, and this represented a relative
reduction of 22% (p<0.001). Hospital admissions for coronary heart disease and coronary
revascularisation were reduced by 20%. During this period, the cost of pravastatin was
$A4,913 per person but reduced total hospitalisation costs by $A1,385 and costs of other long
term medications by $A360 per person. The incremental cost of pravastatin treatment was
$A3,246 per person. The cost per death prevented within the study period was $A107,730.
Extrapolating long-term survival from the placebo group, the discounted cost per life year
saved was $A19,938. These results are considered cost effective for accepted treatments in
high income countries.
Modelling has been used to assess the cost-effectiveness of pravastatin for reduction in serum
cholesterol level in people with Type 2 diabetes and a high total cholesterol level of 5.2
mmol/L (The CDC Diabetes Cost-effectiveness Group, 2002). The risk reduction of 31% was
achieved with pravastatin in people without a history of CHD and of 25% in people with
CHD. While reduction in serum cholesterol level directly lowered the cumulative incidence
of CHD complications, the increase in life expectancy led to an increase in diabetic
complications cost, and this outweighed cost reductions from CHD. The incremental total
cost was $US18,033. The cost-effectiveness ratio for reduction in serum cholesterol level was
$US51,889 per QALY, and decreased gradually with age, with the lowest cost-effectiveness
ratios for people aged 45-84 years as the risk of CHD increased.
There is very little current information on the cost-effectiveness of lipid modifying therapy
with fibrates in Type 2 diabetes, although data for secondary prevention with gemfibrozil
could be derived from the results of the VAHIT study, which included a high proportion of
men with diabetes. One analysis involving fibrate therapy developed a clinical outcomes
model based on 6 statistically significant CVD risk factors from the Framingham study
(Haffner & Ashraf 2000). Changes of these risk factors in response to treatment with 2
fibrates and 6 statins were used to predict the anticipated reduction of CHD in people with
Type 2 diabetes. Cost comparison analysis found that fenofibrate was equivalent to
simvastatin and atorvastatin in its potential to reduce the medical expenses of treating
cardiovascular events and that these 3 agents were potentially more cost-effective than the
other fibrate and statins that were evaluated.
The primary target in people with Type 2 diabetes is an LDL cholesterol of 2.5mmol/L
There is a lack of consensus to support the routine use of statins in all people with Type 2
diabetes for the primary prevention of a vascular event. As reviewed in the Background to
this Section, the various international and national guidelines advocate different approaches
to controlling blood lipids in people with diabetes. No guideline supports the routine use of
151
lipid lowering agents in all people with diabetes but rather their use is based on above target
lipid levels or if calculated risk of a future vascular event is increased above a certain
threshold. A consideration in this regard is the issue of the co-occurrence and management of
more than one cardiovascular risk factor when the benefits of simultaneous treatment of risk
factors is uncertain. This is highlighted by 2 recent studies which have failed to show a clear
benefit in people with diabetes being well treated with antihypertensive therapy when statins
are added (ALLHAT-LLT, 2002b; Sever et al, 2003).
Most of the beneficial effects of lipid modifying therapy are explained by the changes in lipid
levels achieved during the study. Total and LDL cholesterol lowering have been the most
studied lipid levels and most of the study findings, especially with statins, have equated
outcomes and LDL cholesterol lowering.
None of the many lipid modifying studies has specifically addressed the question of optimal
goals for lipids. Most of the data which can be used to address this question come from
studies using lipid lowering medication. Most lipid lowering therapy studies have used a
fixed dose of a medication (mostly a statin) although a few have compared the effects of
attaining different lipid targets.
Setting a specific lipid target is supported by data which indicate that although statins are
known to have effects on improving endothelial dysfunction, plaque stabilisation, inhibiting
inflammatory processes, antithrombotic effects and reducing smooth muscle proliferation,
most studies show that most of the effect of statins is due to their lipid lowering effects. For
example, Simes et al (2002) showed that in the LIPID study 67% of the pravastatin effect in
reducing fatal CHD and nonfatal myocardial and 96% of the effect in reducing the expanded
endpoint of fatal CHD, nonfatal myocardial infarction, unstable angina and coronary
revascularisation could be explained by on-study lipid levels.
Recommendations on lipid targets are based on
establishing a relationship between a lipid parameter and improved outcomes
actual lipid levels achieved during the study
the characteristics of the relationship between the lipid parameter and improved outcomes
There are 3 models which describe the relationship between lipid levels and cardiovascular
outcomes:
linear model in which there is progressive and continuing benefit with lower (or in the
case of HDL cholesterol higher) lipid levels
curvilinear model in which there is a continuous but progressively smaller benefit at
lower (or in the case of HDL cholesterol higher) lipid levels
threshold model in which the benefits cease when a particular lipid level is reached
Unfortunately, the different lipid lowering intervention studies have reported different
findings on the model which best explains their results.
Baseline and lipid levels achieved in therapeutic randomised controlled trials of studies
designed to evaluate clinical outcomes which involved more than 1,000 people which
included or were exclusively performed in people with diabetes are summarised in Table 20.
LDL Cholesterol
The studies shown in Table 20 achieved a reduction in LDL cholesterol of 1mmol/L or more
and the actual level achieved was influenced by the baseline level. The LDL cholesterol
levels achieved in the secondary prevention statin studies ranged from 1.9 to 3.1 mmol/L.
152
The recent meta-analysis by Law et al (2003) concluded that lipid lowering therapy reduced
the risk of ischaemic heart disease (IHD) by lowering LDL cholesterol. In 58 randomised
controlled trials of different methods of reducing LDL cholesterol including fibrates, statin,
niacin, or resins, 52% of a total of 148,321 subjects (diabetes not specified) had known
vascular disease at entry. The reduction in IHD events increased with the duration of
treatment. With each 1.0mmol/L reduction in LDL cholesterol, the risk of IHD events was
lowered by 11% in the first year, 24% in the second year, 33% in years three to five, and by
36% in the sixth and subsequent years (p<0.001 for trend). Overall, in 49 trials that lasted
more than one year, the reduction in IHD events after treatment for two or more years was
51% with a reduction in mean LDL cholesterol of 1.5mmol/L, compared with a 30% with a
reduction in mean LDL cholesterol of 1.0mmol/L, and 20% with a reduction in mean LDL
cholesterol of 0.5mmol/L (p<0.001 for trend). This is consistent with a curvilinear
relationship between increasing reduction in LDL cholesterol and improved outcomes.
A recent retrospective analysis of 16,470 people (including 3,430 with diabetes) by Rubins et
al (2003) confirmed a beneficial effect of lipid-lowering medications (mainly statins) on total
mortality in people with established CHD in a usual clinical care setting. During an average
5.9 years follow-up, there were 4,821 recorded deaths (51%) in untreated people compared
with 1,245 deaths (18%) in treated people. On average, the treated cohort survived 15 months
(CI 449-493 days) longer than the untreated cohort (1,9816 v 1,5108 days, p<0.0001).
After adjusting for age, previous use of lipid-modifying medication, other cardiovascular
medications and pretreatment cholesterol level, there was a 24% reduction in total mortality
with lipid-modifying treatment (HR 0.76, CI 0.69-0.84, p<0.0001). There was a significant
trend towards greater benefit in those with highest baseline total cholesterol level (p<0.0001
for trend). The beneficial effect of treatment in reducing mortality was less in people with
diabetes (8% reduction [HR 0.92, p>0.38] compared with people without diabetes (32%
reduction [HR 0.68, CI 0.61-0.76, p<0.0001].
The relationship of LDL cholesterol and improved outcomes has been different in the
different studies. The results of the secondary prevention 4S study are consistent with a
curvilinear relationship between LDL cholesterol and major coronary events. Pedersen et al
(1998) analysed the relationship between serum lipids and clinical outcomes. After 1 year of
simvastatin treatment, each 1mmol/L reduction of total and LDL cholesterol was associated
with a 22.5% and a 27.8% reduction (CI 11.9-31.9%, p=0.0001; CI 17.6-36.8%, p<0.0001,
respectively) in major coronary events. Modelling LDL cholesterol showed the incremental
benefit became progressively less as the LDL reduction increased.
On the other hand the results of CARE and LIPID secondary studies favour the threshold
model. In the CARE study CHD event rates decreased progressively as LDL cholesterol
levels fell from 4.5 to 3.2mmol/L but from 3.2 to 1.8mmol/L, CHD events did not decline
further. (Sacks et al, 1998) The LIPID study reported a 24% reduction in the primary end
point of coronary death and nonfatal myocardial infarction. However in the pravastatin
treated subjects with a baseline LDL cholesterol level <3.6mmol/L there was a non
significant 16% reduction in events (CI -4, 32%) (LIPID Study Group, 1998). A pooled
analysis of the CARE and LIPID data showed a reduction in coronary death and nonfatal
infarction of 22% (CI 7-34%; p=0.005) in subjects with LDL cholesterol <3.6mmol/L at
baseline. However further analyses showed no difference in event rates with LDLcholesterol
<3.2mmol/L again suggesting that treating to a LDL cholesterol level of 3.2mmol/L may be
sufficient and that further LDL-cholesterol lowering might not provide additional benefit.
(Sacks et al, 2002). These data question the benefit of lipid lowering therapy when baseline
LDL cholesterol levels range from 2.6 to 3.3mmol/L.
153
However the situation may be different in people with diabetes. Sacks et al (2002) analysed
the data from the CARE and LIPID trials and found that pravastatin significantly reduced the
CHD event rate in people with diabetes compared with people without diabetes in whom
LDL cholesterol was lower than 3.2mmol/L. Of 13,173 people with CHD (mean age 60
years), 2,607 had a baseline LDL cholesterol less than 3.2mmol/L (mean LDL cholesterol
2.90.3 mmol/L). Treatment with pravastatin lowered LDL cholesterol by 32% and
triglycerides by 14%, and raised HDL cholesterol by 6% compared with placebo in people
with low LDL cholesterol (all p<0.001). During a mean 5.5 years follow-up, pravastatin
reduced the CHD events from 34% to 22% in people with diabetes and low LDL cholesterol
(RR 0.56, CI 0.37-0.83, p=0.004). This risk reduction was significantly different from the
effect in nondiabetic people with low LDL of <3.2mmol/L (RR 1.06, CI 0.89-1.27) (diabetes
v nondiabetic, p=0.005).
In the PROSPER study (Shepherd et al, 2002), 5,804 elderly people (aged 70-82 years, 623
with diabetes) with previous cardiovascular disease were randomised to pravastatin 40
mg/day or placebo for an average of 3.2 years. Pravastatin resulted in a 15% reduction in the
incidence of the combined primary endpoint (HR 0.85, CI 0.74-0.97; p=0.014), 19%
reduction in CHD death or nonfatal myocardial infarction (HR 0.81, CI 0.69-0.94, p=0.006)
and 24% reduction in mortality from CHD (HR 0.76, CI 0.58-0.99, p=0.043). Fatal or
nonfatal stroke was not affected (HR 1.03, CI 0.81-1.31, p=0.8). With regard to baseline LDL
cholesterol levels, the incidence of the primary endpoint was significantly reduced in people
with LDL cholesterol >4.1mmol/L (HR 0.77, CI 0.60-0.98) compared with people with LDL
<3.4mmol/L (HR 0.88, CI 0.80-1.10) and LDL 3.4-4.1mmol/L (HR 0.88, CI 0.70-1.10).
Among people with diabetes (n=623) the incidence of the primary endpoint was higher (HR
1.27, CI 0.90-1.80) compared with people without diabetes (HR 0.79, CI 0.59-0.91) (between
groups p=0.015).
The findings of the Heart Protection Study (2002a) strongly support the linear model in that
there was no threshold effect evident and the benefit of lipid lowering therapy applied equally
to people with a baseline LDL cholesterol above and below 3.5mmol/L. In the HPS the
average difference in LDL cholesterol between the simvastatin and placebo group over 5
years was 1mmol/L. In people with an initial LDL cholesterol <3mmol/L the average LDL
cholesterol difference was 0.9mmol/L (actual level 1.8mmol/L in the simvastatin group v
2.7mmol/L in the placebo group). In people with a baseline LDL cholesterol <3 mmol/L,
there was a 4.8% reduction in first major vascular event with simvastatin treatment, which
was similar to the 5.7% reduction in people with a baseline LDL cholesterol of 3-3.5mmol/L
and a 5.2% reduction with baseline LDL cholesterol > 3.5mmol/L. The absolute event rate
with simvastatin was 17.6%, 19.0% and 22.0% respectively for the 3 groups. In people with
LDL cholesterol < 2.5mmol/L which was further reduced to 1.7mmol/L with simvastatin, the
risk reduction was about as great as those with higher LDL cholesterol levels.
In the HPS report on people with diabetes (HPS Collaborative Group, 2003), the above
findings were also apparent. However, although the risk reductions were similar in the
diabetic and non diabetic cohorts, it is interesting to note that the diabetic subgroup with a
baseline LDL cholesterol <3.0mmol/L had a lower absolute event rate than in the non
diabetic subgroup with an LDL cholesterol < 3.0mmol/L.
The results of studies which have compared more and less aggressive lipid lowering have all
shown better outcomes with lower lipid levels, a finding which is consistent with either the
linear or curvilinear model.
154
In a 24-month multicentre, randomised controlled trial, Cannon et al (2004) compared the

effects of pravastatin 40mg/day with atorvastatin 80mg/day in 4,162 people (mean age 58
years, 17.6% with diabetes) who had experienced an acute myocardial infarction or unstable
angina within the proceeding 10 days. At baseline, the lipid levels were comparable between
the two groups. During the follow-up, the median LDL cholesterol level achieved was
2.46mmol/L (interquartile rage 2.04-2.92mmol/L) in the pravastatin group and 1.60mmol/L
(interquartile range 1.29-2.04mmol/L) in the atorvastatin group (atorvastatin v pravastatin,
p<0.001). The median HDL cholesterol level rose by 8.1% in the pravastatin group and 6.5%
in the atorvastatin group (p<0.001). Overall, high-dose atorvastatin therapy resulted in a 16%
reduction (CI 5-26) in the rate of combined primary endpoint compared with standard-dose
pravastatin therapy (22.4 v 26.3%, p=0.005). The benefit appeared to be greater among
people with a baseline LDL cholesterol of 3.24mmol/L, with a 34% reduction, compared
with a 7% reduction in the event rate among those with a baseline LDL cholesterol of
<3.24mmol/L (p<0.02). Among 734 people with diabetes, the 2-year event rates were
reduced from 34.6% in the pravastatin group to 28.8% in the atorvastatin group (no p value
reported but not significant from Figure 5) compared with a significant reduction from 24.6%
with pravastatin to 21.0% with atorvastatin in the 3,428 people without diabetes.
In the Post Coronary Artery Bypass Graft (Post-CABG) Trial (Knatterud et al, 2000) lipid
lowering therapy was used to achieve an LDL cholesterol of <2.2mmol/L (aggressive
therapy) or <3.6mmol/L (moderate therapy) from a baseline LDL cholesterol of between 3.4
and 4.5mmol/L. The achieved LDL-cholesterol levels were 2.4-2.5mmol/L with aggressive
therapy and 3.4-3.5mmol/L with moderate therapy. There was significantly less progression
of saphenous vein bypass graft narrowing, cardiovascular death or nonfatal infarction (15.1%
v 20.3%; p=0.03), and composite endpoint of death, nonfatal infarction, stroke, or coronary
revascularisation (30.6% v 40.2%; p=0.001) in the aggressively treated subjects.
White et al (2001) compared the effect of aggressive lipid-lowering therapy on progression of
atherosclerosis in the left main coronary artery (LMCA) in 402 people (7% with diabetes)
randomly selected from the Post-CABG Trial. Lovastatin 40-80mg/day achieved an LDL of
1.6-2.2mmol/L in the aggressive lipid-lowering group (n=203), and 2.5-5mg/day lovastatin
achieved an LDL of 3.4-3.6mmol/L in the moderate lipid-lowering group (n=199). People
with aggressive treatment had less progression of luminal narrowing in the LMCA segment,
less substantial lesion progression and fewer developed occlusion in the LMCA compared
with the moderate treatment group.
In the Post-CABG trial reported by Hoogwerf et al (1999) 116 people had Type 2 diabetes of
whom 63 were randomly assigned to aggressive lipid lowering and 53 were assigned to
moderate lipid lowering. LDL cholesterol was reduced from 3.9mmol/L at baseline to 2.5
mmol/L with aggressive therapy and to 3.5mmol/L with moderate therapy. Over the 4-year
period, there was a general reduction in RR for clinical events associated with aggressive
lipid lowering therapy, with a 47% reduction in combined endpoint (14.9 v 26.2%, RR 0.53
[CI 0.18-1.60]), a 33% reduction in death (6.5 v 9.6%, RR 0.67 [CI 0.12-3.75]) and a 60%
reduction in MI (4.8 v 11.6%, RR 0.40 [CI 0.07-2.47]) but none of these was significant.
Also fewer people treated with aggressive lipid lowering therapy had a PTCA during the
study period (4.9 v 7.9%, RR 0.61 [CI 0.09-4.39]), but again this did not reach significance.
In the GREACE study (Athyros et al, 2002b), 1,600 people (19.6% with diabetes) were
randomly assigned to atorvastatin (10-80mg/day) treatment or to usual care. Treatment with
atorvastatin lowered total cholesterol to 4.3mmol/L, LDL cholesterol to 2.6mmol/L and
increased HDL cholesterol to 1.09mmol/L. In the usual care group the corresponding levels
were 6.4mmol/L, 4.4mmol/L and 1.04mmol/L. After 3 years, 97% of people in the
atorvastatin group compared with only 3% of people in the usual care group achieved the
155
NCEP recommended LDL cholesterol target of <2.6mmol/L. Overall, atorvastatin

significantly reduced risk of total mortality (RR 0.57, CI 0.39-0.78; p=0.0021), CHD
mortality (RR 0.53, CI 0.29-0.74, p=0.0017), coronary morbidity (RR 0.46, CI 0.25-0.71;
p<0.0001) and stroke (RR 0.53, CI 0.30-0.82; p=0.034). People with diabetes also benefited
from atorvastatin therapy, with a 58% reduction in all cardiac events (p<0.0001).
In the open-label, multicentre Atorvastatin Versus Revascularization Treatments (AVERT)
Trial, 341 people (54 with diabetes) with stable coronary artery disease who were referred for
revascularisation were randomised to receive lipid-lowering therapy with atorvastatin
80mg/day (n=164) or to undergo PTCA followed by usual care (n=177) (Pitt et al, 1999).
Atorvastatin treatment achieved an LDL cholesterol of 2.0mmol/L while in the
angioplasty/usual care group LDL cholesterol was 3.1mmol/L. Over an 18-month period,
people in the atorvastatin group had 36% (CI 5-67%) fewer ischaemic events (p=0.048).
A number of studies in progress should provide more data on this issue. The Treating to New
Targets (TNT) Study has randomised 10,000 people with coronary disease and LDL
cholesterol levels between 3.4 and 6.5mmol/L to treatment with atorvastatin 10mg/day or 80
mg/day with the aim of achieving LDL cholesterol levels of 2.6 and 1.9mmol/L on the low
and high doses, respectively. The study will assess the effect on coronary death or nonfatal
myocardial infarction over a 5 year period and is due for completion in 2004. The Study of
the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial
has enrolled 12,000 people with a myocardial infarction with LDL cholesterol levels >3.5
mmol/L. Participants have been randomized to 20mg/day or 80mg/day of simvastatin. This 5year study is due to finish at the end of 2004. The Incremental Decrease in Endpoints through
Aggressive Lipid Lowering (IDEAL) study has randomised 8,888 people with previous
myocardial infarction to simvastatin 20mg/day, increasing to 40mg/day if total cholesterol
remains >4.9mmol/L, or to atorvastatin 80mg/day. The study will run for 5.5 years and will
finish in early 2005.
The above studies, with the exception of a subset of the HPS, were all conducted in people
with established heart disease. There are insufficient data available on the relationship
between lipid levels and outcomes in people without established vascular disease.
Furthermore no studies have examined outcomes in relation to aggressive and less aggressive
lipid lowering for the primary prevention of cardiovascular disease.
Data from the analysis of the WOSCOPS primary prevention study (West of Scotland
Coronary Prevention Study Group, 1998) show that the benefit of pravastatin was
independent of baseline LDL cholesterol with maximal risk reduction occurring when LDL
cholesterol concentrations fell by 24%, and greater lowering of LDL gave no additional
reduction in risk. In WOSCOPS, the average LDL cholesterol level achieved on pravastatin
therapy was relatively high at 3.8 mmol/L and this relationship may be different with lower
levels.
In the HPS report in people with diabetes (HPS Collaborative Group, 2003), there were 1,343
people without known occlusive arterial disease at randomisation whose pretreatment LDL
cholesterol was 3.0 mmol/L. There was a marginally significant 30% (CI 1-50%) reduction in
first major vascular events (p<0.05).
Overall, these studies support either a linear or curvilinear model to explain the relationship
between LDL cholesterol lowering and improved cardiovascular outcomes. The continued
benefit with lower LDL cholesterol levels is not consistent with the threshold model, unless
the threshold is well below 2 mmol/L.
156
Table 20 Lipid Levels Achieved in the Studies with Lipid Modifying Medications
LDL Cholesterol
HDL Cholesterol
Triglycerides
Baseline
After
Baseline
After
Baseline
After
2.70
2.28
2.57
2.57
2.3
2.91
2.49
(aggressive)
3.49
1.23
1.31
0.97
1.01
1.06
0.93
1.26
1.30
1.01
1.09
1.07
0.98
1.70
1.66
1.85
2.08
2.3
1.60
1.64
1.32
1.61
1.45
2.0
1.42
0.93
2.09
2.5
1.30
1.37
1.5
1.3
2.46
1.01
1.09
1.71
2.75
1.60
0.98
4S
4.80
3.10
1.13
Primary Prevention
AFCAPS/
3.89
2.96
0.98
TEXCAPS
WOSCOPS
4.97
3.68
1.14
CARDS
3.10
1.90
1.30
HPS
No separate data reported
FIBRATE Studies
BIP
3.83
0.90
DAIS
3.38
3.14
1.01
VA-HIT
2.9
2.9
0.82
Primary Prevention
HHS
5.18
4.44
1.18
SENDCAPS
3.66
3.31
1.02
1.04
1.21
1.79
1.69
1.54
1.05
1.78
1.61
1.20
1.32
1.83
1.70
1.61
1.30
1.06
1.09
0.89
1.64
2.59
1.8
1.30
1.84
1.3
1.26
1.04
2.42
2.24
1.79
1.44
STATIN Studies
ALLHAT-LLT 3.77
ASCOT
3.44
CARE
3.52
GREACE
4.66
HPS
3.2
LIPID
3.88
Post-CABG
(diabetes cohort)
3.93
(moderate)
PROSPER
TIMI
3.8
Pravastatin
2.75
Atorvastatin
157
The currently available combined data from the various intervention studies and studies
which have compared aggressive with less aggressive treatment support an LDL cholesterol
target of 2.5mmol/L or less. This conclusion has also been reached by other guidelines
discussed in the Background to this Section including NCEP (NCEP, 2001; NCEP, 2002) and
American Diabetes Association (ADA, 2003). It should be noted that these data are derived
from studies which have focussed on secondary prevention in people who have had a
previous vascular event. Data on primary prevention are limited.
It should also be noted that the majority of people treated with statins do not achieve LDL
cholesterol levels of 2.5mmol/l. The lipid assessment project (L-TAP) showed that among
4,888 people treated with statins only 38% reached NCEP LDL cholesterol targets (Pearson
et al, 2000). However the Atorvastatin Comparative Cholesterol Efficacy and Safety Study
(ACCESS) demonstrated that it is possible to achieve NCEP targets in 80% or more of
people with aggressive statin treatment (Andrews et al, 2001).
Some programs have been shown to increase the achievement of lipid targets. In an
Australian randomised controlled trial, Vale et al (2002) compared the coach model (n=121)
with usual medical care (n=124) on the change of total cholesterol level over a 6-month
period. The five-step coaching intervention, which assisted people with established CHD to
achieve the target total cholesterol level of <4.5mmol/L was achieved by a dietitian who
ascertained attitude and beliefs about achieving the target lipid level, explaining the rationale
of recommended therapy, assertiveness training, goal setting and reassessment at the next
coaching session. The number of people taking lipid-lowering medications was 67 in both
groups. At 6 months, the mean total and LDL cholesterol levels were significantly lower in
the coaching group than in the usual care group (5.0 v 5.5mmol/L, p=0.0001; 3.1 v
3.6mmol/L, p=0.0004, respectively). 31% of people in the coaching group compared with
only 10% in the usual care group achieved the target total cholesterol of <4.5mmol/L
(p<0.001). Multivariate analysis showed that coaching intervention and being prescribed
statins were both highly significant predictors of the final total cholesterol level (p<0.0001
and p<0.0003, respectively).
158
HDL Cholesterol and Triglycerides

Although the role of LDL cholesterol as a risk factor for CVD is established, the statin
studies show that lowering LDL cholesterol produces only a partial reduction in CVD of the
order of 30% or so. Clearly other lipids and risk factors are important in determining CVD.
This is emphasised by the results of intervention studies with fibrates which have little effect
on LDL cholesterol but have a significant effect in reducing CVD.
As reviewed in Section 1 a low HDL cholesterol and elevated triglycerides are frequently
observed in people with Type 2 diabetes. Epidemiological studies have shown that a low
HDL cholesterol predicts an increased risk of coronary artery disease for any LDL
cholesterol level (Assmann et al, 1996) and the risk associated with a low HDL cholesterol is
as high as for a high LDL cholesterol (Castelli et al, 1986).
Hokanson and Austin (1996) performed a meta-analysis of prospective population based
studies and showed that triglycerides were an independent risk factor for CVD. Among
57,277 subjects aged 15-81 years (diabetes not specified), a 1mmol/L increase in mean
triglycerides level was significantly associated with increased risk of CVD in both men
(n=46,413) (RR 1.32, CI 1.26-1.29) and in women (n=10,864) (RR 1.76, CI 1.50-2.07). After
adjustment for HDL cholesterol and other risk factors, there was still a 14% increased CVD
risk (RR 1.14, CI 1.05-1.28) in men and a 37% increased CVD risk (RR 1.37, CI 1.13-1.66)
in women.
The results of intervention studies emphasise that non-LDL cholesterol and possibly
triglycerides are important in reducing CVD. The Veterans Affairs High-Density Lipoprotein
Intervention Trial (VA-HIT) Rubins et al, 1999) studied 2,531 men (mean age 64.7 years)
with established CHD, HDL cholesterol 1.0mmol/L and LDL cholesterol 3.6mmol/L.
People randomised to treatment with gemfibrozil 600mg twice daily had a 31% reduction in
triglycerides (1.3mmol/L v 1.9mmol/L, p<0.001), a 6% increase in HDL cholesterol
(0.9mmol/L v 0.8mmol/L, p<0.001), but no change in LDL cholesterol at one year
(2.9mmol/L for both groups) compared with placebo. Gemfibrozil reduced nonfatal
myocardial infarction or CHD death by 22% (p<0.006). Although baseline triglycerides
predicted coronary artery events in univariate analysis, this relationship became non
significant in mutlivariate analysis which included HDL cholesterol. In the VA-HIT study, a
separate analysis of the pre-specified group with diabetes (627 individuals or 25% of
subjects) showed a 24% reduction of the endpoint nonfatal myocardial infarction, CHD death
and confirmed stroke (p=0.05).
The Bezafibrate Infarction Prevention (BIP) study randomised 3,090 people with established
CHD, HDL cholesterol 1.17mmol/L, triglycerides 3.3mmol/L and LDL cholesterol 4.7
mmol/L to bezafibrate 400mg daily or placebo (BIP Study, 2000). On treatment, HDL
cholesterol increased to 1.06mmol/L and triglycerides decreased to 1.3mmol/L from a
baseline of 0.90mmol/L and 1.6mmol/L respectively. While the 7.3% reduction in the
primary endpoint of nonfatal myocardial infarction or CHD death was not significant
(p=0.26), the post hoc analysis of the subgroup with triglycerides 2.2mmol/L showed a 39%
reduction in this endpoint (p<0.02).
The Diabetes Atherosclerosis Intervention Study (DAIS) randomised 418 people with
diabetes aged 40 to 65 years to treatment with fenofibrate 200mg daily or placebo for an
average of 4 years (DAIS, 2001). At baseline mean LDL cholesterol was 3.4mmol/L, HDL
cholesterol was 1.03mmol/L, triglycerides were 2.4mmol/L and 48% had prior clinical
evidence of CHD. There was a significant 0.24mmol/L reduction in LDL cholesterol, a
0.07mmol/L increase in HDL cholesterol and 0.75mmol/L reduction in triglycerides in the
159
fenofibrate treated group. Primarily an angiographic study, the DAIS results show that
fenofibrate treatment was associated with 40% less progression in minimum lumen diameter
(p=0.029), 42% less progression in percentage diameter stenosis (p=0.02) and a 23% non
significant reduction in combined clinical endpoints.
The Helsinki Heart Study (Frick et al, 1987), a primary prevention study, randomised 4,081
asymptomatic men to treatment with gemfibrozil 600mg twice daily or placebo and showed a
34% reduction (p<0.02) in nonfatal myocardial infarction and cardiac death. A post hoc
analysis (Manninen et al, 1989) showed that the reduction of CHD with gemfibrozil was
greatest in subjects with HDL cholesterol in the lower tertile (<1.08mmol/L) or triglycerides
in the upper tertile (>2.08mmol/L). In the subgroup of 1,131 people with LDL cholesterol
4.5mmol/L and triglycerides >2.0mmol/L there was a 43% reduction in CHD events
(p<0.02) with only a 7.5% reduction in LDL cholesterol level for gemfibrozil compared with
placebo treatment.
In the 4S study, apart from the significant influence of LDL cholesterol lowering in
improving outcomes, each 0.1mmol/L increase of HDL cholesterol was associated with a
3.7% reduction (CI -0.3, 7.5%, p=0.07) in major coronary events. Reductions in triglycerides
did not contribute to risk reduction but all 4S participants were recruited on the basis of
having triglycerides 2.5mmol/L (Pedersen et al, 1998).
In the Pravastatin Pooling Project (Sacks et al, 2000), in both the pravastatin and placebo
treated groups there was a parallel inverse relationship between coronary events and HDL
cholesterol, demonstrating that low levels of HDL cholesterol were an independent risk factor
despite a decrease in LDL cholesterol produced by pravastatin and that statins did affect the
HDL cholesterol associated risk.
In summary there is strong epidemiological and clinical trial data which support a significant
role for low HDL cholesterol as an independent risk factor for coronary artery disease.
However there are few data to guide recommendations on initiation of treatment or
therapeutic goals for HDL cholesterol and other lipid parameters in people with Type 2
diabetes.
Implications for clinical practice
The following is a summary of the current evidence used to make the clinical practice
recommendations for interventions to improve lipid levels for the primary prevention of
cardiovascular disease in people with Type 2 diabetes:
Most of the evidence on improved outcomes relates to lowering LDL cholesterol

Increasing HDL cholesterol also has a role in improving outcomes
Reducing triglycerides seem important only when levels are at least more than 2mmol/L
Although individual studies report variable results, the following average changes can be
achieved with interventions to improve lipids
LDL Cholesterol HDL Cholesterol Triglycerides
10%
10%
15%
Lifestyle changes
5-10%
5%
10%
Improved diabetes control
35%
5%
10%
Statins
5-10%
10%
35%
Fibrates
Therapeutic interventions are available to substantially change LDL cholesterol (statins)

and triglcyerides (fibrates)
No therapeutic agent is available which can alter HDL cholesterol by a similar magnitude
160
Most statin intervention studies achieved a mean LDL cholesterol of the order of
2.5mmol/L
Taking the above into consideration and acknowledging that more data are required before
the evidence base is complete, current data support the NCEP recommendations which set an
LDL target of 2.5mmol/L for people with diabetes and which recommend interventions to
reduce triglycerides as shown in the following flow chart.
161
Lipid Control Treatment Algorithm for People with Type 2 Diabetes and no Known
Vascular Disease (Adapted from NCEP Guidelines)
LDL Cholesterol
<2.5 mmol/L
No statin therapy
LDL Cholesterol
2.5 3.5 mmol/L
LDL Cholesterol
>3.5 mmol/L
Lifestyle advice
Improve diabetes control
Lifestyle advice
Commence statin therapy
LDL cholesterol remains >2.5

mmol/L after 3 months
Consider statin therapy
Triglycerides 2-4 mmol/L
Triglycerides > 4 mmol/L
Lifestyle advice
Lifestyle advice
Triglycerides remain 2-4 mmol/L

after 3 months
If taking a statin, intensify therapy
Or
consider treatment with a fibrate
Triglycerides remain >4 mmol/L

after 3 months
Commence fibrate
162
Summary - effects of lipid modifying agents or hormone replacement therapy on

cardiovascular disease risk
In the diabetic subgroup of the 4S study treatment with simvastatin reduced major CHD
events by 42%, not significantly different from the 32% reduction in the cohort with
normal glucose tolerance
In the CARE study pravastatin resulted in a 13% reduction (p=NS) of myocardial
infarction or CHD death in the group with diabetes and a 26% reduction (p=0.04) in the
non-diabetic group, but a significant reduction in revascularisation procedures (32%,
p=0.04) and total coronary events (25%, p=0.05) for those with diabetes
In the LIPID study there was a 19% reduction of myocardial infarction or CHD death in
the group with diabetes and a 25% reduction in the non-diabetic group (p=NS for diabetes
compared with non-diabetes)
Because the absolute risk of major CHD events (myocardial infarction or CHD death) is
greater in people with diabetes, an equivalent reduction in relative risk with statin therapy
means a greater number of cardiac events prevented in the diabetic group
In the AFCAPS/TexCAPS study using lovastatin there was a 43% risk reduction in acute
major coronary events in the diabetic group which was not different from the 36%
reduction for the total cohort
A post hoc analysis of the 4S in people with IFG showed a relative risk reduction for
major coronary events of 38% with simvastatin, not significantly different to the 32%
reduction in people with normal fasting glucose. A similar outcome was observed with
IFG in the CARE study using pravastatin
In VA-HIT treatment with gemfibrozil 600mg twice daily in the diabetic subgroup
showed a 24% reduction of the endpoint nonfatal myocardial infarction, CHD death and
confirmed stroke
Although there are some data in people without diabetes, there is no evidence that -3
polyunsaturated fatty acids (fish oil) reduce the risk of recurrent cardiovascular disease in
people with Type 2 diabetes
disease in postmenopausal women with Type 2 diabetes
Based on the results of the 4S trial, savings from reduced hospitalisation of the diabetic
group offset 67 to 76% of the drug cost and each life-year gained was estimated to cost
from 1,600 Euros (based on clinical history of diabetes) to 3,200 Euros (based on fasting
glucose 7.0 mmol/L)
Estimates of the cost-effectiveness of primary prevention therapy indicate that for men
with pretreatment LDL cholesterol of 5.46mmol/L, costs per life year saved range from
$US 4,000 for 60 year olds to $US10,000 for 70 year olds; for women the range is about
$US9,000 to $US15,000
163

Effects of lipid modifying agents or hormone replacement therapy on
cardiovascular disease risk
Author
Evidence
Level of Evidence
Level
Study Type
Andrews TC (2001)
(Adults US)
ALLHAT Collaborative
Research Group (2002b)
(Adults US; Canada; Puerto
Rico)
Assmann G (1996)
(Adults Germany)
Athyros VG (2002b)
(Adults Greece)
BIP Study Group (2000)
(Adults Israel)
Blauw GJ (1997)
Brandle M (2003)
(Adults US)
Byington RP (2001)
(Adults US)
Burr ML (1989)
(Adults-UK)
Cannon CP (2004)
(Adults US; Canada)
CARDS (2004)
(Adults multicountries)
Caro J (1997)
(Men Scotland)
Castelli WP (1986)
(Adults US)
DAIS (2001)
(Adults Canada, Finland,
Sweden, France)
Downs JR (1998)
(Adults US)
Elkeles RS (1998)
(Adults UK: England)
Friedberg CE (1998)
Frick MH (1987)
(Adult men Finland)
GISSI (1999)
(Adults Italy)
Glasziou PP (2002)
(Adults Australia; NZ)
Goldberg RB (1998)
(Adults US, Canada)
Grover SA (2000)
(Adults Canada)
Grover SA (2001)
(Adults Canada, UK & Europe)
Haffner SM (1999)
Haffner SM (2000)
Quality
Rating
Magnitude
Rating
Relevance
Rating
III-2
Cohort
High
High +
Low
II
RCT
High
Low
Low
III-2
Cohort
High
High +
Low
High
II
RCT
High
High
II
RCT
Medium
High +
Low
Meta-analysis
High
High +
Low
II
RCT
High
High +
High
III-2
Cohort
High
High +
High
II
RCT
High
High +
High
High
II
RCT
High
High
II
RCT
High
High +
High
Low
II
RCT
Medium
High
III-2
Cohort
High
High +
Low
II
RCT
High
High +
High
II
RCT
High
High +
Low
II
RCT
High
High +
High
Meta-analysis
High
High+
High
II
RCT
Medium
High +
Low
II
RCT
High
High +
Low
II
RCT
High
High +
Low
II
RCT
High
High +
High
III-2
Cohort
Medium
Medium+
High
III-2
Cohort
Medium
High +
High
II
RCT
High
High +
High
Systematic review
High
High +
High
Heart Protection Study (2002a)

High
II
RCT
High
High +
(Adults UK)
Heart Protection Study (2002b)
High
II
RCT
High
High +
(Adults UK)
Heart Protection Study (2003)
High
II
RCT
High
High +
(Adults UK)
+
lipid modifying agents reduce cardiovascular disease; High = clinically important & statistically significant; Medium = small clinical
E= estrogen therapy
164

Author
Evidence
Level of Evidence
Level
Type
Quality
Rating
Magnitude
Rating
Relevance
Rating
Heart Protection Study (2004)

(Adults UK)
II
RCT
High
High +
High
Hokanson JE (1996)
Meta-analysis
High
High +
Low
Hoogwerf BJ (1999)
(Adults US)
II
RCT
Medium
Low
High
Huang ES (2001)
Systematic
review
High
High +
High
II
RCT
High
Low
Low
III-2
Cohort
Medium
High +
Low
III-2
Cohort
Medium
High +
High
III-2
Case-control
High
High +
High
II
RCT
High
High +
Low
II
RCT
High
High +
High
II
RCT
High
High +
Low
II
RCT
High
Low
High
Hulley S (1998)
(Adult women US)
Inoue I (1994)
(Adults Japan)
Jonsson B (1999)
(Adults Sweden)
Kaplan RC (1998)
(Adults women US)
Keech A (2001)
(Adults-Australia, NZ)
Keech A (2003)
(Adults-Australia, NZ)
Knatterud GL (2000)
(Adults US)
Koskinen P (1992)
(Adult men Finland)
Law MR (2003)
LIPID Study Group (1998)
(Adults Australia, NZ)
Manninen V (1989)
Manson JE (2003)
(Women multicentres)
McIntosh A (2001)
Low
Meta-analysis
High
High
II
RCT
High
High +
Low
Low
II
RCT
High
High
II
RCT
High
Low
High
Systematic
review
High
High +
High
Pearson TA (2000)
Low
III-2
Cohort
High
High +
(Adults US)
Pedersen TR (1998)
Low
III-2
Cohort
High
High +
(Adults Pyorala K (1997)
+
High
II
RCT
High
High
Robins SJ (2001)
Low
II
RCT
High
High +
(Adult men US)
Rubins HB (1999)
+
High
II
RCT
High
High
(Adult men US)
Rubins HB (2002)
High
II
RCT
High
High +
(Adult men US)
Rubins HB (2003)
III
Cohort
Medium
High +
High
(Adult US)
Sacks FM (1996)
High
II
RCT
High
High +
(Adults US, Canada)
Sacks FM (1998)
Low
III-2
Cohort
High
High +
(Adults US, Canada)
Sacks FM (2000)
High
II
RCT
High
High +
(Adults US, Canada)
Sacks FM (2002)
High
II
RCT
High
High +
(Adults US, Canada)
4S Study (1994)
+
II
RCT
High
High
Low
Sever PS (2003)
High
II
RCT
High
High +
(Adults multi countries)
Shepherd J (1995)
+
Low
II
RCT
High
High
(Adults UK: Scotland)
Shepherd J (2002)
High
II
RCT
High
High +
(Adults UK; the Netherlands)
+
E= estrogen therapy
165

Evidence
Author
Quality
Rating
Level of Evidence
Level
Type
Magnitude
Rating
Relevance
Rating
Simes RJ (2002)
Low
III-2
Cohort
High
High +
(Adults Australia, NZ)
Stampfer MJ (1991)
Low
III-2
Cohort
High
High E+
(Adult women US)
Teo KK (2000)
High
II
RCT
High
High +
(Adults Canada)
The CDD Diabetes CostII
RCT
High
High +
High
Effectiveness Group (2002)
Vale MJ (2002)
Low
II
RCT
High
High +
(Adults Australia)
Vasilios G (2002)
Low
II
RCT
High
High +
(Adults Greece)
Waters D (1994)
+
High
II
RCT
High
High
(Adults Canada)
White HD (2000)
High
(Adults Australia, New
II
RCT
High
High +
Zealand)
White CW (2001)
Low
II
RCT
High
High +
(Adults US)
WOSCOPS Study Group
Low
III-2
Cohort
High
High+
(1998)
(Adulsts UK: Scotland)
+
E= estrogen therapy
166
Lipid Disease: Evidence References

Abraira C, Derler J. Large variations of sucrose in constant carbohydrate diets in Type II diabetes. Am J Med
1988;84:193-200.
Abu-Lebdeh HS, Hodge DO, Nguyen TT. Predictors of macrovascular disease in patients with Type 2 diabetes
mellitus. Mayo Clin Proc 2001;76:707-12.
ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomised to
angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart attack Trial (ALLHAT). JAMA 2002a;288:2981-2997.
ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolaemic, hypertensive
patients randomised to pravastatin vs usual care. The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAR-LLT). JAMA 2002b;288:2998-3007.
Anderson JW, Allgood LD, Turner J, Oeltgen PR, Daggy BP. Effects of psyllium on glucose and serum lipid
responses in men with Type 2 diabetes and hypercholesterolaemia. Am J Clin Nutr 1999;70:466-73.
Andrews TC, Ballantyne CM, Hsia JA, Kramer JH. Achieving and maintaining National Cholesterol Education
Program low-density lipoprotein cholesterol goals with five statins. Am J Med 2001;111:185-91.
Assmann G, Cullen P, Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years.
European Heart Journal 1998;19:A2-11.
Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of
coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse
choesterol transport. Atherosclerosis 1996;124 (Suppl):S11-20.
Athyros VG, Papageorgiou AA, Athyrou VV, Demitriadis DS, Kontopoulos AG. Atorvastatin and micronised
fenofibrate alone and in combination in Type 2 diabetes with combined hyperlipidaemia. Diabetes Care
2002a;25:1198-202.
Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeouidis AN, Basayannis EO, Demitriadis DS,
Kontopoulos AG. Treatment with atorvastatin to the National Cholesterol Educational Program Goal versus
'usual' care in secondary coronary heart disease prevention. Cur Med Res Opin 2002b;18:220-8.
Avogaro A, Piliego T, Catapano A, Miola M, Tiengo A. The effect of gemfibrozil on lipid profile and glucose
metabolism in hypertriglyceridaemic well-controlled non-insulin-dependent diabetic patients. Acta Diabetol
1999;36:27-33.
Bantle JP, Swanson JE, Thomas W, Laine DC. Metabolic effects of dietary sucrose in type II diabetic subjects.
Diabetes Care 1993;16:1301-5.
Barnard RJ, Jung T, Inkeles SB. Diet and exercise in treatment of NIDDM - the need for early emphasis.
Barrett-Connor E, Ensrud KE, Harper K, Mason TM, Sashegyi A, Krueger KA, Anderson PW. Post hoc
analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial on the effects of three
years of raloxifene treatment on glycaemic control and cardiovascular disease risk factors in women with and
without Type 2 diabetes. Clin Ther 2003;25:919-30.
Bell RA, Mayer-Davis EJ, Martin MA, DAgostino Jr RB, Haffner SM. Association between alcohol
consumption and insulin sensitivity and cardiovascular disease risk factors. The Insulin Resistance
Atherosclerosis Study. Diabetes Care 2000;23:1630-6.
Ben G, Gnudi L, Maran A, Gigante A, Duner E, Iori E, Tiengo A, Avogaro A. Effects of chronic alcohol intake
on carbohydrate and lipid metabolism in subjects with Type II (non-insulin-dependent) diabetes. Am J Med
1991;90:70-6.
Billingham MS, Milles JJ, Bailey CJ, Hall RA. Lipoprotein subfraction composition in non-insulin-dependent
diabetes treated by diet, sulphonylurea, and insulin. Metabolism 1989;38:850-7.
167
BIP Group. Bezafibrate Infarction Prevention. Secondary prevention by raising HDL cholesterol and reducing
triglycerides in patients with coronary artery disease. The Benzafibrate Infarction Prevention (BIP) Study.
Circulation 2000;102:21-7.
Bishop N, Scorah CJ, Wales JK. The effect of vitamin C supplementation on diabetic hyperlipidaemia: a double
blind crossover study. Diabetic Medicine 1985;2:121-4.
Blauw GJ, Lagaay AM, Smelt AHM, Westendorp RGJ. Stroke, statins, and cholesterol. A meta-analysis of
randomised, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke 1997;28:94650.
Bonanome A, Visona A, Lusiani L, Beltramello G, Confortin L, S. B, Sorgato F, Costa F, Pagnan A.
Carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus: effects of a lowfat, high-carbohydrate diet vs a diet high in monounsaturated fatty acids. Am J Clin Nutr 1991;54:586-90.
Bos G, Dekker JM, Nijpels G, de Vegt F, Diamant M, Stehouwer CDA, Bouter LM, Heine RJ. A combination
of high concentrations of serum triglyceride and non-high-density-lipoprotein-cholesterol is a risk factor for
cardiovascular disease in subjects with abnormal glucose metabolism - The Hoorn Study. Diabetologia
2003;46:910-6.
Brand JC, Colagiuri S, Crossman S, Allen A, Roberts DC, Truswell AS. Low-glycaemic index foods improve
long-term glycemic control in NIDDM. Diabetes Care 1991;14:95-101.
Brandle M, Davidson MB, Schriger DL, Lorber B, Herman WH. Cost effectiveness of statin therapy for the
primary prevention of major coronary events in individuals with type 2 diabetes. Diabetes Care 2003;26:1796801.
Brown SA, Upchurch S, Anding R. Winter M, Ramirez G. Promoting weight loss in Type II diabetes. Diabetes
Care 1996;19:613-24.
Brussaard HE, Gevers Leuven JA, Kluft C, Krans HM, van Duyvenvoorde W, Buytenhek R, van der Laarse A,
Princen HMG. Effect of 17 beta-estradiol on plasma lipids and LDL oxidation in postmenopausal women with
Type II diabetes mellitus. Arterioscler Thromb Vasc Biol 1997;17:324-30.
Burchfiel CM, Hamman RF, Marshall JA, Baxter J, Kahn LB, Amirani JJ. Cardiovascular risk factors and
impaired glucose tolerance: the San Luis Valley Diabetes Study. Am J Epidemiol 1990;31:57-70.
Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM. Effects of
changes in fat, fish, and fibre intakes on death and myocardial infarction: diet and reinfarction trial (DART).
Lancet 1989;8666:757-61.
Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J. Reduction of stroke events with
pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation 2001;103:387-92.
Byrne CD, Wareham NJ, Brown DC, Clark PMS, Cox LJ, Day NE, Palmer CR, Wang TWM. Williams DR.
Hales CN. Hypertriglyceridaemia in subjects with normal and abnormal glucose tolerance: relative contributions
of insulin secretion, insulin resistance and suppression of plasma non-esterified fatty acids. Diabetelogia
1994;37:889-96.
Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA,
Skene AM. Intensive versus moderate lipid owering with statins after acute coronary syndromes. N Engl J Med
2004;350:1495-504.
Caro J, KlittichW, McGuire A, Ford J, Norrie J, Pettitt D, McMurray J, Shepherd J. The West of Scotland
coronary prevention study: economic benefit analysis of primary prevention with pravastatin. BMJ
1997;315:1577-82.
Castelli WP. Epidemiology of triglycerides: A View from Framingham. Am J Cardiol 1992;70:H3-9.
Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart
disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986;256:2835-8.
168
Cathelineau G, de Champvallins M, Bouallouche A, Lesobre B. Management of newly diagnosed non-insulindependent diabetes mellitus in the primary care setting: effects of 2 years of gliclazide treatment - the Diadem
Study. Metabolism 1997;46(Suppl 1):31-4.
Ceriello A, Bortolotti N, Pirisi M, Crescentini A, Tonutti L, Motz E, Russo A, Giacomello R, Stel G, Taboga C.
Total radical-trapping antioxidant parameter in NIDDM patients. Diabetes Care 1997b;20:194-7.
Ceriello A, Bortolotti N, Pirisi M, Crescentini A, Tonutti L, Motz E, Russo A, Giacomello R, Stel G, Taboga C.
Total plasma antioxidant capacity predicts thrombosis-prone status in NIDDM patients. Diabetes Care
1997a;20:1589-93.
Chandalia M, Garg A, Lutjohann DVB, von Bergmann K, Grundy SM, Brinkley LJ. Beneficial Effects of High
Dietary Fiber Intake in Patients with Type 2 Diabetes Mellitus. N Engl J Med 2000;342:1392-8.
Chang CJ, Kao JT, Wu TJ, Lu FH, Tai TY. Serum lipids and lipoprotein (a) concentrations in Chinese NIDDM
patients. Relation to metabolic control. Diabetes Care 1995;18:1191-4.
Chen YD, Coulston AM, Zhou MY, Hollenbeck CB, Reaven GM. Why do low-fat high-carbohydrate diets
accentuate postprandial lipemia in patients with NIDDM? Diabetes Care 1995;18:10-6.
Chen YD, Swami S, Skowronski R, Coulston A, Reaven GM. Effect of variations in dietary fat and
carbohydrates intake on postprandial lipemia in patients with noninsulin dependent diabetes mellitus. J Clin
Endocrinol Metab 1993;76:347-51.
Chew EY, Klein ML, Ferris FL 3rd, Remaley NA, Murphy RP, Chantry K, Hoogwerf BJ, Miller D. Association
of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Arch Ophthalmol
1996;114:1079-84.
Christiansen C, Thomsen C, Rasmussen O, Hansen C, Hermansen K. The acute impact of ethanol on glucose,
insulin, triacylglycerol, and free fatty acid responses and insulin sensitivity in type 2 diabetes. Br J Nutr
1996;76:669-75.
Christiansen E, Schnider S, Palmvig B, Tauber-Lassen E, Pedersen O. Intake of a diet high in trans
monounsaturated fatty acids or saturated fatty acids: effects on postprandial insulinemia and glycemia in obese
patients with NIDDM. Diabetes Care 1997;20:881-7.
Colagiuri S, Miller JJ, Edwards RA. Metabolic effects of adding sucrose and aspartame to the diet of subjects
with noninsulin-dependent diabetes mellitus. Am J Clin Nutr 1989;50:474-8.
Colhoun HM, Thomason MJ, Mackness MI, Maton SM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,
Fuller JH; Collaborative AtoRvastatin Diabetes Study (CARDS). Design of the Collaborative AtoRvastatin
Diabetes Study (CARDS) in patients with Type 2 diabetes. Diabet Med 2002;19:201-11.
Collaborative Atorvastatin Diabetes Study (CARDS) Group. www.cardstrial.org. Accessed June 23, 2004.
Coniff RF, Shapiro JA, Robbins D, Kleinfield R, Seaton TB, Beisswenger P, McGill JB. Reduction of
glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. A placebocontrolled dose-comparison study. Diabetes Care 1995a;18:817-24.
Coniff RF, Shapiro JA, Seaton TB, Bray GA. Multicenter, placebo-controlled trial comparing acarbose (BAY g
5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am
J Med 1995b;98:443-51.
Cooper PL, Wahlqvist ML, Simpson RW. Sucrose versus saccharin as an added sweetener in non-insulindependent diabetes: short-and medium-term metabolic effects. Diabet Med 1988;5:676-80.
Coulston AM, Hollenbeck CB, Donner CC, Williams R, Chiou YA, Reaven GM. Metabolic effects of added
dietary sucrose in individuals with non-insulin-dependent diabetes mellitus (NIDDM). Metabolism
1985;34:962-6.
Coulston AM, Hollenbeck CB, Swislocki AL, Reaven GM. Persistence of hypertriglyceridemic effect of low-fat
high-carbohydrate diets in NIDDM patients. Diabetes Care 1989;12:94-101.
169
Cowie CC, Howard BV, Harris MI. Serum lipoproteins in African Americans and Whites with non-insulindependent diabetes in the US population. Circulation 1994;90:1185-93.
Csaszar A, Dieplinger H, Sandholzer C, Karadi I, Juhasz E, Drexel H, Halmos T, Romics L, Patsch JR,
Utermann G. Plasma lipoprotein (a) concentration and phenotypes in diabetes mellitus. Diabetologia
1993;36:47-51.
Dailey GE 3rd, Mohideen P, Fiedorek FT. Lipid effects of glyburide/metformin tablets in patients with Type 2
diabetes mellitus with poor glycaemic control and dyslipidaemia in an open-label extension study. Clin Ther
2002;24:1426-38.
DAIS Investigators. Effects on fanofibrate on progression of coronary-artery disease in type 2 diabetes: the
Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001;357:905-10.
Dean JD, Owens DR, Matthews SB. Apolipoprotein and lipid ratios in treated non-insulin dependent diabetics.
Diabetes Res 1990;15:21-5.
DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus.
The Multicenter Metformin Study Group. N Engl J Med 1995;333:541-9.
Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R. Comparison between repaglinide and glimepiride
in patients with Type 2 diabetes mellitus: a one-year, randomised, double-blind assessment of metabolic
parameters and cardiovascular risk factors. Clin Ther 2003;25:472-84.
Devaraj S, Jialal I. Low-Density Lipoprotein Postsecretory Modicafiaction, monoctye Function, and Circulating
Adhesion molecules in Type 2 Diabetic patients with and without Macrovascular complications: The Effect of
alpha-Tocopherol Supplementation. Circulation 2000;102:191-6.
Dimitriadis E, Griffin M, Owens D, Johnson A, Collins P, Tomkin GH. Oxidation of low-density lipoprotein in
NIDDM: its relationship to fatty acid composition. Diabetologia 1995;38:1300-6.
Dodson PM, Gibson JM. Long term follow-up of and underlying medical conditions in patients with diabetic
exudative maculopathy. Eye 1991;5:699-703.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W,
Gotto AMJr. Primary prevention of acute coronary events with lovastatin in men and women with average
cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
JAMA 1998;279:1615-22.
Dunstan DW, Mori TA, Puddey IB, Beilin LJ, Burke V, Morton AR, Stanton KG. The independant and
combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control in NIDDM. A
randomized controlled study. Diabetes Care 1997;20:913-21.
Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB, Sheps DS, Brinton EA. Effect
of niacin on lipid and lipoprotein levels and glycaemic control in patients with diabetes and peripheral arterial
disease. The ADMIT Study: A randomised trial. JAMA 2000;284:1263-70.
Elkeles RS, Diamond JR, Poulter C, Dhanjil S, Nicolaides AN, Mahmood S, Richmond W, Mather H, Sharp P,
Feher MD. Cardiovascular outcomes in Type 2 diabetes. A double-blind placebo-controlled study of
bezafibrate: the St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP)
Study. Diabetes Care 1998;21:641-8.
Emanuele N, Azad N, Abraria C, Henderson W, Colwell J, Levin S, Nuttall F, Comstock J, Sawin C, Silbert C,
Marcovina S, Lee HS, for the Veterans Affairs Cooperative Study in Diabetes Mellitus Group. Effect of
intensive glycemic control on fibrinogen, lipids, and lipoproteins. Veterans Affairs Cooperative Study in Type II
Diabetes Mellitus. Arch Intern Med 1998;158:2485-90.
Eriksson J, Kohvakka A. Magnesium and Ascorbic Acid Supplementation in Diabetes Mellitus. Ann Nutr
Metab 1995;39:217-23.
Fanghanel G, Sanchez-Reyes L, Trujillo C, Sotres D, Espinosa-Campos J. Metformin's effects on glucose and
lipid metabolism in patients with secondary failure to sulfonylureas. Diabetes Care 1996;19:1185-9.
170
Farrer M, Winocour PH, Evans K, Neil HA, Laker MF, Kesteven P, Alberti KG. Simvastatin in non-insulindependent diabetes mellitus: effect on serum lipids, lipoproteins and haemostatic measures. Diabetes Res Clin
Pract 1994;23:111-9.
Fasching P, Rohac M, Liener K, Schneider B, Nowotny P, Waldhausl W. Fish oil supplementation versus
gemfibrozil treatment in hyperlipidemic NIDDM. Horm Metab Res 1996;28:230-6.
Field Study Investigators. Personal communication. 2001.
Fontbonne A, Eschwege E, Cambien F, Richard JL, Ducimetiere P, Thibult N, Warnet JM, Claude JR, Rosselin
GE. Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose
tolerance or diabetes. Results from the 11-year follow-up of the Paris Prospective Study. Diabetologia
1989;32:300-4.
Franz MJ, Monk A, Barry B, McClain K, Weaver T, Cooper N, Upham P, Bergenstal R, Mazze R. Effectiveness
of medical nutrition therapy provided by the dietitians in the management of non-insulin dependent diabetes
mellitus: a randomised, controlled clinical trial. J Am Diet Assoc 1995;95:1009-17.
Freed MI, Ratner R, Marcovina SM, Kreider MM, Biswas N, Cohen BR, Brunzell JD, Rosiglitazone Study 108
investigators. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities
in Type 2 diabetes mellitus. Am J Cardiol 2002;90:947-52.
Freitas JP, Filipe PM, Rodrigo FG. Lipid peroxidation in type 2 normolipidemic diabetic patients. Diabetes Res
Clin Pract 1997;36:71-5.
Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P,
Manninen V, Maenpaa H, Malkonen M, Manttari M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjoblom
T, Nikkila EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with
dyslipidemia. Saftey of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J
Med 1987;317:1237-45.
Friedberg CE, Janssen MJ, Heine RJ, Grobbee DE. Fish oil and glycaemic control in diabetes. A meta-analysis.
Frost G, Wilding J, Beecham J. Dietary advice based on the glycaemic index improves dietary profile and
metabolic control in Type 2 diabetic patients. Diabet Med 1994;11:397-401.
Fuh MM, Lee MM, Jeng CY, Ma F, Chen YD, Reaven GM. Effect of low fat-high carbohydrate diets in
hypertensive patients with non-insulin-dependent diabetes mellitus. Am J Hypertens 1990;3:527-32.
Fuller JH, Stevens LK, Wang SL. Risk factors for cardiovascular mortality and morbidity: The WHO
multinational study of vascular diseases in diabetes. Diabetologia 2001;44(Suppl 2):S54-64.
Gardner SF, Marx MA, White LM, Granberry MC, Skelton DR, Fonseca VA. Combination of low-dose niacin
and pravastatin improves the lipid profile in diabetic patients without compromising glycaemic control. Ann
Pharmacother 1997;31:677-82.
Garg A. High-monounsaturated-fat diets for patients with diabetes mellitus: a meta-analysis. Am J Clin Nutr
1998;67(Suppl 1):577-82.
Garg A, Bantle JP, Henry RR, Coulston AM, Griver KA, Raatz SK, Brinkley L, Chen YD, Grundy SM, Huet
BA, Reaven GM. Effects of varying carbohydrate content of diet in patients with non-insulin-dependent
diabetes mellitus. JAMA 1994a;271:1421-8.
Garg A, Grundy SM. Cholestyramine therapy for dyslipidaemia in non-insulin-dependent diabetes mellitus. Ann
Intern Med 1994b;121:416-22.
Garg A, Grundy SM, Koffler M. Effect of high carbohydrate intake on hyperglycemia, islet function, and
plasma lipoproteins in NIDDM. Diabetes Care 1992a;15:1572-80.
Garg A, Grundy SM, Unger RH. Comparison of effects of high and low carbohydrate diets on plasma
lipoproteins and insulin sensitivity in patients with mild NIDDM. Diabetes 1992b;41:1278-85.
171
Gavish D, Leibovitz E, Shapira I, Rubinstein A. Bezafibrate and simvastatin combination therapy for diabetic
dyslipidaemia: efficacy and safety. J Intern Med 2000;247:563-9.
Gentile S, Turco S, Guarino G, Sasso CF, Amodio M, Magliano P, Salvatore T, Corigliano G, Agrusta M, De
Simone G, Gaeta I, Oliviero B, Torella R. Comparative efficacy study of atorvastatin vs. simvastatin,
pravastatin, lovastatin and placebo in Type 2 diabetic patients with hyercholesterolaemia. Diabetes Obes Metab
2000;2:355-62.
Giansanti R, Rabini RA, Romagnoli F, Fumelli D, Sorichetti P, Boemi M, Fumelli P. Coronary heart disease,
type 2 diabetes mellitus and cardiovascular disease risk factors: a study on a middle-aged and elderly
population. Ach Gerontol Geriatr 1999;29:175-82.
GISSI. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction:
results of the GISSI-Prevenzione Trial. Lancet 1999;354:447-55.
Giugliano D, Quatraro A, Consoli G, Minei A, Ceriello A, De Rosa N, D'Onofrio F. Metformin for obese,
insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur
J Clin Pharmacol 1993;44:107-12.
Glasziou PP, Eckermann SD, Mulray SE, Simes RJ, Martin AJ, Kirby AC, Hall JP, Caleo S, White HD, Tonkin
AM. Cholesterol-lowering therapy with pravastatin in patients with average cholesterol levels and established
ischaemic heart disease: is it cost-effective? Med J Aust 2002;177:428-34.
Goldberg R, La Belle P, Zupkis R, Ronca P. Comparison of the effects of lovastatin and gemfibrozil on lipids
and glucose control in non-insulin-dependent diabetes mellitus. Am J Cardiol 1990;66:B16-21.
Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA,
Braunwald E. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant
myocardial infarction survivors with average cholesterol levels. Subgroup analysis in the Cholesterol and
Recurrent Events (CARE) Trial. Circulation 1998;98:2513-9.
Grigoresco C, Rizkalla SW, Halfon P, Bornet F, Fontvieille AM, Bros M, Dauchy F, Tchobroutsky G, Slama G.
Lack of detectable deleterious effects on metabolic control of daily fructose ingestion for 2 months in NIDDM
patients. Diabetes Care 1988;11:546-50.
Groop PH, Aro A, Stenman S, Groop L. Long-term effects of guar gum in subjects with non-insulin dependent
diabetes mellitus. Am J Clin Nutr 1993;58:513-8.
Grover SA, Coupal L, Zowall H, Alexander CM, Weiss TW, Gomes DR. How cost-effective is the treatment of
dyslipidemia in patients with diabetes but without cardiovascular disease? Diabetes Care 2001;24:45-50.
Grover SA, Coupal L, Zowall H, Dorais M. Cost-effectiveness of treating hyperlipidemia in the presence of
diabetes: who should be treated? Circulation 2000;102:722-7.
Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS,
Buse JB, Robertson DD, Sheehan JP; Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of
once-daily niacin for the treatment of dyslipidaemia associated with Type 2 diabetes. Results of the Assessment
of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial. Arch Intern Med 2002;162:1568-76.
Gumbiner B, Low CC, Reaven PD. Effects of a monounsaturated fatty acid-enriched hypocaloric diet on
cardiovascular risk factors in obese patients with type 2 diabetes. Diabetes Care 1998;21:9-15.
Gupta RR, Agrawal CG, Singh GP, Ghatak A. Lipid-lowering efficacy of psyllium hydrophilic mucilloid in non
insulin dependent diabetes mellitus with hyperlipidaemia. Indian J Med Res 1994;100:237-41.
Gylling H, Miettinen TA. Serum cholesterol and cholesterol and lipoprotein metabolism in
hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment. Diabetologia
1994;37:773-80.
Gylling H, Miettinen TA. Effects of inhibiting cholesterol absorption and synthesis on cholesterol and
lipoprotein metabolism in hypercholesterolaemic non-insulin-dependent diabetic men. J Lipid Res
1996;37:1776-85.
172
Gylling H, Miettinen TA. Cholesterol reduction by different plant stanol mixtures and with variable fat intake.
Metabolism 1999;48:575-80.
Haffner SM, Agil A, Mykkanen L, Stern MP, Jialal I. Plasma oxidisability in subjects with normal glucose
tolerance, impaired glucose tolerance, and NIDDM. Diabetes Care 1995;18:646-53.
Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K.
Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired
fasting glucose levels. Subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med
1999;159:2661-7.
Haffner SM, Ashraf T. Predicting risk reduction of coronary disease in patients who are glucose intolerant: a
comparison of treatment with fenofibrate and other lipid-modifying agents. Managed Care Interface 2000;13:528.
Haffner SM, Morales PA, Stern MP, Gruber MK. Lp(a) concentrations in NIDDM. Diabetes 1992a;41:1267-72.
Haffner SM, Moss SE, Klein BEK, Klein R. Lack of association between lipoprotein (a) concentrations and
coronary heart disease mortality in diabetes: The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
Metabolism 1992b;41:194-7.
Haffner SM, Mykkanen L, Stern MP, Paidi M, Howard BV. Greater effect of diabetes on LDL size in women
than in men. Diabetes Care 1994;17:1164-71.
Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch HJ, Lindner J, the DIS
Group. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention
Study, 11-year follow-up. Diabetologoia 1996;39:1577-83.
Hanefeld M, Fischer S, Schulze J, Spengler M, Wargenau M, Schollberg K, Fucker K. Therapeutic potentials of
acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991;14:732-7.
Hanninen J, Takala J, Keinanen-Kiukaanniemi S. Albuminuria and other risk factors for mortality in patients
with non-insulin-dependent diabetes mellitus aged under 65 years: a population-based prospective 5-year study.
Diabetes Res Clin Prac 1999;43:121-6.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with
simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002a;360:7-22
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant supplementation
in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002b;360:23-33
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with
simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16.
Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and
other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet
2004;363:757-67.
Heine RJ, Mulder C, Popp-Snijders C, van der Meer J, van der Veen EA. Linoleic-acid-enriched diet: long-term
effects on serum lipoprotein and apolipoprotein concentrations and insulin sensitivity in noninsulin-dependent
diabetic patients. Am J Clin Nutr 1989;49:448-56.
Heilbronn LK, Noakes M, Clifton PM. Effect of energy restriction, weight loss, and diet composition on plasma
lipids and glucose in patients with Type 2 diabetes. Diabetes Care 1999;22:889-95.
Heilbronn LK, Noakes M, Clifton PM. The effect of high- and low-glycaemic index energy restricted diets on
plasma lipid and glucose profiles in Type 2 diabetic subjects with varying glycaemic control. J Am Coll Nutr
2002;21:120-7.
Hermann LS, Schersten B, Bitzen PO, Kjellstrom T, Lingarde F, Melander A. Therapeutic comparison of
metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Diabetes Care
1994;17:1100-9.
173
Hermansen K, Sondergaard M, Hoie L, Carstensen M, Brock B. Beneficial effects of a soy-based dietary

supplement on lipid levels and cardiovascular risk markers in Type 2 diabetic subjects. Diabetes Care
2001;24:228-33.
Herz M, Johns D, Reviriego J, Grossman LD, Godin C, Duran S, Hawkins F, Lochnan H, Escobar-Jimenez F,
Hardin PA, Konkoy CS, Tan MH. A randomised, double-blind, placebo-controlled, clinical trial of the effects of
pioglitazone on glycaemic control and dyslipidaemia in oral antihyperglycaemic medication-nave patients with
Type 2 diabetes mellitus. Clin Ther 2003;25:1074-95.
Hiraga T, Kobayashi T, Okubo M, Nakanishi K, Sugimoto T, Ohashi Y, Murase T. Prospective study of
lipoprotein (a) as a risk factor for atheroslcerotic cardiovascular disease in patients with diabetes. Diabetes Care
1995;18:241-4.
Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietarytreated NIDDM patients: the Essen-II Study. Am J Med 1997;103:483-90.
Hokanson JE, Austin MA. Plasma triglycerides level is a risk factor for cardiovascular disease independent of
high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc
Risk 1996;3:213-9.
Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR, Crockett SE, Kaplan RA,
Comstock J, Lucas CP, Lodewick PA, Canovatchel W, Chung J, Hauptman J. Role of orlistat in the treatment of
obese patients with Type 2 diabetes. A 1-yr randomised double-blind study. Diabetes Care 1998;21:1288-94.
Honkola A, Forsen T, Eriksson J. Resistance training improves the metabolic profile in individuals with type 2
diabetes. Acta Diabetol 1997;34:245-8.
Hoogwerf BJ, Waness A, Cressman M, Canner J, Campeau L, Domanski M, Geller N, Herd A, Hickey A,
Hunninghake DB, Knatterud GL, White C. Effects of aggressive cholesterol lowering and low-dose
anticoagulation on clinical and angiographic outcomes in patients with diabetes. The Post Coronary Artery
Bypass Graft Trial. Diabetes 1999;48:1289-94.
Huang ES, Meigs JB, Singer DE. The effect of interventions to prevent cardiovascular disease in patients with
Type 2 diabetes mellitus. Am J Med 2001;111:633-42.
Hughes K, Choo M, Kuperan P, Ong CN, Aw TC. Cardiovascular risk factors in non-insulin-dependent
diabetics compared to non-diabetic controls: a population-based survey among Asians in Singapore.
Atherosclerosis 1998;136:25-31.
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus
progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and
Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.
James RW, Boemi M, Sirolla C, Amadio L, Fumelli P, Pometta D. Lipoprotein (a) and vascular disease in
diabetic patients. Diabetologia 1995;38:711-4.
Jonsson B, Cook JR, Pedersen TR. The cost-effectiveness of lipid lowering in patients with diabetes: results
from the 4S trial. Diabetologia 1999;42:1293-301.
Kanters SD, Algra A, de Bruint TW, Erkelens DW, Banga JD. Intensive lipid-lowering strategy in patients with
diabetes mellitus. Diabet Med 1999;16:500-8.
Kaplan RC, Heckbert SR, Weiss NS, Wahl PW, Smith NL, Newton KM, Psaty BM. Postmenopausal estrogens
and risk of myocardial infarction in diabetic women. Diabetes Care 1998;21:1117-21.
Keech A. Personal communication. 2001.
Keech A, Colquhoun D, Best J, Kirby A, Simes RJ, Hunt D, Hague W, Beller E, Arulchelvam M, Baker J,
Tonkin A; LIPID Study Group. Secondary prevention of cardiovascular events with long-term pravastatin in
patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 2003;26:2713-21.
Kelley DE, Wing R, Buonocore C, Sturis J, Polonsky K, Fitzsimmons M. Relative effects of calorie restriction
and weight loss in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1993;77:1287-93.
174
Kirchgassler KU, Schmitz H, Bach G. Effectiveness and tolerability of 12-week treatment with micronised
fenofibrate 200 mg in a drug-monitoring programme involving 9884 patients with dyslipidaemia. Clin Drug
Invest 1998;15:197-204.
Knatterud GL, Rosenberg Y, Campeau L, Geller NL, Hunninghake DB, Forman SA, Forrester JS, Gobel FL,
Herd JA, Hickey A, Hoogwerf BJ, Terrin ML, White C. Long-term effects on clinical outcomes of aggressive
lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery
bypass graft trial. Circulation 2000;102:157-65.
Knopp RH, Frohlich J, Jokubaitis LA, Dawson K, Broyles FE, Gomez-Coronado D. Efficacy and safety of
fluvastatin in patients with non-insulin-dependent diabetes mellitus and hyperlipidemia. Am J Med
1994b;96(Suppl 6A):S69-78.
Koskinen P, Manttari M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence
in NIDDM patients in the Helsinky Heart Study. Diabetes Care 1992;15:820-5.
Kudlacek S, Schernthaner G. The effect of insulin treatment on HbA1c, body weight and lipids in Type 2
diabetic patients with secondary-failure to sulfonylureas. A five year follow-up study. Horm Metab Res
1992;24:478-83.
Laakso M, Pyorala K. Adverse effects of obesity on lipid and lipoprotein levels in insulin-dependent and noninsulin-dependent diabetes. Metabolism 1990;39:117-22.
Laakso M, Voutilainen E, Sarlund H, Aro A, Pyorala K, Penttila I. Serum lipids and lipoproteins in middle-aged
non-insulin-dependent diabetics. Atherosclerosis 1985;56:271-81.
Lahdenpera S, Tilly-Kiesi M, Vuorinen-Markkola H, Kuusi T, Taskinen MR. Effects of gemfibrozil on lowdensity liporotein particle size, density distribution, and composition in patients with Type 2 diabetes. Diabetes
Care 1993;16:584-92.
Lam KSL, Tui SC, Tsang MW, Ip TP, Tam SCF. Acarbose in NIDDM patients with poor control on
conventional oral agents. A 24-week placebo-controlled study. Diabetes Care 1998;21:1154-8.
Landstedt-Hallin L, Adamson U, Arner P, Bolinder J, Lins PE. Comparison of bedtime NPH or preprandial
regular insulin combined with glibenclamide in secondary sulfonylurea failure. Diabetes Care 1995;18:1183-6.
Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol,
ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-7.
Lee YM, Haastert B, Scherbaum W, Hauner H. A phytosterol-enriched spread improves the lipid profile of
subjects with Type 2 diabetes mellitus. A randomised controlled trial under free-living conditions. Eur J Nutr
2003;42:111-7.
Lehmann R, Vokac A, Niedermann K, Agosti K, Spinas GA. Loss of abdominal fat and improvement of the
cardiovascular risk profile by regular moderate exercise training in patients with NIDDM. Diabetelogia
1995;38:1313-9.
Lehmann R, Engler H, Honegger R, Riesen W, Spinas GA. Alterations of lipolytic enzymes and high-density
lipoprotein subfractions induced by physical activity in Type 2 diabetes mellitus. Eur J Clin Invest 2001;31:3744.
Lehto S, Ronnemaa T, Haffner SM, Pyorala K, Kallio V, Laakso M. Dyslipidemia and hyperglycemia predict
coronary heart disease events in middle-aged patients with NIDDM. Diabetes 1997;46:1354-9.
Leinonen J, Rantalaiho V, Lehtimaki T, Koivula T, Wirta O, Pasternack A, Alho H. The association between the
total antioxidant potential of plasma and the presence of coronary heart disease and renal dysfunction in patients
with NIDDM. Free Rad Res 1998b;29:273-81.
Leinonen JS, Rantalaiho V, Solakivi T, Koivula T, Wirta O, Pasternack A, Alho H, Lehtimaki T. Susceptibility
of LDL to oxidation is not associated with the presence of coronary heart disease or renal dysfunction in
NIDDM patients. Clin Chim Acta 1998a;275:163-74.
175
Leonhardt W, Hanefeld M, Muller G, Hora C, Meissner D, Lattke P, Paetzold A, Jaross W, Schroeder HE.
Impact of concentrations of glycated hemoglobin, alpha-tocopherol, copper, and manganese on oxidation of
low-density lipoproteins in patients with type I diabetes, type II diabetes and control subjects. Clin Chim Acta
1996;254:173-86.
Ligtenberg PC, Hoekstra JB, Bol E, Zonderland ML, Erkelens DW. Effects of physical training on metabolic
control in elderly type 2 diabetes mellitus patients. Clin Sci 1997;93:127-35.
LIPID Study Group. Long-Term Intervention with Pravastatin in Ischaemic Disease. Prevention of
cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of
initial cholesterol levels. N Engl J Med 1998;339:1349-57.
Low CC, Grossman EB, Gumbiner B. Potentiation of effects of weight loss by monounsaturated fatty acids in
obese NIDDM patients. Diabetes 1996;45:569-75.
Luscombe ND, Noakes M, Clifton PM. Diets high and low in glycemic index versus high monounsaturated fat
diets: effects on glucose and lipid metabolism in NIDDM. Eur J Clin Nutr 1999;53:473-8.
MacRury SM, Gordon D, Wilson R, Bradley H, Gemmell CG, Paterson JR, Rumley AG, MacCuish AC. A
comparison of different methods of assessing free radical activity in Type 2 diabetes and peripheral vascular
disease. Diabet Med 1993;10:331-5.
Malerbi DA, Paiva ES, Duarte AL, Wajchenberg BL. Metabolic effect of dietary sucrose and fructose in type II
diabetic subjects. Diabetes Care 1996;19:1249-56.
Manley SE, Stratton IM, Cull CA, Frighi V, Eeley EA, Matthews DR, Holman RR, Turner RC, Neil HA,
UKPDS Group. Effects of three months' diet after diagnosis of Type 2 diabetes on plasma lipids and lipoprotein
(UKPDS 45). Diabet Med 2000;17:518-23.
Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick MH. Relation between baseline lipid and
lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study. Am J Cardiol
1989;63:H42-7.
Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of
serum triglycerides and LDL cholesterol and HDL cholesterol concentration on coronary heart disease risk in
the Helsinki Heart Study. Circulation 1992;85:37-45.
Manning PJ, Allum A, Jones S, Sutherland WH, Williams SM. The effect of hormone replacement therapy on
cardiovascular risk factors in Type 2 diabetes. A randomised controlled trial. Arch Intern Med 2001;161:1772-6.
Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, Arky RA, Speizer FE, Hennekens
CH. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in
women. Arch Intern Med 1991;151:1141-7.
Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR,
Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M; Women's Health Initiative
Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-34.
Manzato E, Zambon A, Lapolla A, Zambon S, Braghetto L, Crepaldi G, Fedele D. Lipoprotein abnormalities in
well-treated Type II diabetic patients. Diabetes Care 1993;16:469-75.
Markovic TP, Campbell LV, Balasubramanian S, Jenkins AB, Fleury AC, Simons LA, Chisholm DJ. Beneficial
effect on average lipid levels from energy restriction and fat loss in obese individuals with or without type 2
diabetes. Diabetes Care 1998;21:695-700.
Mattock MB, Keen H, Viberti GC, El-Gohari MR, Murrells TJ, Scott GS, Wing JR, Jackson PG. Coronary heart
disease and urinary albumin excretion rate in Type 2 (non-insulin-dependent) diabetic patients. Diabetologia
1988;31:82-7.
Mayer-Davis EJ, Levin S, Marshall JA. Heterogeneity in associations between macronutrient intake and
lipoprotein profile in individuals with Type 2 diabetes. Diabetes Care 1999;22:1632-9.
176
McIntosh A, Hutchinson A, Feder G, Durrington P, Elkeles R, Hitman GA, Robson J, Home P, Peters J, Pandor
A, Kaltenthaler E (2002). Clinical guidelines and evidence review for Type 2 diabetes: Lipids management.
Sheffield: ScHARR, University of Sheffield.
Meigs JB, Singer DE, Sullivan LM, Dukes KA, D'Agostino RB, Nathan DM, Wagner EH, Kaplan SH,
Greenfield S. Metabolic control and prevalent cardiovacular disease in non-insulin-dependent diabetes mellitus
(NIDDM): the NIDDM Patient Outcomes Research Team. Am J Med 1997;102:38-47.
Milan Study on Atherosclerosis and Diabetes (MiSAD) Group. Prevalence of unrecognized silent myocardial
ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus. Am J
Cardiol 1997;79:134-9.
Milne RM, Mann JI, Chisholm AW, Williams SM. Long-term comparison of three dietary prescriptions in the
treatment of NIDDM. Diabetes Care 1994;17:74-80.
Montori VM, Farmer A, Wollan PC, Dinneen SF. Fish oil supplementation in type 2 diabetes. Diabetes Care
2000;23:1407-15.
Nacitarhan S, Ozben T, Tuncer N. Serum and urine malondialdehyde levels in NIDDM patients with and
without hyperlipdemia. Free Radic Biol Med 1995;19:893-6.
Nielsen FS, Voldsgaard AI, Gall MA, Rossing P, Hommel E, Andersen P, Dyerberg J, Parving HH.
Apolipoprotein (a) and cardiovascular disease in Type 2 (non-insulin-dependent) diabetic patients with and
without diabetic nephropathy. Diabetologia 1993;36:438-44.
Niemeijer-Kanters SD, Dallinga-Thie GM, de Ruijter-Heijstek FC, Algra A, Erkelens DW, Banga JD, Jansen H.
Effect of intensive lipid-lowering strategy on low-density lipoprotein particle size in patients with Type 2
diabetes mellitus. Atherosclerosis 2001;156:209-16.
Niemi MK, Keinanen-Kiukaanniemi SM, Salmela PI. Long-term effects of guar gum and microcrystalline
cellulose on glycaemic control and serum lipids in Type 2 diabetes. Eur J Clin Pharmacol 1988;34:427-9.
Niskanen L, Turpeinen A, Penttila I, Uusitupa MI. Hyperglycemia and compositional lipoprotein abnormalities
as predictors of cardiovascular mortality in type 2 diabetes. Diabetes Care 1998;21:1861-9.
Niskanen L, Uusitupa M, Sarlund H, Siitonen O, Voutilainen E, Penttila I, Pyorala K. Microalbuminuria
predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed Type 2
(non-insulin-dependent) diabetic patients. Diabetologia 1990;33:237-43.
O'Brien T, Nguyen TT, Harrison JM, Bailey KR, Dyck PJ, Kottke BA. Lipids and Lp (a) lipoprotein levels and
coronary artery disease in subjects with non-insulin-dependent diabetes mellitus. Mayo Clin Proc 1994;69:4305.
O'Dea K, Traiandes K, Irealnd P, Niall M, Sadler J, Hopper J, DeLuise M. The effects of diet differing in fat,
carbohydrate and fibre on carbohydrate and lipid metabolism in Type II diabetes. Journal of the American
Dietetic Association 1989;89:1076-86.
Ogawa S, Takeuchi K, Sugimura K, Fukuda M, Lee R, Ito S, Sato T. Bezafibrate reduces blood glucose in Type
2 diabetes mellitus. Metabolism 2000;49:331-4
O'Neal DN, O'Brien RC, Timmins KL, Grieve GD, Lau KP, Nicholson GC, Kotowicz MA, Best JD.
Gemfibrozil treatment increases low-density lipoprotein particle size in type 2 diabetes mellitus but does not
alter in vitro oxidisability. Diabet Med 1998;15:870-7.
Osei K, Bossetti B. Dietary fructose as a natural sweetener in poorly controlled Type 2 diabetes: a 12-month
crossover study of effects on glucose, lipoprotein and apolipoprotein metabolism. Diabet Med 1989;6:506-11.
Osei K, Falko J, Bossetti BM, Holland GC. Metabolic effects of fructose as a natural sweetener in the
physiologic meals of ambulatory obese patients with Type II diabetes. Am J Med 1987;83:249-55.
Paolisso G, Balb iV, Volpe C, Varricchio G, Gambardella A, Saccomanno F, Ammendola S, Varricchio M,
D'Onofrio F. Metabolic benefits deriving from chronic vitamin C supplementation in aged non-insulin
dependent diabetics. J Am Coll Nutr 1995;14:387-92.
177
Parfitt VJ, Desomeaux K, Bolton CH, Hartog M. Effects of high monounsaturated and polyunsaturated fat diets
on plasma lipoproteins and lipid peroxidation in Type 2 diabetes mellitus. Diabet Med 1994;11:85-91.
Parillo M, Giacco R, Ciardullo AV, Rivellese AA, Riccardi G. Does a high carbohydrate diet have different
effects in NIDDM patients treated with diet alone or hypoglycemic drugs? Diabetes Care 1996;19:498-500.
Parker B, Noakes M, Luscombe N, Clifton, P. Effect of a high-protein, high-monounsaturated fat weight loss
diet on glycaemic control and lipid levels in Type 2 diabetes. Diabetes Care 2002;25:425-30.
Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment assessment project (L-TAP). A multicentre
survey to evaluate the percentages of dyslipidaemic patients receiving lipid-lowering therapy and achieving lowdensity cholesterol goals. Arch Int Med 2000;160:459-67.
Pedersen TR, Olsson AG, Faergeman O, Kjekshus J, Wedel H, Berg K, Wilhelmsen L, Haghfelt T,
Thorgeirsson G, Pyorala K, Miettinen T, Christophersen B, Tobert JA, Musliner TA, Cook TJ, for the
Scandinavian Simvastatin Survival Study Group. Lipoprotein changes and reduction in the incidence of major
coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:145360.
Perera M, Sattar N, Petrie JR, Hillier C, Small M, Connell JM, Lowe GD, Lumsden MA. The effects of
transdermal estradiol in combination with oral morethisterone on lipoproteins, coagulation, and endothelial
markers in postmenopausal women with Type 2 diabetes: A randomised, placebo-controlled study. J Clin
Endocrinol Metab 2001;86:1140-3.
Petersen M, Pedersen H, Major-Pedersen A, Jensen T, Marckmann P. Effect of fish oil versus corn oil
supplementation on LDL and HDL subclasses in Type 2 diabetic patients. Diabetes Care 2002;25:1704-8.
Pick ME, Hawrysh ZJ, Gee MI, Toth E, Garg ML, Hardin RT. Oat bran concentrate bread products improve
long-term control of diabetes: a pilot study. J Am Diet Assoc 1996;96:1254-61.
Poirier P, Catellier C, Tremblay A, Nadeau A. Role of body fat loss in the exercise-induced improvement of the
plasma lipid profile in non-insulin-dependent diabetes mellitus. Metabolism 1996;45:1383-7.
Pownall HJ, Ballantyne CM, Kimball KT, Simpson SL, Yeshurun D, Gotto AM Jr. Effect of moderate alcohol
consumption on hypertriglyceridemia. Arch Intern Med 1999;159:981- 87.
Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with
simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the
Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614-20.
Rains SG, Wilson GA, Richmond W, Elkeles RS. The effect of glibenclamide and metformin on serum
lipoproteins in Type 2 diabetes. Diabet Med 1988;5:653-8.
Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R. Main risk factors for nephropathy in Type 2 diabetes
mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med
1998;158:998-1004.
Raz I, Hauser E, Bursztyn M. Moderate exercise improves glucose metabolism in uncontrolled elderly patients
with non-insulin-dependent diabetes mellitus. Isr J Med Sci 1994;30:766-70.
Reaven PD, Herold DA, Barnett J, Edelman S. Effects of vitamin E on susceptibility of low-density lipoprotein
and low density lipoprotein subfractions to oxidation and on protein glycation in NIDDM. Diabetes Care
1995;18:807-16.
Rigla M, Sanchez-Quesada JL, Ordonez-Llanos J, Prat T, Caixas A, Jorba O, Serra JR, de Leiva A, Perez A.
Effect of physical exercise on lipoprotein(a) and low-density lipoprotein modification in Type 1 and Type 2
diabetic patients. Metabolism 2000;49:640-7.
Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary
heart disease: metanalysis of effects on lipids and haemostatic factors. BMJ 1999;319:1523-8.
178
Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML,
Hershman JM, Wexler LF, Rubins HB; VA-HIT Study Group. Relation of gemfibrozil treatment and lipid levels
with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585-91.
Rodier M, Colette C, Gouzes C, Michel F, Crastes de Paulet A, Monnier L. Effects of insulin therapy upon
plasma lipid fatty acids and platelet aggregation in NIDDM with secondary failure to oral antidiabetic agents.
Diabetes Res Clin Pract 1995;28:19-28.
Rodriguez-Moran M, Guerrero-Romero F, Lazcano-Burciaga G. Lipid- and glucose-lowering efficacy of
plantago psyllium in Type II diabetes. J Diabetes Complications 1998;12:273-8.
Ronnemaa T, Laakso M, Kallio V, Pyorala K, Marniemi J, Puukka P. Serum lipids, lipoproteins, and
apolipoproteins and the excessive occurrence of coronary heart disease in non-insulin-dependent diabetic
patients. Am J Epidemiol 1989;130:632-45.
Ronnemaa T, Marniemi J, Puukka P, Kuusi T. Effects of long-term physical exercise on serum lipids,
lipoproteins and lipid metabolizing enzymes in Type 2 (non-insulin-dependent) diabetic patients. Diabetes Res
1988;7:79-84.
Rosenblatt S, Miskin B, Glazer NB, Prince MJ, Robertson KE; Pioglitazone 026 Study Group. The impact of
pioglitazone on glycaemic control and atherogenic dyslipidaemia in patients with Type 2 diabetes mellitus.
Coron Artery Dis 2001;12:413-23.
Rovellini A, Sommariva D, Branchi A, Maraffi F, Montalto C, Gandini R, Fasoli A. Effects of slow release
bezafibrate on the lipid pattern and on blood glucose of Type 2 diabetic patients with hyperlipidaemia.
Pharmacol Res 1992;25:237-45.
Rubins HB, Nelson DB, Noorbaloochi S, Nugent S. Effectiveness of lipid-lowering medications in outpatients
with coronary heart disease in the Department of Veterans Affairs System. Am J Cardiol 2003;92:1177-82.
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ,
Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention
Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels
of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-8.
Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ, Faas FH, Anderson JW. Diabetes,
plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs highdensity lipoprotein intervention trial (VA-HIT). Arch Int Med 2002;162:2597-604.
Ruiz J, Thillet J, Huby T, James RW, Erlich D, Flandre P, Froguel P, Chapman J, Passa P. Association of
elevated lipoprotein (a) levels and coronary heart disease in NIDDM patients. Relationship with apolipoprotein
(a) phenotypes. Diabetologia 1994;37:585-91.
Rustemeijer C, Schouten JA, Voerman HJ, Hensgens HE, Donker AJ, Heine RJ. Pravastatin compared to
bezafibrate in the treatment of dyslipidaemia in insulin-treated patients with Type 2 diabetes mellitus. Diabetes
Metab Res Rev 2000;16:82-7.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM,
Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in
patients with average cholesterol levels. N Engl J Med 1996;335:1001-9.
Sacks FM, Moye LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA, Braunwald E. Relationship
between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the
Cholesterol and Recurrent Events trial. Circulation 1998;97:1446-52.
Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CM, Keech A, Packard C, Simes J,
Byington R, Furberg CD, for the Prospective Pravastatin Pooling Project Investigators Group. Effect of
pravastatin on coronary disease events in subgroups defined by coronary risk factors. The Prospective
Pravastatin Pooling Project. Circulation 2000;102:1893-900.
Sacks FM, Tonkin AM, Craven T, Pfeffer MA, Shepherd J, Keech A, Furberg CD, Braunwald E. Coronary
heart disease in patients with low LDL-cholesterol. Benefit of pravastatin in diabetics and enhanced role for
HDL-cholesterol and triglycerides as risk factors. Circulation 2002;105:1424-8.
179
Saito I, Folsom AR, Brancati FL, Duncan BB, Chambless LE, McGovern PG. Nontraditional risk factors for
coronary heart disease incidence among persons with diabetes: The Atherosclerosis Risk in Communities
(ARIC) Study. Ann Intern Med 2000;133:81-91.
Salomaa VV, Tuomilehto J, Jauhiainen M, Korhonen HJ, Stengard J, Uusitupa M, Pitkanen M, Penttila I.
Hypertriglyceridemia in different degrees of glucose intolerance in a Finnish population-based study. Diabetes
Care 1992;15:657-65.
Scandinavian Simvistatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with
coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.
Scheffer PG, Bos G, Volwater HG, Deker JM, Heine RJ, Teerlink T. Association of LDL size with in vitro
oxidisability and plasma levels of in vivo oxidised LDL in Type 2 diabetic patients. Diabet Med 2003;20:563-7.
Schneider J, Erren T, Zofel P, Kaffarnik H. Metformin-induced changes in serum lipids, lipoproteins, and
apoproteins in non-insulin-dependent diabetes mellitus. Atherosclerosis 1990;82:97-103.
Schneider SH, Khachadurian AK, Amorosa LF, Clemow L, Ruderman NB. Ten-year experience with an
exercise-based outpatient life-style modification program in the treatment of diabetes mellitus. Diabetes Care
1992;15:1800-10.
Schweitzer M, Tessier D, Vlahos WD, Leiter L, Collet JP, McQueen MJ, Harvey L, Alaupovic P. A comparison
of pravastatin and gemfibrozil in the treatment of dyslipoproteinaemia in patients with non-insulin-dependent
Seghieri G, Alviggi L, Caselli P, De Giorgio LA, Breschi C, Gironi A, Niccolai M, Bartolomei GC. Serum
lipids and lipoproteins in Type 2 diabetic patients with persistent microalbuminuria. Diabet Med 1990;7:810-4.
Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A,
McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT investigators. Prevention of coronary
and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol
concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a
multicentre randomised controlled trial. Lancet 2003;361:1149-58.
Seviour PW, Teal TK, Richmond W, Elkeles RS. Serum lipids, lipoproteins and macrovascular disease in noninsulin-dependent diabetics: a possible new approach to prevention. Diabet Med 1988;5:166-71.
Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, Patsch W; Atherosclerosis Risk in
Communities Study Group. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides,
lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions. The Atherosclerosis Risk in
Communities (ARIC) Study. Circulation 2001;104:1108-13.
Sheehan JP, Wei IW, Ulchaker M, Tserng KY. Effect of high fiber intake in fish oil-treated patients with noninsulin-dependent diabetes mellitus. Am J Clin Nutr 1997;66:1183-7.
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema
JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ,
Twomey C, Westendorp RG; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk.
Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet
2002;360:1623-30.
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention
of coronary heart disease with pravastatin in men with hypercholesterolaemia. N Engl J Med 1995;333:1301-7.
Siegel RD, Cupples A, Schaefer EJ, Wilson PW. Lipoproteins, apolipoproteins, and low-density lipoprotein size
among diabetics in the Framingham Offspring Study. Metabolism 1996;45:1267-72.
Simes RJ, Marschner IC, Hunt D, Colquhoun D, Sullivan D, Stewart RA, Hague W, Keech A, Thompson P,
White H, Shaw J, Tonkin A; LIPID Study Investigators. Relationship between lipid levels and clinical outcomes
in the LongpTerm Intervention with Pravastatin in Ischemic Disease (LIPIDS) trial: to what extent is the
reduction in coronary events with Pravastatin explained by on-study lipid levels? Circulation 2002;105:1162-9.
180
Skarfors ET, Wegener TA, Lithell H, Selinus I. Physical training as treatment for Type 2 (non-insulindependent) diabetes in elderly men. A feasibility study over 2 years. Diabetologia 1987;30:930-3.
Smith SJ, Cooper GR, Myers GL, Sampson EJ. Biological variability in concentrations of serum lipids: sources
of variation among results from published studies and composite predicted values. Clin Chem 1993;39:1012-22.
Soedamah-Muthu SS, Colhoun HM, Thomason MJ, Betteridge DJ, Durrington PN, Hitman GA, Fuller JH,
Julier K, Mackness MI, Neil HA; CARDS Investigators. The effect of atorvastatin on serum lipids, lipoproteins
and NMR spectroscopy defined lipoprotein subclasses in Type 2 diabetic patients with ischaemic heart disease.
Solfrizzi V, Panza F, Colacicco AM, Capurso C, D'Introno A, Torres F, Baldassarre G, Capurso A. Relation of
lipoprotein(a) as coronary risk factor to Type 2 diabetes mellitus and low-density lipoprotein cholesterol in
patients 65 years of age (The Italian Longitudinal Study on Aging). Am J Cardiol 2002;89:825-9.
Sprecher DL, Pearch GL, Park EM, Pashkow F, Hoogwerf BJ. Preoperative triglycerides predict post-coronary
artery bypass graft survival in diabetic patients. Diabetes Care 2000;23:1648-53.
Stamler J, Vaccaro O, Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research
Group. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk
Factor Intervention Trial. Diabetes Care 1993;16:434-44.
Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal
estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses' Health Study. N Engl J Med
1991;325:756-62.
Suraniti S, Bled F, Girault A, Fressinaud P, Marre M. Serum lipids and urinary albumin excretion in non
insulin-dependent diabetics. Mol Cell Biochem 1992;109:197-200.
Syvanne M, Hilden H, Taskinen MR. Abnormal metabolism of postprandial lipoproteins in patients with noninsulin-dependent diabetes mellitus is not related to coronary artery disease. J Lipid Res 1994;35:15-26.
Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W, Dzavik V, Taylor D, Yokoyama S,
Montague TJ, for the SCAT Investigators. Long-term effects of cholesterol lowering and angiotensin-converting
enzyme inhibition on coronary atherosclerosis. The Simvastatin/Enalapril Coronary Atherosclerosis Trial
(SCAT). Circulation 2000;102;1748-54.
The CDC Diabetes Cost-effectiveness Group. Cost-effectiveness of intensive glycaemic control, intensified
hypertension control, and serum cholesterol level reduction for Type 2 diabetes. JAMA 2002;287:2542-51.
The Diabetes Atorvastatain Lipid Intervention (DALI) Study Group. The effect of aggressive versus standard
lipid lowering by atorvastatin on diabetic dyslipidemia: the DALI study: a double-blind, randomized, placebocontrolled trial in patients with type 2 diabetes and diabetic dyslipidemia. Diabetes Care 2001;24:1335-41.
Thomsen C, Rasmussen OW, Hansen KW, Vesterlund M, Hermansen K. Comparison of the effects on the
diurnal blood pressure, glucose, and lipid levels of a diet rich in monounsaturated fatty acids with a diet rich in
polyunsaturated fatty acids in Type 2 diabetic subjects. Diabet Med 1995;12:600-6.
Tikkanen MJ, Laakso M, Ilmonen M, Helve E, Kaarsalo E, Kilkki E, Saltevo J. Treatment of
hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM.
A multicenter comparison study. Diabetes Care 1998;21:477-81.
Tkac I, Kimball BP, Lewis G, Uffelman K, Steiner G. The severity of coronary atherosclerosis in Type 2
diabetes mellitus is related to the number of circulating triglycerides-rich lipoprotein particles. Arterioscler
Thromb Vasc Biol 1997;17:3633-8.
Tsalamandris C, Panagiotopoulos S, Sinha A, Cooper ME, Jerums G. Complementary effects of pravastatin and
nicotinic acid in the treatment of combined hyperlipidaemia in diabetic and non-diabetic patients. J Cardiovasc
Risk 1994;1:231-9.
Tsalamandris C, Panagiotopoulos S, Allen TJ, Waldrip L, Van Gaal B, Goodall I, Jerums G. Long-term
intraindividual variability of serum lipids in patients with type 1 and type II diabetes. J Diab Complications
1998;12:208-14.
181
Tsihlias EB, Gibbs AL, McBurney MI, Wolever TM. Comparison of high- and low-glycaemic-index breakfast
cereals with monounsaturated fat in the long-term dietary management of Type 2 diabetes. Am J Clin Nutr
2000;72:439-49.
Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR, for the United Kingdom
Prospective Diabetes Study Group. Risk factors for coronary artery disease in non-insulin dependent diabetes
mellitus: United Kingdom Prospective Diabetes Study (UKPDS:23). BMJ 1998;316:823-8.
UKPDS 11. UK Prospective Diabetes Study (UKPDS) XI: Biochemical risk factors in Type 2 diabetic patients
at diagnosis compared with age-matched normal subjects. Diabet Med 1994;11:534-4.
Upritchard JE, Sutherland WH, Mann JI. Effect of supplementation with tomato juice, vitamin E, and vitamin C
on LDL oxidation and products of inflammatory activity in Type 2 diabetes. Diabetes Care 2000;23:733-8.
Uusitupa M, Siitonen O, Voutilainen E, Aro A, Hersio K, Pyorala K, Penttila I, Ehnholm C. Serum lipids and
lipoproteins in newly diagnosed non-insulin-dependent (Type II) diabetic patients, with special reference to
factors influencing HDL-cholesterol and triglycerides levels. Diabetes Care 1986;9:17-22.
Vakkilainen J, Steiner G, Ansquer JC, Aubin F, Rattier S, Foucher C, Hamsten A, Taskinen MR; DAIS Group.
Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary
artery disease. The Diabetes Atherosclerosis Intervention Study (DAIS). Circulation 2003;107:1733-7.
Vale MJ, Jelinek MV, Best JD, Santamaria JD. Coaching patients with coronary heart disease to achieve the
target cholesterol: a method to bridge the gap between evidence-based medicine and the "real world" randomized controlled trial. J Clin Epidemiol 2002;55:245-52.
Vanninen E, Uusitupa M, Siitonen O, Laitinen J, Lansimies E. Habitual physical activity, aerobic capacity and
metabolic control in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus: effect of
1-year diet and exercise intervention. Diabetologia 1992;35:340-6.
Velho G, Erlich D, Turpin E, Neel D, Cohen D, Froguel P, Passa P. Lipoprotein (a) in diabetic patients and
normoglycaemic relatives in familial NIDDM. Diabetes Care 1993;16:742-7.
Vessby B, Karlstrom B, Boberg M, Lithell H, Berne C. Polyunsaturated fatty acids may impair blood glucose
control in Type 2 diabetic patients. Diabet Med 1992;9:126-33.
Vinik AI, Colwell JA. Effects of gemfibrozil on triglycerides levels in patients with NIDDM. Diabetes Care
1993;16:37-44.
Vuorinen-Markkola H, Yki-Jarvinen H, Taskinen MR. Lowering of triglycerides by gemfibrozil affects neither
the glucoregulatory nor antilipolytic effect of insulin in type 2 (non-insulin-dependent) diabetic patients.
Diabetologia 1993;36:161-9.
Wagner AM, Jorba O, Bonet R, Ordonez-Llanos J, Perez A. Efficacy of atorvastatin and gemfibrozil, alone and
in low does combination, in the treatment of diabetic dyslipidaemia. J Clin Endocrinol Metab 2003;88:3212-7.
Walker KZ, Piers LS, Putt RS, Jones JA, O'Dea K. Effects of regular walking on cardiovascular risk factors and
body composition in normoglycaemic women and women with Type 2 diabetes. Diabetes Care 1999;22:555-61.
Wasenius A, Stugaard M, Otterstad JE, Froyshov D. Diurnal and monthly intra-individual variability of the
concentration of lipids, lipoproteins and apoproteins. Scand J Clin Lab Invest 1990;50:635-42.
Waters D, Higginson L, Gladstone P, Kimball B, Le May M, Boccuzzi SJ, Lesperance J, the CCAIT Study
Group. Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary
atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis
Intervention Trial. Circulation 1994;89:959-68.
Wei M, Gibbons LW, Mitchell TL, Kampert JB, Blair SN. Alcohol intake and incidence of Type 2 diabetes in
men. Diabetes Care 2000;23:18-22.
West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical
events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440-5.
182
White HD, Simes RJ, Anderson NE, Hankey GJ, Watson JD, Hunt D, Colquhoun DM, Glasziou P, MacMahon
S, Kirby AC, West MJ, Tonkin AM. Pravastatin therapy and the risk of stroke. N Engl J Med 2000;343:317-26.
White CW, Gobel FL, Campeau L, Knatterud GL, Forman SA, Forrester JS, Geller NL, Herd JA, Hickey A,
Hoogwerf BJ, Hunninghake DB, Rosenberg Y, Terrin ML; Post Coronary Artery Bypass Graft Trial
Investigators. Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main
coronary artery from patients in the Post Coronary Artery Bypass Graft Trial. Circulation 2001;104:2660-5.
Wing RR, Blair E, Marcus M, Epstein LH, Harvey J. Year-long weight loss treatment for obese patients with
type II diabetes: does including an intermittent very-low-calorie diet improve outcome? Am J Med
1994;97:354-62.
Wolever TM. Tsihlias EB. McBurney MI. Le NA. Long-term effect of reduced carbohydrate or increased fiber
intake on LDL particle size and HDL composition in subjects with type 2 diabetes. Nutr Res 2003;23:15-26.
Wolffenbuttel BH, Sels JP, Rondas-Colbers GJ, Menheere PP, Nieuwenhuijzen Kruseman AC. Comparison of
different insulin regimens in elderly patients with NIDDM. Diabetes Care 1996;19:1326-32.
183
Lipid Disease: General References

American Diabetes Association. Dyslipidaemia management in adults with diabetes. Diabetes Care
2003;26(Suppl 1):S83-6.
Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J
1991;121:293-8
Assmann G. Cullen P. Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years. Eur
Heart J 1998;19(Suppl A):A2-11.
Assmann G, Funke H. HDL metabolism and atherosclerosis. J Cardiovasc Pharmacol 1990;16 (Suppl 9):S15-20.
Barakat HA, Carpenter JW, McLendon VD, Khazanie P, Leggett N, Heath J, Marks R. Influence of obesity,
impaired glucose tolerance, and NIDDM on LDL structure and composition. Possible link between
hyperinsulinemia and atherosclerosis. Diabetes 1990;39:1527-33.
Barter PJ, O'Brien RC. Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being
treated in general practice. Atherosclerosis 2000;149:199-205.
Branchi A, Rovellini A, Torri A, Sommariva D. Accuracy of calculated serum low-density lipoprotein
cholesterol for the assessment of coronary heart disease risk in NIDDM patients. Diabetes Care 1998;21:1397402.
British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic
Association. Joint British recommendations on prevention of coronary heart disease in clinical practice:
summary. BMJ 2000; 320:705-8.
Brunzell JD, Hokanson JE. Dyslipidemia of central obesity and insulin resistance. Diabetes Care 1999;22(Suppl
3):C10-3.
Carey DG, Jenkins AB, Campbell LV, Freund J, Chisholm DJ. Abdominal fat and insulin resistance in normal
and overweight women: Direct measurements reveal a strong relationship in subjects at both low and high risk
of NIDDM. Diabetes 1996;45:633-8.
Castelli WP. Epidemiology of triglycerides: A View from Framingham. Am J Cardiol 1992;70:H3-9.
Colagiuri S, Best J. Lipid-lowering therapy in people with Type 2 diabetes. Curr Opin Lipidol 2002;13:617-23.
De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman
O, Graham I, Mancia G, Manger Cats V, Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V,
Sechtem U, Silber S, Thomsen T, Wood D. Third Joint Task Force of European and Other Societies on
Cardiovascular Disease Prevention in Clinical Practice. European guidelines on cardiovascular disease
prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular
Disease Prevention in Clinical Practice. Eur Heart J 2003;24:1601-10.
Expert Committee on the diagnosis and classification of diabetes mellitus. Report of the Expert Committee on
the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.
Expert Panel on Detection, Evaluation, and Treatment in High Blood Cholesteral in Adults. Executive summary
of the third report of the National Cholesterol Education Program (NCEP) Expert panel on detection, evaluation,
and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
Flegal KM. Blood lipid levels in Type 2 diabetes. What are the effects of diet? Diabetes Care 1999;22:1605-6.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein
cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
Garg A. Insulin resistance in the pathogenesis of dyslipidemia. Diabetes Care 1996;19:387-9.
Garg A, Grundy M. Diabetic dyslipidemia and its therapy. Diabetes Rev 1997;5:425-33.
184
Goldberg RB. The benefits of lowering cholesterol in subjects with mild hyperglycaemia. Arch Intern Med
1999;159:2627-8.
Gomez-Perez FJ, Aguilar-Salinas CA, Lopez-Alvarenga JC, Perez- Jauregui J, Guillen-Pineda LE, Rull JA.
Lack of agreement between the World Health Organization category of impaired glucose tolerance and the
American Diabetes Association category of impaired fasting glucose. Diabetes Care 1998;21:1886-8.
Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka LF, Houston-Miller N, Kris-Etherton P,
Krumholz HM, LaRosa J, Ockene IS, Pearson TA, Reed J, Washington R, Smith SC Jr. Primary prevention of
coronary heart disease: Guidance from Framingham: A statement for healthcare professionals from the AHA
task force on risk reduction. Circulation 1998;97:1876-87.
Haffner SM. The insulin resistance syndrome revisited. Diabetes Care 1996;19:275-7.
Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes Care 1998;21:160-78.
Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed
prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical
diabetes? JAMA 1990;263:2893-8.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with
simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002a;360:7-22
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with
simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16.
Himsworth HP. Diabetes mellitus. It's differentiation into insulin-sensitive and insulin-insensitive types. Lancet
1936;1:127-30.
Jackson R. Guidelines on preventing cardiovascular disease in clinical practice. BMJ 2000a;320:659-61.
Jackson R. Updated New Zealand cardiovascular disease risk-benefit prediction guide. BMJ 2000b;320:709-10.
Kannel WB. Cholesterol and risk of coronary heart disease and mortality in men. Clin Chem 1988;34 (Suppl
B):53-9.
Karter AJ, Mayer-Davis EJ, Selby JV, D'Agostino RB Jr, Haffner SM, Sholinsky P, Bergman R, Saad MF,
Hamman RF. Insulin sensitivity and abdominal obesity in African-American, Hispanic, and non-Hispanic white
men and women. The Insulin Resistance and Atherosclerosis Study. Diabetes 1996;45:1547-55.
Laakso M. Lipids and lipoproteins as risk factors for coronary heart disease in non-insulin-dependent diabetes
mellitus. Ann Med 1996;28:341-5.
Laakso M. Dyslipidemia, morbidity, and mortality in non-insulin-dependent diabetes mellitus. Lipoproteins and
coronary heart disease in non-insulin-dependent diabetes mellitus. J Diabetes Complications 1997;11:137-41.
Laakso M, Lehto S, Penttila I, Pyorala K. Lipids and lipoproteins predicting coronary heart disease mortality
and morbidity in patients with non-insulin-dependent diabetes. Circulation 1993;88:1421-30.
LIPID Study Group. Long-Term Intervention with Pravastatin in Ischaemic Disease. Prevention of
cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of
initial cholesterol levels. N Engl J Med 1998;339:1349-57.
Manninen V, Koskinen P, Manttari M, Huttunen JK, Canter D, Frick HM. Predictive value for coronary heart
disease of baseline high-density and low-density lipoprotein cholesterol among Fredrickson type IIa subjects in
the Helsinki Heart Study. Am J Cardiol 1990;66:A24-7.
Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of
serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in
the Helsinki Heart Study. Implications for treatment. Circulation 1992;85:37-45.
McGarry JD. What if Minkowski had been ageusic? An alternative angle on diabetes. Science 1992;258:766-70.
185
McIntosh A, Hutchinson A, Feder G, Durrington P, Elkeles R, Hitman GA, Robson J, Home P, Peters J, Pandor
A, Kaltenthaler E (2002). Clinical guidelines and evidence review for Type 2 diabetes: Lipids Management.
Sheffield: ScHARR, University of Sheffield.
McPhillips JB, Barrett-Connor E, Wingard DL. Cardiovascular disease risk factors prior to the diagnosis of
impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults. Am J
Epidemiol 1990;131:443-53.
MRC/BHF Heart Protection Study. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of
antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease
death: Early safety and efficacy experience. Eur Heart J 1999;20:725-41.
MRFIT Research Group. Relationship between baseline risk factors and coronary heart disease and total
mortality in the multiple risk factor intervention trial. Prev Med 1986;15:254-73.
National Heart Foundation of Australia & The Cardiac Society of Australia and New Zealand. Lipid
Management Guidelines - 2001. MJA 2001;175(Suppl):S57-88.
Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart
disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial
Research Group. Arch Intern Med 1992;152:56-64.
Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000
people in 45 prospective cohorts. Lancet 1995;346:1647-53.
Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607.
Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in
individuals with small, dense low density lipoprotein particles. J Clin Invest 1993;92:141-6.
Rivellese AA. Monounsaturated and marine omega-3 fatty acids in NIDDM patients. Metabolic effects of highMUFA diets in comparison with high-CHO diets. Ann NY Acad Sci 1997;827:302-9.
Ruderman NB, Schneider SH. Diabetes, Exercise and Atheroscierosis. Diabetes Care 1992;15:1787-93.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO,
Wun C, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in
patients with average cholesterol levels. N Engl J Med 1996;335:1001-9.
Sattar N, Jaap AJ, MacCuish AC. Hormone replacement therapy and cardiovascular risk in post-menopausal
women with NIDDM. Diabet Med 1996;13:782-8.
Shaw JTE, Purdie DM, Neil HAW, Levy JC, Turner RC. The relative risks of hyperglycaemia, obesity and
dyslipidaemia in the relatives of patients with Type II diabetes mellitus. Diabetologia 1999;42:24-7.
Simopoulos AP. Omega-6/omega-3 fatty acid ratio and trans fatty acids in non-insulin-dependent diabetes
mellitus. Ann NY Acad Sci 1997;827:327-38.
Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality
for men screened in the multiple risk factor intervention trial. Diabetes Care 1993;16:434-44.
Steiner G. Lipid intervention trials in diabetes. Diabetes Care 2000;23(Suppl 2):B49-53.
Stern MP, Mitchell BD, Haffner SM, Hazuda HP. Does glycemic control of type II diabetes suffice to control
diabetic dyslipidemia? A community perspective. Diabetes Care 1992;15:638-44.
Stevens RJ, Kothari V, Adler AI, Stratton IM, United Kingdom Prospective Diabetes Study (UKPDS) Group.
The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56). Clin
Sci 2001;101:671-9.
Stewart MW, Humphriss DB, Berrish TS, Barriocanal LA, Trajano LR, Alberti KG, Walker M. Features of
syndrome X in first-degree relatives of NIDDM patients. Diabetes Care 1995;18:1020-2.
186
The National Cholesterol Education Program Expert Panel. Third Report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). Final Report. National Institute of Health. 2002
UK Department of Health. National Services Framework for Coronary Disease. Modern Standards and Service
Models. London, Department of Health, 2000.
UKPDS. The UK Prospective Diabetes Study 33: Intensive blood glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet
1998;352:837-53.
Utermann G. The mysteries of lipoprotein(a). Science 1989;246:904-10.
Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes,
atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956;4:20-34.
Wadden TA. Treatment of obesity by moderate and severe caloric restriction. Results of clinical research trials.
Ann Intern Med 1993;119:688-93.
White HD, Simes RJ, Anderson NE, Hankey GJ, Watson JD, Hunt D, Colquhoun DM, Glasziou P, MacMahon
S, Kirby AC, West MJ, Tonkin AM. Pravastatin therapy and the risk of stroke. N Engl J Med 2000;343:317-26.
Wilson PW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality. The Framingham heart
study. Arteriosclerosis 1988;8:737-41.
Wilson PW. High-density lipoprotein, low-density lipoprotein and coronary artery disease. Am J Cardiol
1990;66:A7-10.
Women's Health Initiative Study Group. Design of the Women's Health Initative clinical trial and observational
study. Control Clin Trials 1998;19:61-109.
Yeo WW, Yeo KR. Predicting CHD in patients with diabetes mellitus. Diabet Med 2001:18:341-4.
187
Lipid Disease: Others References

Abate N, Vega GL, Garg A, Grundy SM. Abnormal cholesterol distribution among lipoprotein fractions in
normolipidemic patients with mild NIDDM. Atherosclerosis 1995;118:111-22.
Abbate SL, Brunzell JD. Pathophysiology of hyperlipidemia in diabetes mellitus. J Cardiovasc Pharmacol
1990;16(Suppl 9):1-7.
Abbott WG, Boyce VL, Grundy SM, Howard BV. Effects of replacing saturated fat with complex carbohydrate
in diets of subjects with NIDDM. Diabetes Care 1989;12:102-7.
Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock JP, Emanuele NV, Levin SR, Pacold I, Lee
HS. Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs
Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Int Med 1997;157:181-8.
Adkins JC, Faulds D. Micronised fenofibrate. A review of its pharmacodynamic properties and clinical efficacy
in the management of dyslipidaemia. Drugs 1997;54:615-33.
Agardh CD, Nilsson-Ehle P, Schersten B. Improvement of the plasma lipoprotein pattern after institution of
insulin treatment in diabetes mellitus. Diabetes Care 1982;5:322-5.
Aguilar-Salinas CA, Gomez-Perez FJ, Posadas-Romero C, Vazquez-Chavez C, Meaney E, Gulias-Herrero A,
Guillen LE, Alvarado Vega A, Mendoza Perez E, Eduardo Romero-Nava L, Angelica Gomez-Diaz R, SalinasOrozco S, Moguel R, Novoa G. Efficacy and safety of atorvastatin in hyperlipidaemic, Type 2 diabetic patients.
A 34-week, multicentre, open-label study. Atherosclerosis 2000;152:489-96.
Ajani UA, Gaziano JM, Lotufo PA, Liu S, Hennekens CH, Buring JE, Manson JE. Alcohol consumption and
risk of coronary heart disease by diabetes status. Circulation 2000;102:500-5.
Alberti KG, Jones IR, Laker MF, Swai AB, Taylor R. Effect of bezafibrate on metabolic profiles in non-insulindependent diabetes mellitus. J Cardiovasc Pharmacol 1990;16(Suppl 9):S21-4.
Alcolado JC, Pacy PJ, Beevers M, Dodson PM. Risk factors for peripheral vascular disease in hypertensive
subjects with Type 2 diabetes mellitus. Diabet Med 1992;9:904-7.
Allen JK, Hensley WJ, Nicholls AV, Whitfield JB. An enzymatic and centrifugal method for estimating highdensity lipoprotein cholesterol. Clin Chem 1979;25:325-7.
Altomare E, Vendemiale G, Chicco D, Procacci V, Cirelli F. Increased lipid peroxidation in Type 2 poorly
controlled diabetic patients. Diabete Metab 1992;18:264-71.
American Diabetes Association. Consensus Statement. Detection and management of lipid disorders in diabetes.
Diabetes Care 1993;16(Suppl 2):106-12.
American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care
1998;21:179-82.
American Diabetes Association. Nutrition recommendations and principles for people wirh diabetes mellitus.
Diabetes Care 1998;(Suppl 1):32-5.
American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care
1998;21(Suppl 1):523-31.
American Diabetes Association. Role of fat replacers in diabetes medical nutrition therapy. Diabetes Care
1999;22(Suppl 1):90-1.
American Diabetes Association. Evidence-based nutrition principles and recommendations for the treatment and
prevention of diabetes and related complications. Diabetes Care 2003;26(Suppl 1):S51-61.
American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care
2004;27(Suppl 1):S68-71.
188
American Diabetes Association. Physical activity/exercise and diabetes. Diabetes Care 2004;27(Suppl 1):S5862.
American Diabetes Association. Hypertension management in adults with diabetes. Diabetes Care
2004;27(Suppl 1):S65-7.
Andersen E, Hellstrom P, Kindstedt K, Hellstrom K. Effects of a high-protein and low-fat diet vs a low-protein
and high-fat diet on blood glucose, serum lipoproteins, and cholesterol metabolism in noninsulin-dependent
diabetics. Am J Clin Nutr 1987;45:406-13.
Anderson JW. Physiological and metabolic effects of dietary fiber. Fed Proc 1985;44:2902-6.
Andersson B, Mattsson LA, Hahn L, Marin P, Lapidus L, Holm G, Bengtsson BA, Bjorntorp P. Estrogen
replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in
postmenopausal women with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997;82:638-43.
Annuzzi G, Rivellese A, Capaldo B, Di Marino L, Iovine C, Marotta G, Riccardi G. A controlled study on the
effects of n-3 fatty acids on lipid and glucose metabolism in non-insulin-dependent diabetic patients.
Ansell BJ, Waters DD; National Cholesterol Education Program Adult Treatment Panel-III Guidelines.
Reassessment of National Cholesterol Education Pprograme Adults Treatment Panel-III Guidelines: one year
later. Am J Cardiol 2002;90:524-5.
Appel LJ, Stason WB. Ambulatory blood pressure monitoring and blood pressure self-measurement in the
diagnosis and management of hypertension. Ann Intern Med 1993;118:867-82.
Armstrong D, Abdella N, Salman A, Miller N, Rahman EA, Bojancyzk M. Relationship of lipid peroxides to
diabetic complications. Comparison with conventional laboratory tests. J Diabetes Comp 1992;6:116-22.
Armstrong AM, Chestnutt JE, Gormley MJ, Young IS. The effect of dietary treatment on lipid peroxidation and
antioxidant status in newly diagnosed noninsulin dependent diabetes. Free Radic Biol Med 1996;21:719-26.
Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride
monotherapy improves glycemic control in the treatment of patients with type 2 diabetes. A 6-month
randomized placebo-controlled dose-response study. Diabetes Care 2000;23:1605-11.
Attia N, Durlach V, Paul JL, Soni T, Betoulle D, Girard-Globa A. Modulation of low density lipoprotein
subclasses by alimentary lipemia in control and normotriglyceridemic non-insulin-dependent diabetic subjects.
Austin MA, Edwards KL. Small, dense low density lipoproteins, the insulin resistance syndrome and
noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167-71.
Austin MA, Mykkanen L, Kuusisto J, Edwards KL, Nelson C, Haffner SM, Pyorala K, Laakso M. Prospective
study of small LDLs as a risk factor for non-insulin dependent diabetes mellitus in elderly men and women.
Circulation 1995;92:1770-8.
Axelrod L. Perspectives in diabetes. Omega-3 fatty acids in diabetes mellitus. Gift from the sea? Diabetes
1989;38:539-43.
Axelrod L, Camuso J, Williams E, Kleinman K, Briones E, Schoenfeld D. Effects of a small quantity of w-3
fatty acids on cardiovascular risk factors in NIDDM. A randomized, prospective, double-blind, controlled study.
Axelsen M, Smith U, Eriksson JW, Taskinen MR, Jansson PA. Postprandial hypertriglyceridemia and insulin
resistance in normoglycemic first-degree relatives of patients with Type 2 diabetes. Ann Intern Med
1999;131:27-31.
Babiy AV, Gebicki JM, Sullivan DR, Willey K. Increased oxidizability of plasma lipoproteins in diabetic
patients can be decreased by probucol therapy and is not due to glycation. Biochem Pharmacol 1992;43:9951000.
189
Bagdade JD, Kelley DE, Henry RR, Eckel RH, Ritter MC. Effects of multiple daily insulin injections and
intraperitoneal insulin therapy on cholesteryl ester transfer and lipoprotein lipase activities in NIDDM. Diabetes
1997;46:414-20.
Bak JF, Gerdes LU, Sorensen NS, Pedersen O. Effects of perindopril on insulin sensitivity and plasma lipid
profile in hypertensive non-insulin-dependent diabetic patients. Am J Med 1992;92(Suppl 4B):S69-72.
Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown
WV, Miller VT, Shurzinske LJ, Black DM. Efficacy and safety of a new HMG-CoA reductase inhibitor,
atorvastatin, in patients with hypertriglyceridemia. JAMA 1996;275:128-33.
Bakogianni MC, Kalofoutis CA, Skenderi KI, Kalofoutis AT. Clinical evaluation of plasma high-density
lipoprotein subfractions (HDL2, HDL3) in non-insulin-dependent diabetics with coronary artery disease. J
Diabetes Complications 2001;15:265-9.
Bantle JP, Swanson JE, Thomas W, Laine DC. Metabolic effects of dietary fructose in diabetic subjects.
Barnard RJ, Ugianskis EJ, Martin DA, Inkeles SB. Role of diet and exercise in the management of
hyperinsulinemia and associated atherosclerotic risk factors. Am J Cardiol 1992;69:440-4.
Barrett-Connor E. Postmenopausal estrogen and prevention bias. Ann Intern Med 1991a;115:455-6.
Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991b;265:1861-7.
Barrett-Connor E, Grundy SM, Holdbrook MJ. Plasma lipids and diabetes mellitus in an adult community. Am J
Epidemiol 1982;115:657-63.
Barrett-Connor E, Philippi T, Khaw KT. Lipoproteins as predictors of ischemic heart disease in non-insulindependent diabetic men. Am J Prev Med 1987;3:206-10.
Bassett DR Jr, Ainsworth BE, Leggett SR, Mathien CA, Main JA, Hunter DC, Duncan GE. Accuracy of five
electronic pedometers for measuring distance walked. Med Sci Sports Exerc 1996;28:1071-7.
Baynes C, Elkeles RS, Henderson AD, Richmond W, Johnston DG. The effects of glibenclamide on glucose
homeostasis and lipoprotein metabolism in poorly controlled Type 2 diabetes. Horm Metab Res 1993;25:96101.
Baynes C, Feher MD, Elkeles RS. The effect of treatment of non-insulin-dependent diabetes mellitus (NIDDM)
on serum lipids and lipoproteins. Q J Med 1989;72:579-87.
Baynes C, Henderson AD, Hughes CL, Richmond W, Johnston DG, Elkeles RS. Determinants of mild fasting
hypertriglyceridaemia in non-insulin-dependent diabetes. J Intern Med 1991;229:267-73.
Beckman JA, Creager MA, Libby P. Diabetes and atherossclerosis: Epidemiology, pathophysiology, and
management. JAMA 2002;287:2570-81.
Bell DS. A comparison of lovastatin, an HMG-CoA reductase inhibitor, with gemfibrozil, a fibrinic acid
derivative, in the treatment of patients with diabetic dyslipidemia. Clin Ther 1995;17:901-10.
Bell DS, Wagenknecht LE. Effect of gemfibrozil on intermediate-density lipoproteins in NIDDM patients. A
retrospective study. Diabetes Care 1992;15:146-7.
Berglund L. Diet and drug therapy for lipoprotein (a). Curr Opin Lipidol 1995;6:48-56.
Bermudez OI, Velez-Carrasco W, Schaefer EJ, Tucker KL. Dietary and plasma lipid, lipoprotein, and
apolipoprotein profiles among elderly Hispanics and non-Hispanics and their association with diabetes. Am J
Clin Nutr 2002;76:1214-21.
Best JD, Jerums G, Newnham HH, O'Brien RC. Diabetic dyslipidaemia. Australian Diabetes Society position
statement. Med J Aust 1995;162:91-3.
190
Best JD, Nicholson GC, O'Neal DN, Kotowicz MA, Tebbutt NC, Chan KW, Sanders KM. Atorvastatin and
simvastatin reduce elevated cholesterol in non-insulin dependent diabetes. Diab Nutr Metab 1996;9:74-80.
Bestehorn HP, Rensing UF, Roskamm H, Betz P, Benesch L, Schemeitat K, Blumchen G, Claus J, Mathes P,
Kappenberger L, Wieland H, Neiss A. The effect of simvastatin on progression of coronary artery disease. The
Multicenter coronary Intervention Study (CIS). Eur Heart J 1997;18:226-34.
Betteridge D. Cholesterol is the major atherogenic lipid in NIDDM. Diabetes Metab Rev 1997;13:99-104.
Betteridge DJ. Diabetic dyslipidemia. Am J Med 1994;96(Suppl 6A):S25-31.
Betteridge DJ. LDL heterogeneity: implications for atherogenicity in insulin resistance and NIDDM.
Diabetologia 1997;40(Suppl 1):S149-51.
Betteridge DJ. Diabetic dyslipidaemia. Eur J Clin Invest 1999;29(Suppl 2):12-6.
Bhatnagar D, Durrington PN, Kumar S, Mackness MI, Dean J, Boulton AJ. Effect of treatment with a
hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and
cholesteryl ester transfer activity in patients with NIDDM. Diabetes 1995;44:460-5.
Bierman EL. Atherogenesis in diabetes. Arterioscler Thromb 1992;12:647-56.
Biesbroeck RC, Albers JJ, Wahl PW, Weinberg CR, Bassett ML, Bierman EL. Abnormal composition of high
density lipoproteins in non-insulin-dependent diabetics. Diabetes 1982;31:126-31.
Billingham MS, Milles JJ, Green A, Bailey CJ, Hall RA. Apolipoprotein assays: methodological considerations
and studies in non-insulin-dependent diabetes treated by diet glibenclamide and insulin. Scand J Clin Invest
1989;49:239-47.
Blaak EE, van Aggel-Leijssen DP, Wagenmakers AJ, Saris WH, van Baak MA. Impaired oxidation of plasmaderived fatty acids in Type 2 diabetic subjects during moderate-intensity exercise. Diabetes 2000;49:2102-7.
Blair SN, Capuzzi DM, Gottlieb SO, Nguyen T, Morgan JM, Cater NB. Incremental reduction of serum total
cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to
statin thearpy. Am J Cardiol 2000;86:46-52.
Blanchard P, Anton B, Larousse C, Auget D, Mainard F, Charbonnel B, Krempf M. Plasma vitamin E, nonhigh-density lipoprotein cholesterol, and apolipoprotein B in diabetic patients. Clin Chem 1992;38:2339-40.
Blonk MC, Jacobs MA, Friedberg CE, Nauta JJ, Teerlink T, Popp-Snijders C, Heine RJ. Determinants of insulin
sensitivity and consequences for lipoproteins and blood pressure in subjects with non-insulin-dependent diabetes
mellitus. Metabolism 1994;43:501-8.
Bloomgarden ZT. American Diabetes Association Annual Meeting, 1999. Dyslipidemia, endothelial
dysfunction, and glycosylation. Diabetes Care 2000;23:690-8.
Bloomgarden ZT. American Diabetes Association Annual Meeting, 1999. More on cardiovascular disease.
Bo S, Gentile L, Cavallo-Perin P, Vineis P, Ghia V. Sex- and BMI-related differences in risk factors for
coronary artery disease in patients with Type 2 diabetes mellitus. Acta Diabetol 1999;36:147-53.
Boberg M, Pollare T, Siegbahn A, Vessby B. Supplementation with n-3 fatty acids reduces triglycerides but
increases PAI-1 in non-insulin-dependent diabetes mellitus. Eur J Clin Invest 1992;22:645-50.
Boemi M, Sirolla C, Amadio L, Fumelli P, Pometta D, James RW. Apoliprotein E polymorphism as a risk factor
for vascular disease in diabetic patients. Diabetes Care 1995;18:504-8.
Bonora E, Tessari R, Micciolo R, Zenere M, Targher G, Padovani R, Falezza G, Muggeo M. Intimal-medial
thickness of the carotid artery in non-diabetic and NIDDM patients. Diabetes Care 1997;20:627-31.
191
Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S,

Raffaelli A, Cacciatori V, Santi L, Targher G, Bonadonna R, Muggeo M. HOMA-Estimated insulin resistance is
an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Diabetes Care 2002;25:1135-41.
Boogaerts JR, Malone-McNeal M, Archambault-Schexnayder J, Davis RA. Dietary carbohydrate induces
lipogenesis and very-low-density lipoprotein synthesis. Am J Physiol 1984;246:E77-84.
Borkman M, Chisholm DJ, Furler SM, Storlien LH, Kraegen EW, Simons LA, Chesterman CN. Effects of fish
oil supplementation on glucose and lipid metabolism in NIDDM. Diabetes 1989;38:1314-9.
Bowie A, Owens D, Collins P, Johnson A, Tomkin GH. Glycosylated low density lipoprotein is more sensitive
to oxidation: implications for the diabetic patient? Atherosclerosis 1993;102:63-7.
Boyne MS, Saudek CD. Effect of insulin therapy on macrovascular risk factors in Type 2 diabetes. Diabetes
Care 1999;22(Suppl 3):C45-53.
Brown WV. Lipoprotein disorders in diabetes mellitus. Med Clin North Am 1994;78:143-61.
Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL,
Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the
preventionof coronary disease: the HDL Atherosclerosis Treatment Study (HATS). N Engl J Med
2001;345:1583-92.
Bruno G, Cavallo-Perin P, Bargero G, Borra M, D'Errico N, Pagano G. Glycaemic control and cardiovascular
risk factors in Type 2 diabetes: a population-based study. Diabet Med 1998;15:304-7.
Bruno G, Cavallo-Perin P, Bargero G, Borra M, D'Errico N, Macchia G, Pagano G. Hyperfibrinogenemia and
metabolic symdrome in Type 2 diabetes: a population-based study. Diabetes Metab Res Rev 2001;17:124-30.
Brussaard HE, Gevers Leuven JA, Frolich M, Kluft C, Krans HM. Short-term oestrogen replacement therapy
improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia
1997;40:843-9.
Buemann B, Tremblay A. Effects of exercise training on abdominal obesity and related metabolic
complications. Sports Med 1996;21:191-212.
Byington RP, Jukema JW, Salonen JT, Pitt B, Bruschke AV, Hoen H, Furberg CD, Mancini GB. Reduction in
cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the pravastatin
atherosclerosis intervention program. Circulation 1995;92:2419-25.
Caixas A, Ordonez-Llanos J, de Leiva A, Payes A, Homs R, Perez A. Optimisation of glycaemic control by
insulin therapy decreases the proportion of small dense LDL particles in diabetic patients. Diabetes
1997;46:1207-13.
Caixas A, Perez A, Qrdonez-Llanos J, Bonet R, Rigla M, Castellvi A, Bayen L, de Leiva A. Lack of change of
lipoprotein (a) levels by the optimization of glycemic control with insulin therapy in NIDDM patients. Diabetes
Care 1997;20:1459-61.
Calvert GD, Blight L, Franklin J, Oliver J, Wise P, Gallus AS. The effects of clofibrate on plasma glucose,
lipoproteins, fibrinogen, and other biochemical and haematological variables in patients with mature onset
diabetes mellitus. Eur J Clin Pharmacol 1980;17:355-62.
Camelon KM, Hadell K, Jamsen PT, Ketonen KJ, Kohtamaki HM, Makimatilla S, Tormala ML, Valve RH. The
Plate Model: a visual method of teaching meal planning. DAIS Project Group. Diabetes Atherosclerosis
Intervention Study. J Am Diet Assoc 1998;98:1155-8.
Campbell LV, Marmot PE, Dyer JA, Borkman M, Storlien LH. The high mono-unsaturated fat diet as a
practical alternative for NIDDM. Diabetes Care 1994;17:177-82.
Caplan GA, Colagiuri R, Lord SR, Ward JA. Execrise in older people with Type II diabetes maintains bone
density despite weight loss. Aust J Ageing 1995;14:71-5.
192
Capstick F, Brooks BA, Burns CM, Zilkens RR, Steinbeck KS, Yue DK. Very low calorie diet (VLCD): a
useful alternative in the treatment of the obese NIDDM patient. Diabetes Res Clin Pract 1997;36:105-11.
Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary
Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988;223:405-18.
Cavallero E, Dachet C, Neufcour D, Wirquin E, Mathe D, Jacotot B. Postprandial amplification of lipoprotein
abnormalities in controlled Type II diabetic subjects: relationship to postprandial lipemia and Cpeptide/glucagon levels. Metabolism 1994;43:270-8.
Ceriello A, Bortolotti N, Crescentini A, Motz E, Lizzio S, Russo A, Ezsol Z, Tonutti L, Taboga C. Antioxidant
defences are reduced during the oral glucose tolerance test in normal and non-insulin-dependent diabetic
subjects. Eur J Clin Invest 1998;28:329-33.
Ceriello A, Bortolotti N, Motz E, Crescentini A, Lizzio S, Russo A, Tonutti L, Taboga C. Meal-generated
oxidative stress in Type 2 diabetic patients. Diabetes Care 1998;21:1529-33.
Chaiyakunapruk N, Boudreau D, Ramsey SD. Pharmaco-economic impact of HMG-CoA reductase inhibitors in
Type 2 diabetes. J Cardiovasc Risk 2001;8:127-32.
Chan JC, Tomlinson B, Nicholls MG, Swaminathan R, Cheung CK, Woo J, Cockram CS. Albuminuria, insulin
resistance and dyslipidaemia in Chinese patients with non-insulin-dependent diabetes (NIDDM). Diabet Med
1996;13:150-5.
Chen YD, Swami S, Skowronski R, Coulston A, Reaven GM. Differences in postprandial lipemia between
patients with normal glucose tolerance and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab
1993;76:172-7.
Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart
disease in population with low cholesterol concentration. BMJ 1991;303:276-82.
Chlup R, Vaverkova H, Bartek J. Complementary insulin therapy improves blood glucose and serum lipid
parameters in type 2 (non-insulin-dependent) diabetic patients. I. Effects on blood glucose control. Exp Clin
Endocrinol Diabetes 1997;105(Suppl 2):70-3.
Christiansen C, Thomsen C, Rasmussen O, Balle M, Hauerslev C, Hansen C, Hermansen K. Wine for Type 2
diabetic patients? Diabet Med 1993;10:958-61.
Cohen MV, Byrne MJ, Levine B, Gutowski T, Adelson R. Low rate of treatment of hypercholesterolemia by
cardiologists in patients with suspected and proven coronary artery disease. Circulation 1991;83:1294-304.
Cole TG. Glycerol blanking in triglycerides assays: is it necessary? Clin Chem 1990;36:1267-8.
Cominacini L, Garbin U, Fratta Pasini A, Campagnola M, Davoli A, Foot E, Sighieri G, Sironi AM, Lo Cascio
V, Ferrannini E. Troglitazone reduces LDL oxidation and lowers plasma E-selectin concentration in NIDDM
patients. Diabetes 1998;47:130-3.
Coniff RF, Shapiro JA, Seaton TB, Hoogwerf BJ, Hunt JA. A double-blind placebo-controlled trial evaluating
the safety and efficacy of acarbose for the treatment of patients with insulin-requiring Type 2 diabetes. Diabetes
Care 1995;18:928-32.
Connor WE, Prince MJ, Ullmann D, Riddle M, Hatcher L, Smith FE, Wilson D. The hypotriglyceridemic effect
of fish oil in adult-onset diabetes without adverse glucose control. Ann NY Acad Sci 1993;683:337-40.
Coppack SW. Postprandial lipoproteins in non-insulin-dependent diabetes mellitus. Diabet Med 1997;14(Suppl
1):S67-74.
Cowie CC, Harris MI. Physical and metabolic characteristics of persons with diabetes. In: Harris MI, Cowie CC,
Stern MP, Boyko EJ, Reiber GE, Bennett PH. Diabetes in America. 2nd ed. Washington DC: US Government
Printing Office; 1995. p 117-64.
Crepaldi G, Manzato E. Atherogenic factors in diabetes: the role of lipoprotein metabolism. Postgrad Med J
1988;64(Suppl 3):10-2.
193
Crespin SR. What does the future hold for diabetic dyslipidaemia? Acta Diabetol 2001;38(Suppl 1):S21-6.
Crespo N, Alvarez R, Mas R, Illnait J, Fernandez L, Fernandez JC. Effects of polycosanol on patients with noninsulin-dependent diabetes mellitus and hypercholesterolemia: a pilot study. Curr Ther Res 1997;58:44-51.
Cullen P. Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol
2000;86:943-9.
Cullen P, Schulte H, Assmann G. Smoking, lipoproteins and coronary heart disease risk. Data from the Munster
Heart Study (PROCAM). Eur Heart J 1998;19:1632-41.
Curtin A, Deegan P, Owens D, Collins P, Johnson A, Tomkin GH. Intestinally derived lipoprotein particles in
non-insulin-dependent diabetic patients with and without hypertriglyceridaemia. Acta Diabetol 1995;32:244-50.
Curtin A, Deegan P, Owens D, Collins P, Johnson A, Tomkin GH. Alterations in apolipoprotein B-48 in the
postprandial state in NIDDM. Diabetologia 1994;37:1259-64.
Curtin A, Deegan P, Owens D, Collins P, Johnson A, Tomkin GH. Elevated triglycerides-rich lipoproteins in
diabetes. A study of apolipoprotein B-48. Acta Diabetol 1996;33:205-10.
Cusi K, Cunningham GR, Comstock JP. Safety and efficacy of normalizing fasting glucose with bedtime NPH
insulin alone in NIDDM. Diabetes Care 1995;18:843-51.
Dall'Aglio E, Strata A, Reaven G. Abnormal lipid metabolism in treated hypertensive patients with non-insulindependent diabetes mellitus. Am J Med 1988;84:899-903.
Darko DA, Dornhorst A, Kennedy G, Mandeno RC, Seed M. Glycaemic control and plasma lipoproteins in
menopausal women with Type 2 diabetes treated with oral and transdermal combined hormone replacement
therapy. Diabetes Res Clin Pract 2001;54:157-64.
Davidson MB, Peters AL. An overview of metformin in the treatment of Type 2 diabetes mellitus. Am J Med
1997;102:99-110.
Davis TM, Cull CA, Holman RR; UK Prospective Diabetes Study (UKPDS) Group. Relationship between
ethnicity and glycaemic control, lipid profiles, and blood pressure during the first 9 years of Type 2 diabetes.
(UKPDS 55). Diabetes Care 2001;24:1167-74.
Davoren PM, Kelly W, Gries FA, Hubinger A, Whately-Smith C, Alberti KG. Long-term effects of a sustainedrelease preparation of acipimox on dyslipidemia and glucose metabolism in non-insulin-dependent diabetes
de Man FH, Cabezas MC, Van Barlingen HH, Erkelens DW, de Bruin TW. Triglyceride-rich lipoproteins in
non-insulin-dependent diabetes mellitus: post-prandial metabolism and relation to premature atherosclerosis.
Eur J Clin Invest 1996;26:89-108.
Dean JD, Matthews SB, Dolben J, Carolan G, Luzio S, Owens DR. Cholesterol rich apo B containing
lipoproteins and smoking are independently associated with macrovascular disease in normotensive NIDDM
patients. Diabet Med 1994;11:740-7.
Dean JD, McCarthy S, Betteridge DJ, Whately-Smith C, Powell J, Owens DR. The effect of acipimox in
patients with Type 2 diabetes and persistent hyperlipidaemia. Diabet Med 1992;9:611-5.
Deegan P, Owens D, Collins P, Johnson A, Tomkin GH. Association between low-density lipoprotein
composition and its metabolism in non-insulin-dependent diabetes mellitus. Metabolism 1999;48:118-24.
DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity,
hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-94.
Delisle HF, Rivard M, Ekoe JM. Prevalence estimates of diabetes and of other cardiovascular risk factors in the
two largest Algonquin communities of Quebec. Diabetes Care 1995;18:1255-9.
194
Despres JP. Increasing high-density lipoprotein cholesterol: an update on fenofibrate. Am J Cardiol

2001;88(Suppl 12A):30N-6N.
Diabetes and Dyslipidaemia Working Party (1998). Position Statement on diabetic dyslipidaemia.
Diabetes Drafting Group. Prevalence of small vessel and large vessel disease in diabetic patients from 14
centres. The World Health Organization Multinational Study of Vascular Disease in Diabetics. Diabetologia
1985;28(Suppl 1):615-40.
Dimitriadis E, Griffin M, Collins P, Johnson A, Owens D, Tomkin GH. Lipoprotein composition in NIDDM:
Effects of dietary oleic acid on the composition, oxidisability and function of low and high density lipoproteins.
Donahue RP, Orchard TJ. Diabetes mellitus and macrovascular complications. An epidemiological perspective.
Donnelly JP, McGrath LT, Brennan GM. Lipid peroxidation, LDL glycosylation and dietary fish oil
supplementation in type II diabetes mellitus. Biochem Soc Trans 1993;22(Suppl 1):34S.
Dunn FL, Raskin P, Bilheimer DW, Grundy SM. The effect of diabetic control on very low-density lipoproteintriglycerides metabolism in patients with type II diabetes mellitus and marked hypertriglyceridemia. Metabolism
1984;33:117-23.
Durrington PN, Winocour PH, Bhatnagar D. Bezafibrate retard in patients with insulin-dependent diabetes:
effect on serum lipoproteins, fibrinogen, and glycemic control. J Cardiovasc Pharmacol 1990;16(Suppl 9):S304.
Dyer RG, Stewart MW, Mitcheson J, George K, Alberti MM, Laker MF. 7-ketocholesterol, a specific indicator
of lipoprotein oxidation, and malondialdehyde in non-insulin dependent diabetes and peripheral vascular
disease. Clin Chim Acta 1997;260:1-13.
Eaton CB, Monroe A, McQuade W, Eimer MJ. Cholesterol testing and management: a national comparison of
family physicians, general internists, and cardiologists. J Am Board Fam Pract 1998;11:180-6.
Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in
combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled
study. The Pioglitazone 027 Study Group. Clin Ther 2000;22:1395-409.
Elkeles RS. The effects of oral hypoglycaemic drugs on serum lipids and lipoproteins in non-insulin-dependent
diabetes (NIDDM). Diabete Metab 1991;17:197-200.
Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic
defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1989;321:337-43.
Erkelens DW. Diabetic dyslipidaemia. Eur Heart J 1998;19(Suppl H):H27-30.
Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Summary of the
Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015-23.
Fagan TC, Sowers J. Type 2 diabetes mellitus. Greater cardiovascular risks and greater benefits of therapy. Arch
Intern Med 1999;159:1033-4.
Fagot-Campagna A, Nelson RG, Knowler WC, Pettitt DJ, Robbins DC, Go O, Welty TK, Lee ET, Howard BV.
Plasma lipoproteins and the incidence of abnormal excretion of albumin in diabetic American Indians: the
Strong Heart Study. Diabetologia 1998;41:1002-9.
Falholt K, Jensen I, Lindkaer Jensen S, Mortensen H, Volund A, Heding LG, Noerskov Petersen P, Falholt W.
Carbohydrate and lipid metabolism of skeletal muscle in Type 2 diabetic patients. Diabet Med 1988;5:27-31.
Falko JM, Parr JH, Simpson RN, Wynn V. Lipoprotein analyses in varying degrees of glucose tolerance.
Comparison between non-insulin-dependent diabetic, impaired glucose tolerant, and control populations. Am J
Med 1987;83:641-7.
195
Farmer A, Dineen S. The effectiveness of diet supplementation with omega-3 fatty acids to improve glycaemic
control and reduce total serum lipids in non-insulin dependent diabetes mellitus. In: The Cochrane Library 1999;
Issue 2:Oxford, Update Software.
Fasching P, Ratheiser K, Schneeweiss B, Rohac M, Nowotny P, Waldhausl W. No effect of short term dietary
supplementation of saturated and poly- and monounsaturated fatty acids on insulin secretion and sensitivity in
healthy men. Ann Nutr Metab 1996;40:116-22.
Feher MD, Caslake M, Foxton J, Cox A, Packard CJ. Atherogenic lipoprotein phenotype in Type 2 diabetes:
reversal with micronised fenofibrate. Diabetes Metab Res Rev 1999;15:395-9.
Feher MD, Stevens J, Lant AF, Mayne PD. Importance of routine measurement of HDL with total cholesterol in
diabetic patients. J Roy Society Med 1992;85:8-11.
Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM. LDL subclass phenotypes and triglycerides
metabolism in non-insulin-dependent diabetes. Arterioscler Thromb 1992;12:1496-502.
Fenkci S, Fenkci V, Yilmazer M, Serteser M, Koken T. Effects of short-term transdermal hormone replacement
therapy on glycaemic control, lipid metabolism, C-reactive protein and proteinuria in postmenopausal women
with Type 2 diabetes or hypertension. Hum Reprod 2003;18:866-70.
Feskens EJ, Virtanen SM, Rasanen L, Tuomilehto J, Stengard J, Pekkanen J, Nissinen A, Kromhout D. Dietary
factors determining diabetes and impaired glucose tolerance. A 20-year follow-up of the Finnish and Dutch
cohorts of the Seven Countries Study. Diabetes Care 1995;18:1104-12.
Finney CP. Measurement issues in cholesterol screening: an overview for nurses. J Cardiovasc Nurs 1991;5:1022.
Fitzgerald AP, Jarrett RJ. Are conventional risk factors for mortality relevant in type 2 diabetes? Diabet Med
1991;8:475-80.
Florkowski CM, Scott RS, Moir CL, Graham PJ. Lipid but not glycaemic parameters predict total mortality
from Type 2 diabetes mellitus in Canterbury, New Zealand. Diabet Med 1998;15:386-92.
Fontbonne A. Relationship between diabetic dyslipoproteinaemia and coronary heart disease risk in subjects
with non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1991;7:179-89.
Fontbonne A, Charles MA, Juhan-Vague I, Bard JM, Andre P, Isnard F, Cohen JM, Grandmottet P, Vague P,
Safar ME, Eschwege E. The effect of metformin on the metabolic abnormalities associated with upper-body fat
distribution. BIGPRO Study Group. Diabetes Care 1996;19:920-6.
Fontvieille AM, Rizkalla SW, Penfornis A, Acosta M, Bornet FR, Slama G. The use of low glycaemic index
foods improves metabolic control for diabetic patients over five weeks. Diabet Med 1992;9:444-50.
Forcheron F, Cachefo A, Thevenon S, Pinteur C, Beylot M. Mechanisms of the triglycerides- and cholesterollowering effect of fenofibrate in hyperlipidaemic Type 2 diabetic patients. Diabetes 2002;51:3486-91.
Franceschini G. Epidemiologic evidence for high-density lipoprotein cholesterol as a risk factor for coronary
artery disease. Am J Cardiol 2001;88(Suppl 12A):9N-13N.
Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A,
Taskinen MR. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by
gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary
Angiography Trial (LOCAT) Study Group. Circulation 1997;96:2137-43.
Friday KE, Childs MT, Tsunehara CH, Fujimoto WY, Bierman EL, Ensinck JW. Elevated plasma glucose and
lowered triglycerides levels from omega-3 fatty acid supplementation in Type II diabetes. Diabetes Care
1989;12:276-81.
Friday KE, Dong C, Fontenot RU. Conjugated equine estrogen improves glycaemic control and blood
lipoproteins in postmenopausal women with Type 2 diabetes. J Clin Endocrinol Metab 2001;86:48-52.
196
Frost RJ, Otto C, Geiss HC, Schwandt P, Parhofer KG. Effects of atorvastatin versus fenofibrate on lipoprotein
profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes
mellitus with mixed hyperlipoproteinaemia. Am J Cardiol 2001;87:44-8.
Fu CC, Chang CJ, Tseng CH, Chen MS, Kao CS, Wu TJ, Wu HP, Chuang LM, Chen CJ, Tai TY. Development
of macrovascular diseases in NIDDM patients in Northern Taiwan. A 4-yr follow-up study. Diabetes Care
1993;16:137-43.
Fuh MM, Shieh SM. Association of low plasma high density lipoprotein (HDL)-cholesterol concentration with
documented coronary artery disease in males with non-insulin dependent diabetes mellitus. Horm Metab Res
1987;19:267-70.
Fujimoto WY, Bergstrom RW, Leonetti DL, Newell-Morris LL, Shuman WP, Wahl PW. Metabolic and adipose
risk factors for NIDDM and coronary disease in third-generation Japanese-American men and women with
impaired glucose tolerance. Diabetologia 1994;37:524-32.
Fulcher GR, Catalano C, Walker M, Farrer M, Thow J, Whately-Smith CR, Alberti KG. A double blind study of
the effect of acipimox on serum lipids, blood glucose control and insulin action in non-obese patients with Type
2 diabetes mellitus. Diabet Med 1992a;9:908-14.
Fulcher GR, Walker M, Catalano C, Agius L, Alberti KG. Metabolic effects of suppression of nonesterified
fatty acid levels with acipimox in obese NIDDM subjects. Diabetes 1992b;41:1400-8.
Fuller CJ, Chandalia M, Garg A, Grundy SM, Jialal I. RRR-alpha tocopheryl acetate supplementation at
pharmacologic doses decreases low-density-lipoprotein oxidative susceptibility but not protein glycation in
patients with diabetes mellitus. Am J Clin Nutr 1996;63:753-9.
Fuller JH, McCartney P, Jarrett RJ, Keen H, Rose G, Shipley MJ, Hamilton PJ. Hyperglycaemia and coronary
heart disease: the Whitehall Study. J Chronic Dis 1979;32:721-8.
Furberg CD, Pitt B, Byington RP, Park JS, McGovern ME. Reduction in coronary events during treatment with
pravastatin. PLAC I and PLAC II Investigators. Pravastatin Limitation of Atherosclerosis in the Coronary
Arteries. Am J Cardiol 1995;76:60C-3C.
Furuseth K, Berg K, Hanssen KF, Rutle O, Bruusgaard D, Vaaler S. Serum lipoprotein (a) and cardiovascular
disease in non-insulin-dependent diabetes mellitus. Scand J Prim Health Care 1998;16:40-3.
Gadsby R. Managing dyslipidaemia in Type 2 diabetes in primary care. Prac Diab Int 2000;17:S1-8.
Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in people with type 2
diabetes mellitus and microalbuminuria: The Steno Type 2 Randomised Study. Lancet 1999;353:617-22.
Gall MA, Rossing P, Skott P, Hommel E, Mathiesen ER, Gerdes LU, Lauritzen M, Volund A, Faergeman O,
Beck-Nielsen H, Parving HH. Placebo-controlled comparison of captopril, metoprolol, and hydrochlorothiazide
therapy in non-insulin-dependent diabetic patients with primary hypertension. Am J Hypertens 1992;5:257-65.
Gallagher A, Henderson W, Abraira C. Dietary patterns and metabolic control in diabetic diets: a prospective
study of 51 outpatient men on unmeasured and exchange diets. J Am Coll Nutr 1987;6:525-32.
Gallou G, Ruelland A, Legras B, Maugendre D, Allanic H, Cloarec L. Plasma malondialdehyde in type 1 and
type 2 diabetic patients. Clin Chim Acta 1993;214:227-34.
Garber AJ. Diabetes and heart disease: a new strategy for managing lipid disorders. Geriatrics 1993;48:34-6, 941.
Garber AJ. Vascular disease and lipids in diabetes. Med Clin North Am 1998;82:931-48.
Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type 2 diabetes: results of
a double-blind, placebo-controlled, dose-response trial. Am J Med 1997;102:491-7.
Garg A. High-monounsaturated fat diet for diabetic patients. Is it time to change the current dietary
recommendations? Diabetes Care 1994;17:242-6.
197
Garg A, Bonanome A, Grundy SM, Zhang Z-J, Unger RH. Comparison of a high-carbohydrate diet with a highmonounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1988;319:82934.
Garg A, Grundy SM. Lovastatin for lowering cholesterol levels in non-insulin-dependent diabetes mellitus. N
Engl J Med 1988;318:81-6.
Garg A, Grundy SM. Gemfibrozil alone and in combination with lovastatin for treatment of
hypertriglyceridemia in NIDDM. Diabetes 1989;38:364-72.
Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidaemia in non-insulin dependent diabetes mellitus.
JAMA 1990;264:723-6.
Garg A, Grundy SM. Management of dyslipidemia in NIDDM. Diabetes Care 1990;13:153-69.
Garg A, Grundy SM. Treatment of dyslipidemia in patients with NIDDM. Diabetes Rev 1995;3:433-45.
Garg A. Treatment of diabetic dyslipidaemia. Am J Cardiol 1998b;81(4A):47-51.
Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, VanDenburgh M, Willett W, Hennekens CH.
Moderate alcohol intake, increased levels of high density lipoprotein and its subfractions, and decreased risk of
myocardial infarction. N Engl J Med 1993;329:1829-34.
Geltner C, Lechleitner M, Foger B, Ritsch A, Drexel H. Patsch JR. Insulin improves fasting and postprandial
lipaemia in Type 2 diabetes. Eur J Intern Med 2002;13:25-63.
Gerstein HC. Cardiovascular and metabolic benefits of ACE inhibition. Moving beyond blood pressure
reduction. Diabetes Care 2000;23:882-3.
Gervaise N, Garigue MA, Lasfargues G, Lecomte P. Triglycerides, apo C3 and Lp B:C3 and cardiovascular risk
in Type II diabetes. Diabetologia 2000;43:703-8.
Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja BW, Whitcomb RW. Cardiac and glycemic
benefits of troglitazone treatment in NIDDM. Diabetes 1997;46:433-9.
Ginsberg HN. Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis. Diabetes
Care 1991;14:839-55.
Godsland IF, Crook D, Simpson R, Proudler T, Felton C, Lees B, Anyaoku V, Devenport M, Wynn V. The
effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J
Med 1990;323:1375-81.
Goh YK, Jumpsen JA, Ryan EA, Clandinin MT. Effect of n-3 fatty acid on plasma lipids, cholesterol and
lipoprotein fatty acid content in NIDDM patients. Diabetologia. 1997;40:45-52.
Goldberg RB. Lipid disorders in diabetes. Endocrinologist 1997;7:436-42.
Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes 1992;16:397-415.
Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor
against coronary heart disease. Am J Med 1977;62:707-14.
Gotto AMJr. Triglycerides as a risk factor for coronary artery disease. Am J Cardiol 1998;82:Q22-5.
Gould AL, Rossouw JE, Santanello NC, Heyse JE, Furberg CD. Cholesterol reduction yields clinical benefits: a
new look at old data. Circulation 1995;91:2274-82.
Grant PJ. The effects of metformin on cardiovascular risk factors. Diabetes Metab Rev 1995;11(Suppl 1):43-50.
Grant PJ. The effects of high-and medium-dose metformin therapy on cardiovascular risk factors in patients
with Type II diabetes. Diabetes Care 1996;19:64-6.
Gray DS. The clinical uses of dietary fibre. American Family Physician 1995;2:419-25.
198
Greenfield M, Kolterman O, Olefsky J, Reaven GM. Mechanism of hypertriglyceridaemia in diabetic patients

with fasting hyperglycaemia. Diabetologia 1980;18:441-6.
Grundy SM. Dietary therapy in diabetes mellitus. Is there a single best diet? Diabetes Care 1991;14:796-801.
Guillausseau P-J, Peynet J, Chanson P, Legrand A, Altman J-J, Poupon J, N'Guyen M, Rousselet F, Lubetzki J.
Lipoprotein (a) in diabetic patients with and without chronic renal failure. Diabetes Care 1992;15:976-9.
Gylling H, Miettinen TA. Cholesterol absorption, synthesis, and LDL metabolism in NIDDM. Diabetes Care
1997;20:90-5.
Gylling H, Miettinen TA. Treatment of lipid disorders in non-insulin-dependent diabetes mellitus. Curr Opin
Lipidol 1997;8:342-7.
Hadden DR, Montgomery DAD, Skelly RJ, Trimble ER, Weaver JA, Wilson EA, Buchanan KD. Maturity onset
diabetes mellitus: response to intensive dietary management. BMJ 1975;iii:276-78.
Haffner SM. Compositional changes in lipoproteins of subjects with non-insulin-dependent diabetes mellitus. J
Lab Clin Med 1991;118:109-10.
Haffner SM. Lipoprotein (a) and diabetes. Diabetes Care 1993;16:835-40.
Haffner SM. The prediabetic problem: development of non-insulin-dependent diabetes mellitus and related
abnormalities. J Diabetes Complications 1997;11:69-76.
Haffner SM. Diabetes, hyperlipidemia, and coronary artery disease. Am J Cardiol 1999b;83:F17-21.
Haffner SM. Lipoprotein disorders associated with Type 2 diabetes mellitus and insulin resistance. Am J Cardiol
2002;90(Suppl):55i-61i.
Haffner SM, Miettinen H. Insulin resistance implications for type II diabetes mellitus and coronary heart
disease. Am J Med 1997;103:152-62.
Haffner SM, Morales PA, Gruber MK, Hazuda HP, Stern MP. Cardiovascular risk factors in non-insulindependent diabetic subjects with microalbuminuria. Arterioscler Thrombo 1993;13:205-10.
Haffner SM, Tuttle KR, Rainwater DL. Lack of change of lipoprotein (a) concentration with improved glycemic
control in subjects with Type II diabetes. Metabolism 1992;41:116-20.
Hancu N, Netea MG, Iancu S. Serum lipoprotein (a) is increased in hypertensive NIDDM patients. Diabetes
Care 1995;18:879-80.
Hanefeld M, Fischer S, Schmechel H, Rothe G, Schulze J, Dude H, Schwanebeck U, Julius U. Diabetes
Intervention Study: multi-intervention trial in newly diagnosed NIDDM. Diabetes Care 1991;14:308-17.
Hanefeld M, Schmechel H, Schwanebeck U, Lindner J, the DIS Group. Predictors of coronary heart disease and
death in NIDDM: the Diabetes Intervention Study experience. Diabetologia 1997;40(Suppl. 1):123-4.
Hanefeld M, Temelkova-Kurkschiev T. The postprandial state and the risk of atherosclerosis. Diabet Med
1997;14:6-11.
Hanefeld M, Temelkova-Kurktschiev T, Kohler C. Effect of oral antidiabetics and insulin on lipids and coronary
heart disease in non-insulin-dependent diabetes mellitus. Ann NY Acad Sci 1997;827:246-68.
Hanefeld M, Weck M. Very low calorie diet therapy in obese non-insulin dependent diabetes patients. Int J
Obes 1989;13(Suppl 2):33-7.
Harano Y, Kageyama A, Nakao Y, Hara Y, Suzuki M, Sato A, Ikebuchi M, Shinozaki K, Tsushima M.
Quantitative and qualitative derangement of apolipoprotein B-containing lipoproteins as a risk factor for diabetic
macroangiopathy in nonobese NIDDM subjects. Diabetes 1996;45(Suppl 3):31-4.
199
Hasslacher C, Bostedt-Kiesel A, Kempe HP, Wahl P. Effect of metabolic factors and blood pressure on kidney
function in proteinuric Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993;36:1051-6.
Hatton DC, Haynes RB, Oparil S, Kris-Etherton P, Pi-Sunyer FX, Resnick LM, Stern JS, Clark S, McMahon M,
Morris C, Metz J, Ward A, Holcomb S, McCarron DA. Improved quality of life in patients with generalized
cardiovascular metabolic disease on a prepared diet. Am J Clin Nutr 1996;64:935-43.
Heesen BJ, Wolffenbuttel BHR, Leurs PB, Sels JPJE, Menheere PPCA, Jackle-Beckers SEC, Nieuwenhuijzen
Kruseman AC. Lipoprotein (a) levels in relation to diabetic complications in patients with non-insulindependent diabetes. Eur J Clin Invest 1993;23:580-4.
Hegele RA, Harris SB, Zinman B, Hanley AJG, Connelly PW. Increased plasma apolipoprotein b-containing
lipoproteins associated with increased urinary albumin within the microalbuminuria range in Type 2 diabetes.
Clin Biochem 1999;32:143-8.
Heller FR, Jamart J, Honore P, Derue G, Novik V, Galanti L, Parfonry A, Hondekijn J-C, Buysschaert M.
Serum lipoprotein (a) in patients with diabetes mellitus. Diabetes Care 1993;16:819-23.
Hendra TJ, Britton ME, Roper DR, Wagaine-Twabwe D, Jeremy JY, Dandona P, Haines AP, Yudkin JS.
Effects of fish oil supplements in NIDDM subjects. Controlled Study. Diabetes Care 1990;13:821-9.
Henry RR, Scheaffer L, Olefsky JM. Glycemic effects of intensive caloric restriction and isocaloric refeeding in
noninsulin- dependent diabetes mellitus. J Clin Endocrinol Metab 1985;61:917-25.
Henry RR, Wiest-Kent TA, Scheaffer L, Kolterman OG, Olefsky JM. Metabolic consequences of very-lowcalorie diet therapy in obese non-insulin-dependent diabetic and nondiabetic subjects. Diabetes 1986;35:155-64.
Herd JA. The Lipoprotein and Coronary Atherosclerosis Study (LCAS): lipid and metabolic factors related to
Atheroma and clinical events. Am J Med 1998;104(6A):42S-9S.
Herd JA, Ballantyne CM, Farmer JA, Ferguson JJ, Jones PH, West S, Gould KL, Gotto Jr AM, for the LCAS
Investigators. Effects of luvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol
elevations (Lipoprotein and Coronary Atherosclerosis Study [[LCAS]). Am J Cardiol 1997;80:278-86.
Hermann LS, Karlsson J-E, Sjostrand A. Prospective comparative study in NIDDM patients of metformin and
glibenclamide with special reference to lipid profiles. Eur J Clin Pharmacol 1991;41:263-5.
Hirano T. Lipoprotein abnormalities in diabetic nephropathy. Kidney Int 1999;56(Suppl 7):22-4.
Hirano T, Naito H, Kurokawa M, Ebara T, Nagano S, Adachi M, Yoshino G. High prevalence of small LDL
particles in non-insulin-dependent diabetic patients with nephropathy. Atherosclerosis 1996;123:57-72.
Hirano T, Oi K, Sakai S, Kashiwazaki K, Adachi M, Yoshino G. High prevalence of small dense LDL in
diabetic nephropathy is not directly associated with kidney damage: a possible role of postprandial lipemia.
Hirata-Dulas CAI, Rith-Najarian SJ, McIntyre MC, Ross C, Dahl DC, Keane WF, Kasiske BL. Risk factors for
nephropathy and cardiovascular disease in diabetic Northern Minnesota American Indians. Clin Nephrol
1996;46:92-8.
Hodge AM, Dowse GK, Zimmet PZ. Microalbuminuria, cardiovascular risk factors, and insulin resistance in
two populations with a high risk of Type 2 diabetes mellitus. Diabet Med 1996;13:441-9.
Hollenbeck CB, Chen YD, Greenfield MS, Lardinois CK, Reaven GM. Reduced plasma high density
lipoprotein-cholesterol concentrations need not increase when hyperglycemia is controlled with insulin in
noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1986;62:605-8.
Hollenbeck CB, Coulston AM. Effects of dietary carbohydrate and fat intake on glucose and lipoprotein
metabolism in individuals with diabetes mellitus. Diabetes Care 1991;14:774-85.
Hollenbeck CB, Coulston AM, Reaven GM. To what extent does increased dietary fibre improve glucose and
lipid metabolism in patients with noninsulin-dependent diabetes mellitus (NIDDM)? Am J Clin Nutr
1986;43:16-24.
200
Hollenbeck CB, Coulston AM, Reaven GM. Effects of sucrose on carbohydrate and lipid metabolism in
NIDDM patients. Diabetes Care 1989;12(Suppl 1):62-6.
Hollenbeck CB, Johnston P, Varasteh BB, Chen YD, Reaven GM. Effects of metformin on glucose, insulin and
lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose
tolerance test criteria. Diabete et Metabolisme 1991;17:483-9.
Holmes J, Hadden DR, Atkinson AB, Kennedy AL, Wilson EA. Assessment of diet adherence in relation to
long-term follow up of non-insulin-dependent diabetics. Pract Diabetes 1987;4:276-8.
Horita K, Eto M, Makino I. Apolipoprotein E2, renal failure and lipid abnormalities in non-insulin-dependent
Hostetter AL. Screening for dyslipidemia. Practice parameter. Am J Clin Pathol 1995;103:380-5.
Howard BV. Lipoprotein metabolism in diabetes mellitus. J Lipid Res 1987;28:613-28.
Howard BV. Diabetes and plasma lipoproteins in Native Americans. Studies of the Pima Indians. Diabetes Care
1993;16(Suppl 1):284-91.
Howard BV, Howard WJ. Dyslipidemia in non-insulin-dependent diabetes mellitus. Endocr Rev 1994;15:26374.
Howard BV, Knowler WC, Vasquez B, Kennedy AL, Pettitt DJ, Bennett PH. Plasma and lipoprotein cholesterol
and triglycerides in the Pima Indian population. Comparison of diabetics and nondiabetics. Arteriosclerosis
1984;4:462-71.
Howard BV, Savage PJ, Nagulesparan M, Bennion LJ, Davis M, Bennett PH. Changes in plasma lipoproteins
accompanying diet therapy in obese diabetics. Atherosclerosis 1979;33:445-56.
Howard BV, Xiaoren P, Harper I, Foley JE, Cheung MC, Taskinen M-R. Effect of sulfonylurea therapy on
plasma lipids and high density lipoprotein composition in non-insulin-dependent diabetes mellitus. Am J Med
1985;79(Suppl 3B):78-85.
Howard BV, Robbins DC, Sievers ML, Lee ET, Rhoades D, Devereux RB, Cowan LD, Gray RS, Welty TK, Go
OT, Howard WJ. LDL Cholesterol as a strong predictor of coronary heart disease in diabetic individuals with
insulin resistance and low LDL. Arterioscler Thromb Vasc Biol 2000;20:830-5.
Hwu CM, Kwok CF, Chen HS, Shih KC, Lee SH, Hsiao LC, Lin SH, Ho LT. Lack of effect of simvastatin on
insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia: results from double-blind,
randomized, placebo-controlled crossover study. Diabet Med 1999;16:749-54.
Hypertension in Diabetes Study Group. Hypertension in Diabetes Study (HDS): I. Prevalence of hypertension in
newly presenting type 2 diabetic patients and the association with the risk factors for cardiovascular and diabetic
complications. J Hypertens 1993;11:309-17.
Ikeda T, Ohtani I, Fujiyama K, Hoshino T, Tanaka Y, Tekeuchi T, Mashiba H. Apolipoprotein levels in noninsulin-dependent diabetes mellitus with clinical macroangiopathy. Diabete Metabolisme 1991;17:373-8.
Imperatore G, Rivellese A, Galasso R, Celentano E, Iovine C, Ferrara A, Riccardi G, Vaccaro O. Lipoprotein (a)
concentrations in non-insulin-dependent diabetes mellitus and borderline hyperglycemia: a population-based
study. Metabolism 1995;44:1293-7.
Inoue Y, Kaku K, Okubo M, Hatao K, Hatao M, Kaneko T, Matsumura S, Ando S, Fujii S. A multi-centre study
of the efficacy and safety of pravastatin in hypercholesterolaemic patients with non-insulin-dependent diabetes
mellitus. Curr Med Res Opin 1994;13:187-94.
Inoue I, Takahashi K, Katayama S, Akabane S, Negishi K, Suzuki M, Ishii J, Kawazu S. Improvement of
glucose tolerance by benzafibrate in non-obese patients with hyperlipidemia and impaired glucose tolerance.
Diabetes Res Clin Pract 1994;25:199-205.
201
Isomaa B, Henricsson M, Almgren P, Tuomi T, Taskinen MR, Groop L. The metabolic syndrome influences the
risk of chronic complications in patients with Type II diabetes. Diabetologia 2001;44:1148-54.
Israelson B. Role of alcohol, glucose intolerance and obesity in hypertriglyceridemia. Atherosclerosis
1986;62:123-7.
Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effect of combination therapy of
troglitazone and sulphonylureas in patients with Type 2 diabetes who were poorly controlled by sulphonylurea
therapy alone. Diabet Med 1996a;13:365-70.
Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effects of troglitazone. A new
hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996b;19:151-6.
Jain SK, McVie R, Jaramillo JJ, Palmer M, Smith T, Meachum ZD, Little RL. The effect of modest vitamin E
supplementation on lipid peroxidation products and other cardiovascular risk factors in diabetic patients. Lipids
1996;31:87-90.
James RW, Pometta D. The distribution profiles of very low density and low density lipoproteins in poorlycontrolled male, Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1991;34:246-52.
Janus ED. Apoliproptein (a) and atherogenesis. Pathology 1993;25:291-3.
Jarvi AE, Karlstrom BE, Granfeldt YE, Bjorck IE, Asp NG, Vessby BO. Improved glycemic control and lipid
profile and normalized fibrinolytic activity on a low-glycemic index diet in Type 2 diabetic patients. Diabetes
Care 1999;22:10-8.
Jeck T, Riesen WF, Keller U. Comparison of bezafibrate and simvastatin in the treatment of dyslipidaemia in
patients with NIDDM. Diabet Med 1997;14:564-70.
Jenkins AB, Chisholm DJ. Glucoregulation during exercise in NIDDM. Diabetes Care 1991;14:350.
Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, Bowling AC, Newman HC, Jenkins
AL, Goff DV. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr
1981;34:362-6.
Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Triglycerides concentration and ischemic heart disease. An
eight-year follow-up in the Copenhagen Male Study. Circulation 1998;97:1029-36.
Jeppesen J, Zhou MY, Chen YD, Reaven GM. Effect of metformin on postprandial lipemia in patients with
fairly to poorly controlled NIDDM. Diabetes Care 1994a;17:1093-9.
Jeppesen J, Zhou MY, Chen YD, Reaven GM. Effect of glipizide treatment on postprandial lipaemia in patients
with NIDDM. Diabetologia 1994b;37:781-7.
Jialal I. A practical approach to the laboratory diagnosis of dyslipidemia. Am J Clin Pathol 1996;106:128-38.
Jiao S, Kameda K, Matsuzawa Y, Kubo M, Nonaka K, Tarui S. Influence of endogenous hyperinsulinism on
high density lipoprotein2 level in Type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose
tolerance. Atherosclerosis 1986;60:279-86.
Johnson BF, LaBelle P, Wilson J, Allan J, Zupkis RV, Ronca PD. Effects of lovastatin in diabetic patients
treated with chlorpropamide. Clin Pharmacol Ther 1990;48:467-72.
Johnson JL, Wolf SL, Kubadi UM. Efficacy of insulin and sulfonylurea combination therapy in type II diabetes.
Arch Intern Med 1996;156:259-64.
Jokubaitis LA, Knopp RH, Frohlich J. Efficacy and safety of fluvastatin in hyperlipidaemic patients with noninsulin-dependent diabetes mellitus. J Intern Med 1994;236(Suppl 736):103-7.
Jones PJ, Ntanios FY, Raeini-Sarjaz M, Vanstone CA. Cholesterol-lowering efficacy of sitostanol-containing
phytosterol mixture with a prudent diet in hyperlipidemic men. Am J Clin Nutr 1999;69:1144-50.
202
Josse RG. Acarbose for the treatment of Type II diabetes: the results of a Canadian multi-centre trial. Diabetes
Res Clin Pract 1995;28(Suppl 1):S167-72.
Joven J, Vilella E. Serum levels of lipoprotein (a) in patients with well-controlled non-insulin-dependent
diabetes mellitus. JAMA 1991;265:1113-4.
Kado S, Murakami T, Aoki A, Nagase T, Katsura Y, Noritake M, Matsuoka T, Nagata N. Effect of acarbose on
postprandial lipid metabolism in type 2 diabetes mellitus. Diabetes Res Clin Pract 1998;41:49-55.
Kahri J, Vuorinen-Markkola H, Tilly-Kiesi M, Lahdenpera S, Taskinen MR. Effect of gemfibrozil on high
density lipoprotein subspecies in non-insulin dependent diabetes mellitus. Relations to lipolytic enzymes and to
the cholesteryl ester transfer protein activity. Athersclerosis 1993;102:79-89.
Kalix B, Meynet MC, Garin MC, James RW. The apolipoprotein epsilon2 allele and the severity of coronary
artery disease in Type 2 diabetic patients. Diabet Med 2001;18:445-50.
Kannel WB. Lipids, diabetes and coronary heart disease: insights from the Framingham Study. Am Heart J
1985;110:1100-6.
Kannel WB. Framingham study insights into hypertensive risk of cardiovascular disease. Hypertens Res
1995;18:181-96.
Karlander SG, Gutniak MK, Efendic S. Effects of combination therapy with glyburide and insulin on serum
lipid levels in NIDDM patients with secondary sulfonlyurea failure. Diabetes Care 1991;14:963-7.
Kasama T, Yoshino G, Iwatani I, Iwai M, Hatanaka H, Kazumi T, Oimomi M, Baba S. Increased cholesterol
concentration in intermediate density lipoprotein fraction of normolipidemic non-insulin-dependent diabetics.
Kasim SE, Stern B, Khilnani S, McLin P, Baciorowski S, Jen C. Effects of omega-3 fish oils on lipid
metabolism, glycemic control, and blood pressure in Type II diabetic patients. J Clin Endocrinol Metab
1988;67:1-5.
Kaukua J, Turpeinen A, Uusitupa M, Niskanen L. Clustering of cardiovascular risk factors in Type 2 diabetes
mellitus: prognostic significance and tracking. Diabetes Obes Metab 2001;3:17-23.
Kaysen GA, de Sain-van der Velden MG. New insights into lipid metabolism in the nephrotic syndrome.
Kidney Int Suppl 1999;71:S18-21.
Kazumi T, Yoshino G, Ishida Y, Iwatani I, Morita S, Tateiwa M, Kasuga M, the Hyogo Pravastatin Study
Group. Long-term efficacy and tolerability of pravastatin in hypercholesterolemia in patients with non-insulindependent diabetes mellitus. Diabetes Res Clin Pract 1995b;27:61-8.
Kazumi T, Yoshino G, Ohki A, Matsuba K, Ino T, Amano M, Kasuga M, the Hyogo Simvastatin Study Group.
Long-term effects of simvastatin in hypercholesterolemic patients with NIDDM and additional atherosclerotic
risk factors. Horm Metab Res 1995a;27:239-43.
Keilani T, Schlueter WA, Levin ML, Batlle DC. Improvement of lipid abnormalities associated with proteinuria
using fosinopril, an angiotensin-converting enzyme inhibitor. Ann Intern Med 1993;118:246-54.
Kennedy L, Walshe K, Hadden DR, Weaver JA, Buchanan KD. The effect of intensive dietary therapy on serum
high density lipoprotein cholesterol in patients with Type 2 (non-insulin-dependent) diabetes mellitus: a
prospective study. Diabetologia 1982;23:24-7.
Kesavulu MM, Rao BK, Giri R, Vijaya J, Subramanyam G, Apparao C. Lipid peroxidation and antioxidant
enzyme status in Type 2 diabetes with coronary heart disease. Diabetes Res Clin Prac 2001;53:33-9.
Kikuchi T, Onuma T, Shimura M, Tsutsui M, Boku A, Matsui J, Takebe K. Different change in lipoprotein (a)
levels from lipid levels of other lipoproteins with improved glycemic control in patients with NIDDM. Diabetes
Care 1994;17:1059-61.
Kimura H, Suzuki Y, Gejyo F, Karasawa R, Miyazaki R, Suzuki S, Arakawa M. Apolipoprotein E4 reduces risk
of diabetic nephropathy in patients with NIDDM. Am J Kidney Dis 1998;31:666-73.
203
King AB. A comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones. Diabetes
Care 2000;23:557.
Kirkman MS, Weinberger M, Landsman PB, Samsa GP, Shortliffe EA, Simel DL, Feussner JR. A telephonedelivered intervention for patients with NIDDM. Effect on coronary risk factors. Diabetes Care 1994;17:840-6.
Kissebah AH. Low density lipoprotein metabolism in non-insulin-dependent diabetes mellitus. Diabetes Metab
Rev 1987;3:619-51.
Kitabchi AE, Sora AG, Radparvar A, Lawson-Grant V. Combined therapy of insulin and tolazamide decreases
insulin requirement and serum triglycerides in obese patients with noninsulin-dependent diabetes mellitus. Am J
Med Sci 1987;294:10-4.
Klaya F, Durlach V, Bertin E, Monier F, Monboisse J-C, Gillery P. Evaluation of serum glycated lipoprotein (a)
levels in noninsulin-dependent diabetic patients. Clin Biochem 1997;30:227-30.
Klein R, Klein EK, Wang Q, Jensen SC. Treatment and control of hypercholesterolemia and hypertension in
persons with and without diabetes. Am J Prev Med 1995;11:329-35.
Klotzsch SG, McNamara JR. Triglycerides measurements: a review of methods and interferences. Clin Chem
1990;36:1605-13.
Knopp RH, Frolich JJ. Efficacy and safety of fluvastatin in patients with non-insulin-dependent diabetes
mellitus and hyperlipidemia: preliminary report. Am J Cardiol 1994a;73:D39-41.
Ko GTC, Mak TWL, Yeung VTF, Chan DCF, Lam CWK, Tsang LWW, Chow C-C, Cockram CS. Short-term
efficacy and tolerability of combination therapy with lovastatin and acipimox in Chinese patients with type 2
diabetes mellitus and mixed dyslipidemia. J Clin Pharmacol 1998;38:912-7.
Ko GTC, Yeung VFY, Tsang LWW, Chow C-C, Cockram CS. Comparison of the effects of gemfibrozil (600
mg twice daily and 900 mg once daily) on lipid and glucose levels in Chinese patients with non-insulin diabetes
mellitus. Curr Ther Res 1995;56:1033-40.
Kobayashi M, Shigeta Y, Hirata Y, Omori Y, Sakamoto N, Nambu S, Baba S. Improvement of glucose
tolerance in NIDDM by clofibrate. Randomized double-blind study. Diabetes Care 1988;11:495-9.
Koch M, Gradaus F, Schoebel F-C, Leschke M, Grabensee B. Relevance of conventional cardiovascular risk
factors for the prediction of coronary artery disease in diabetic patients on renal replacement therapy. Nephrol
Dial Transplant 1997;12:1187-91.
Koch M, Thomas B, Tschope W, Ritz E. Survival and predictors of death in dialysed diabetic patients.
Koev D, Zlateva S, Susic M, Babic D, Profozic V, Skrabalo Z, Langrova H, Cvrkalova A, Rajecova E, Klimes I,
Sebokova E, Hanzen E, Lacko A, Kreze A, Rybka J, Gus M, Kalits I, Karadi I, Romics L, Leoski JJr, Orlandini
L. Improvement of lipoprotein lipid composition in Type II diabetic patients with concomitant
hyperlipoproteinemia by acipimox treatment. Diabetes Care 1993;16:1285-90.
Konttinen A, Kuisma I, Ralli R, Pohjola S, Ojala K. The effect of gemfibrozil on serum lipids in diabetic
patients. Ann Clin Res 1979;11:240-5.
Kostner GM, Karadi I. Lipoprotein alterations in diabetes mellitus. Diabetologia 1988;31:717-22.
Kramer-Guth A, Quaschning T, Greiber S, Wanner C. Potential role of lipids in the progression of diabetic
nephropathy. Clin Nephrol 1996;46:262-5.
Kramer-Guth A, Quaschning T, Pavenstadt H, Galle J, Nauck M, Baumstark MW, Schollmeyer P, Marz W,
Wanner C. Uptake and metabolism of lipoproteins from patients with diabetes mellitus type II by glomerular
epithelial cells. Nephrol Dial Transplant 1997;12:1336-43.
Kreisberg RA. Diabetic dyslipidemia. Am J Cardiol 1998;82:U67-73.
204
Kremph M, Berthezene F, Wemeau JL, Moinade S, Desriac I, Amelineau E, Passa P. Efficacy of low-dose
pravastatin in patients with mild hyperlipidemia associated with Type 2 diabetes mellitus. Diabetes Metab
1997;23:131-6.
Krook A, Holm I, Pettersson S, Wallberg-Henriksson, H. Reduction of risk factors following lifestyle
modification programme in subjects with Type 2 (non-insulin dependent) diabetes mellitus. Clin Physiol & Func
Im 2003;23:21-30.
Kumar S, Prange A, Schulze J, Lettis S, Barnett AH. Troglitazone, an insulin action enhancer, improves
glycaemic control and insulin sensitivity in elderly Type 2 diabetic patients. Diabet Med 1998;15:772-9.
Kuusi T, Yki-Jarvinen H, Kauppinen-Makelin R, Jauhiainen M, Ehnholm C, Kauppila M, Seppala P, Viikari J,
Kujansuu E, Rajala S, Lahti J, Niskanen L, Marjanen T, Salo S, Ryysy L, Tulokas T, Taskinen M-R. Effect of
insulin treatment on serum lipoprotein (a) in non-insulin-dependent diabetes. Eur J Clin Invest 1995;25:194-200.
Kuusisto J, Mykkanen L, Pyorala K, Laakso M. NIDDM and its metabolic control predict coronary heart
disease in elderly subjects. Diabetes 1994;43:960-7.
Kuusisto J, Lempiainen P, Mykkanen L, Laakso M. Insulin resistance syndrome predicts coronary heart disease
events in elderly Type 2 diabetic men. Diabetes Care 2001;24:1629-33.
Laakso M. Epidemiology of diabetic dyslipidemia. Diabetes Rev 1995;3:408-22.
Laakso M, Pyorala K, Voutilainen E, Marniemi J. Plasma insulin and serum lipids and lipoproteins in middleaged non-insulin-dependent and non-diabetic patients. Am J Epidemiol 1987;125:611-21.
Lahdenpera S, Syvanne M, Kahri J, Taskinen MR. Regulation of low-density lipoprotein particle size
distribution in NIDDM and coronary disease: importance of serum triglycerides. Diabetologia 1996;39:453-61.
Laitinen JH, Ahola IE, Sarkkinen ES, Winberg RL, Harmaakorpi-Iivonen PA, Uusitupa MI. Impact of
intensified dietary therapy on energy and nutrient intakes and fatty acid composition of serum lipids in patients
with recently diagnosed non-insulin-dependent diabetes mellitus. J Am Diet Assoc 1993;93:276-83.
Lakatos J, Molnar M, Toth K. Efficacy and tolerance of 400 mg bezafibrate in diabetic and hyperlipidaemic
patients. Acta Physiologica Hungarica 1996;84:433-5.
Lalor BC, Bhatnagar D, Winocour PH, Ishola M, Arrol S, Brading M, Durrington PN. Placebo-controlled trial
of the effects of guar gum and metformin on fasting blood glucose and serum lipids in obese, Type 2 diabetic
patients. Diabet Med 1990;7:242-5.
Lam KSL, Cheng IKP, Janus ED, Pang RWC. Cholesterol-lowering therapy may retard the progression of
diabetic nephropathy. Diabetologia 1995;38:604-9.
Lam KSL, Pang RWC, Wat MS, Lauder IJ, Janus ED. Apolipoprotein (a) levels and phenotypes in NIDDM
patients with microalbuminuria and albuminuria. Nephrol Dial Transplant 1996;11:2229-36.
Lam TH, Liu LJ, Janust ED, Lam SL, Hedley AJ, for the Hong Kong Cardiovascular Risk Factor Prevalence
Study Steering Committee. Fibrinogen, other cardiovascular risk factors and diabetes mellitus in Hong Kong: a
community with high prevalence of Type 2 diabetes mellitus and impaired glucose tolerance. Diabet Med
2000;17:798-806.
Lampman RM, Schteingart DE. Effects of exercise training on glucose control, lipid metabolism, and insulin
sensitivity in hypertriglyceridemia and non-insulin dependent diabetes mellitus. Med Sci Sports Ex
1991;23:703-12.
Lane JT, Subbaiah PV, Otto ME, Bagdade JD. Lipoprotein composition and HDL particle size distribution in
women with non-insulin-dependent diabetes mellitus and the effects of probucal treatment. J Lab Clin Med
1991;118:120-8.
Latinen J, Uusitupa M, Ahola I, Siitonen O. Metabolic and dietary determinants of serum lipids in obese patients
with recently diagnosed non-insulin-dependent diabetes. Ann Med 1994;26:119-24.
205
Lavezzari M, Milanesi G, Oggioni E, Pamparana F. Results of a phase IV study carried out with acipimox in
Type II diabetic patients with concomitant hyperlipoproteinaemia. J Int Med Res 1989;17:373-80.
Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol
concentration lower risk of ischaemic heart disease? BMJ 1994;308:367-72.
Lawrence JR, Campbell GR, Barrington H, Malcolm EA, Brennan G, Wiles DH, Paterson JR. Clinical and
biochemical determinants of plasma lipid peroxide levels in type 2 diabetes. Ann Clin Biochem 1998;35:387-92.
Laws A, Marcus EB, Grove JS, Curb JD. Lipids and lipoproteins as risk factors for coronary heart disease in
men with abnormal glucose tolerance: the Honolulu Heart Program. J Int Med 1993;234:471-8.
Leatherdale B. HRT in diabetes: Time for action. Pract Diabetes Int 1998;15:70.
Lebovitz HE. Effects of oral antihyperglycemic agents in modifying macrovascular risk factors in Type 2
diabetes. Diabetes Care 1999;22(Suppl 3):C41-4.
Ledesma RL, Munari ACF, Dominguez BCH, Montalvo SC, Luna MHH, Juarez C, Lira SM. Monounsaturated
fatty acids (avocado) rich diet for mild hypercholesterolemia. Arch Med Res 1996;27:519-23.
Lee NA, Reasner CA. Beneficial effect of chromium supplementation on serum triglycerides levels in NIDDM.
Lees AM, Mok HYI, Lees RS, McCluskey MA, Grundy SM. Plant sterols as cholesterol-lowering agents:
clinical trials in patients with hypercholesterolemia and studies of sterol balance. Atherosclerosis 1977;28:32538.
Lehto S, Ronnemaa T, Pyorala K, Laakso M. Predictors of stroke in middle-aged patients with non-insulindependent diabetes. Stroke 1996;27:63-8.
Leonhardt W, Hanefeld M, Fischer S, Schulze J. Efficacy of alpha-glucosidase inhibitors on lipids in NIDDM
subjects with moderate hyperlipidaemia. Eur J Clin Invest 1994;24(Suppl 3):45-9.
Lerman-Garber I, Ichazo-Cerro S, Zamora-Gonzalez J, Cardoso-Saldana G, Posadas-Romero C. Effect of a
high-monounsaturated fat diet enriched with avocado in NIDDM patients. Diabetes Care 1994;17:311-5.
Lewis GF. Diabetic dyslipidemia: a case for aggressive intervention in the absence of clinical trial and cost
effectiveness data. Can J Cardiol 1995;11(Suppl C):24-9.
Lewis GF, O'Meara NM, Soltys PA, Blackman JD, Iverius PH, Pugh WL, Getz GS, Polonsky KS. Fasting
hypertriglyceridemia in noninsulin-dependent diabetes mellitus is an important predictor of postprandial lipid
and lipoprotein abnormalities. J Clin Endocrinol Metab 1991;72:934-45.
Lewis GF, Steiner G. Hypertriglyceridemia and its metabolic consequences as a risk factor for atherosclerotic
cardiovascular disease in non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1996;12:37-56.
Lilley SH, Spivey JM, Vadlamudi S, Otvos J, Cummings DM, Barakat H. Lipid and lipoprotein responses to
oral combined hormone replacement therapy in normolipemic obese women with controlled Type 2 diabetes
mellitus. J Clin Pharmacol 1998;38:1107-5.
Lindstrom T, Arnqvist HJ, Olsson AG. Effect of different insulin regimens on plasma lipoprotein and
apolipoprotein concentrations in patients with non-insulin-dependent diabetes mellitus. Atherosclerosis
1990;81:137-44.
Lindstrom T, Olsson AG, Von Schenck H, Wallentin L, Arnqvist HJ. Insulin treatment improves
microalbuminuria and other cardiovascular risk factors in patients with type 2 diabetes mellitus. J Intern Med
1994;235:253-61.
Liu GC, Coulston AM, Lardinois CK, Hollenbeck CB, Moore JG, Reaven GM. Moderate weight loss and
sulfonylurea treatment of non-insulin-dependent diabetes mellitus. Arch Intern Med 1985;145:665-9.
Lopes-Virella MFL, Stone PG, Colwell JA. Serum high density lipoprotein in diabetic patients. Diabetologia
1977;13:285-91.
206
Lu W, Resnick HE, Jablonski KA, Jones KL, Jain AK, Howard WJ, Robbins DC, Howard BV. Non-HDL
cholesterol as a predictor of cardiovascular disease in Type 2 diabetes. The Strong Heart Study. Diabetes Care
2003;26:16-23.
Lucas CP, Patton S, Stepke T, Kinhal V, Darga LL, Carroll-Michals L, Spafford TR, Kasim S. Achieving
therapeutic goals in insulin-using diabetic patients with non-insulin-dependent diabetes mellitus. A weight
reduction-exercise-oral agent approach. Am J Med 1987;83(Suppl 3A):3-9.
Ludvik B, Nolan JJ, Baloga J, Sacks D, Olefsky J. Effects of obesity on insulin resistance in normal subjects and
patients with NIDDM. Diabetes 1995;44:1121-5.
Liu DP, Molyneaux L, Chua E, Wang YZ, Wu CR, Jing H, Hu LN, Liu YJ, Xu ZR, Yue DK. Retinopathy in a
Chinese population with Type 2 diabetes: factors affecting the presence of complications at diagnosis of
diabetes. Diabetes Res Clin Prac 2002;56:125-31.
Luo J, Rizkalla SW, Vidal H, Oppert JM, Colas C, Boussairi A, Guerre-Millo M, Chapuis AS, Chevalier A,
Durand G, Slama G. Moderate intake of n-3 fatty acids for 2 months has no detrimental effect on glucose
metabolism and could ameliorate the lipid profile in type 2 diabetic men. Diabetes Care 1998;21:717-24.
Mani UV, Iyer U, Mani I, Desikachar HSR. Long-term effect of cereal-pulse mix (diabetic mix)
supplementation on serum lipid profile in non-insulin-dependent diabetes mellitus patients. J Nutr Environ Med
1997;7:163-8.
Mann JI. The role of nutritional modifications in the prevention of macrovascular complications of diabetes.
Diabetes 1997;46:(Suppl 2):125-30.
Manzato E, Crepaldi G. Dyslipoproteinaemia in manifest diabetes. J Intern Med 1994;236:27-31.
Marangou AG, Weber KM, Boston RC, Aitken PM, Heggie JCP, Kirsner RLG, Best JD, Alford FP. Metabolic
consequences of prolonged hyperinsulinemia in humans. Evidence for induction of insulin insensitivity.
Diabetes 1986;35:1383-9.
Martinez-Triguero M-L, Salvador A, Samper M-J, Almela M, Vega L, Mora A, Martinez-Diago V. Lipoprotein
(a) and other risk factors in patients with non-insulin-dependent diabetes mellitus. Coron Artery Dis 1994;5:75560.
Maxwell SRJ, Thomason H, Sandler D, LeGuen C, Baxter MA, Thorpe GHG, Jones AF, Barnett AH. Poor
glycaemic control is associated with reduced serum free radical scavenging (antioxidant) activity in non-insulindependent diabetes mellitus. Ann Clin Biochem 1997;34:638-44.
McCarron DA, Oparil S, Chait A, Haynes B, Kris-Etherton P, Stern JS, Resnick LM, Clark S, Morris CD,
Hatton DC, Metz JA, McMahon M, Holcomb S, Snyder GW, Pi-Sunyer FX. Nutritional management of
cardiovascular risk factors. A randomized clinical trial. Arch Intern Med 1997;157:169-77.
McColl AJ, Kong C, Nimmo L, Collins J, Elkeles RS, Richmond W. Total antioxidant status, protein glycation,
lipid hydroperoxides in non insulin dependent diabetes mellitus. Biochem Soc Trans 1997;25:660.
McGrath LT, Brennan GM, Donnelly JP, Johnston GD, Hayes JR, McVeigh GE. Effect of dietary fish oil
supplementation on peroxidation of serum lipids in patients with non-insulin dependent diabetes mellitus.
Atheroslerosis 1996;121:275-83.
McIntosh A, Hutchinson A, Feder G, Home P (2001). Clinical guidelines for Type 2 diabetes: Lipid
management. London, RCGP.
McKenney JM. Understanding and treating dyslipidemia associated with noninsulin-dependent diabetes mellitus
and hypertension. Pharmacotherapy 1993;13:340-52.
McManus RM, Jumpson J, Finegood DT, Clandinin MT, Ryan EA. A comparison of the effects of n-3 fatty
acids from linseed oil and fish oil in well-controlled Type II diabetes. Diabetes Care 1996;19:463-7.
Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised
controlled trial. BMJ 2002;325:1139-43.
207
Mero N, Syvanne M, Taskinen MR. Postprandial lipid metabolism in diabetes. Atherosclersis 1998;141(Suppl
1):S53-5.
Merrin PK, Feher MD, Elkeles RS. Diabetic macrovascular disease and serum lipids: is there a connection?
Diab Med 1992;9:9-14.
Miccoli R, Bertolotto A, Giovannitti MG, Tedesco I, Manfredi S, Galantini G, Navalesi R. Simvistatin for lipid
lowering cholesterol levels in non-insulin-dependent diabetes mellitus and in primary hypercholesterolemia.
Curr Ther Res 1992;51:66-74.
Miccoli R, Giovannitti MG, Ceraudo A, Anichini R, Dolci A, Trifiro R, Navalesi R. Effects of pravastatin
treatment on lipoprotein levels and composition in patients with Type 2 diabetes mellitus and
hypercholesterolaemia. Curr Ther Res Clin Exp 2000;61:107-18.
Michailidou G, Perea D, Katsilambros N. Monounsaturated fat and postprandial triglycerides levels in noninsulin-dependent diabetic persons. Diabet Med 1997;14:406-7.
Mikhail N. The use of niacin in diabetes mellitus. Arch Intern Med 2003;163:369-70.
Mikhailidis DP, Mathur S, Barradas MA, Dandona P. Bezafibrate retard in type II diabetic patients: effects on
hemostasis and glucose homeostasis. J Cardiovasc Pharmacol 1990;16(Suppl 9):26-9.
Miki E, Lu M, Lee ET, Keen H, Bennett PH, Russell D, Fuller J. The incidence of visual impairment and its
determinants in the WHO multinational study of vascular disease in diabetes. Diabetologia 2001;44(Suppl
2):S31-6.
Mogensen CE. Natural history of cardiovascular and renal disease in patients with type 2 diabetes: effect of
therapeutic interventions and risk modification. Am J Cardiol 1998;82(9B):R4-8.
Mohan V, Deepa R, Haranath SP, Premalatha G, Rema M, Sastry NG, Enas EA. Lipoprotein (a) is an
independent risk factor for coronary artery disease in NIDDM patients in South India. Diabetes Care
1998;21:1819-23.
Mohan V, Deepa R, Rani SS, Premalatha G; Chennai Urban Population Study (CUPS No.5). Prevalence of
coronary artery disease and its relationship to lipids in a selected population in South India: The Chennai Urban
Population Study (CUPS No. 5). J Am Coll Cardiol 2001;38:682-7.
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity,
diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76-9.
Molnar GD, Berge KG, Rosevear JW, McGuckin WF, Achor RW. The effect of nicotinic acid in diabetes
Monk A, Barry B, McClain K, Weaver T, Cooper N, Franz MJ. Practice guidelines for medical nutrition therapy
provided by dietitians for persons with non-insulin-dependent diabetes mellitus. J Am Diet Assoc 1995;95:9991006.
Mooradian AD. Increased serum conjugated dienes in elderly diabetic patients. J Am Geriatr Soc 1991;39:5714.
Morgan WA, Raskin P, Rosenstock J. A comparison of fish oil or corn oil supplements in hyperlipidemic
subjects with NIDDM. Diabetes Care 1995;18:83-6.
Mori TA. Fish oils, dyslipidaemia and glycaemic control in diabetes. Pract Diabetes Int 1999;16:223-6.
Mori TA, Vandongen R, Masarei JR, Rouse IL, Dunbar D. Comparison of diets supplemented with fish oil or
olive oil on plasma lipoproteins in insulin-dependent diabetics. Metabolism 1991;40:241-6.
Morisaki N, Yokote K, Tashiro J, Inadera H, Kobayashi J, Kanzaki T, Saito Y, Yoshida S. Lipoprotein(a) is a
risk factor for diabetic retinopathy in the elderly. J Am Geriatr Soc 1994;42:965-7.
208
Morrish NJ, Stevens LK, Fuller JH, Jarrett RJ, Keen H. Risk factors for macrovascular disease in diabetes
mellitus: the London follow-up to the WHO Multinational Study of Vascular Disease in Diabetics. Diabetologia
1991;34:590-4.
Murakami T, Yamada N, Kawakubo K, Oku J, Mizushima Y, Iino S, Sugimoto T. Lipoprotein abnormalities in
non-insulin dependent diabetic patients with ischemic heart disease. Artery 1997;22:206-32.
Myers J, Atwood JE, Froelicher V. Active lifestyle and diabetes. Circulation 2003;107:2392-4.
Nagi DK, Yudkin JS. Effect of metformin on insulin resistance, risk factors for cardiovascular disease, and
plasminogen activator inhibitor in NIDDM subjects. Diabetes Care 1993;16:621-9.
Nakata H, Horita K, Eto M. Alterations of lipoprotein(a) concentration with glycemic control in non-insulindependent diabetic subjects without diabetic complications. Metabolism 1993;42:1323-6.
Nash DT. Statins: Evidence of effectiveness in older patients. Geriatrics 2003;58:35-42.
Nathan DM, Meigs J, Singer DE. The epidemiology of cardiovascular disease in type 2 diabetes mellitus: How
sweet it is...or is it? Lancet 1997;350(Suppl 1):SI4-9.
National Cholesterol Education Program Expert Panel on Detection Evaluation and Treatment of High Blood
Cholesterol in Adults. Report of the National Cholesterol Education Program Expert Panel on Detection,
Evaluation and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988;148:36-68.
National Heart Foundation. www.heartfoundation.com.au. 2001.
National Institutes of Health Consensus Development Panel. Treatment of hypertriglyceridemia. NIH Consensus
Development Conference summary. Arteriosclerosis 1984;4:296-301.
Nicholl JP, Coleman P, Brazier JE. Health and healthcare costs and benefits of exercise. Pharmacoeconomics
1994;5:109-22.
Nielsen FS, Rossing P, Gall MA, Skott P, Smidt UM, Parving HH. Long-term effects of lisinopril and atenolol
on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes 1997;46:1182-8.
Niort G, Gambino R, Cassader M, Pagano G. Bezafibrate affects lipid, lipo- and apolipoprotein pattern in noninsulin-dependent diabetic patients. Horm Metab Res 1993;25:372-4.
Notarbartolo A, Galletti F, Averna MR, Barbagallo CM, Piliego T. Effects of gemfibrozil in hyperlipidemic
patients with or without diabetes. Curr Ther Res 1993;53:381-93.
Nourooz-Zadeh J, Tajaddini-Sarmadi J, McCarthy S, Betteridge DJ, Wolff SP. Elevated levels of authentic
plasma hydroperoxides in NIDDM. Diabetes 1995;44:1054-8.
O'Brien SF, Watts GF, Playford DA, Burke V, O'Neal DN, Best JD. Low-density lipoprotein size, high-density
lipoprotein concentration, and endothelial dysfunction in non-insulin-dependent diabetes. Diabet Med
1997;14:974-8.
O'Brien T, Nguyen TT, Hallaway BJ, Hodge D, Bailey K, Kottke BK. HDL subparticles and coronary artery
disease in NIDDM. Atherosclerosis 1996;121:285-91.
O'Brien T, Nguyen TT, Zimmerman BR. Hyperlipidemia and diabetes mellitus. Mayo Clin Proc 1998;73:96976.
Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Rancho Bernardo Study. Endogenous sex hormones and
the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care
2002;25:55-60.
Ohrvall M, Lithell H, Johansson J, Vessby B. A comparison between the effects of gemfibrozil and simvastatin
on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia.
Metabolism 1995;44:212-7.
209
Oi K, Komori H. Escape phenomenon with pravastatin during long-term treatment of patients with
hyperlipidemia associated with diabetes mellitus. Curr Ther Res 1998;59:130-8.
Okada S, Ishii K, Hamada H, Tanokuchi S, Ichiki K, Ota Z. The effect of an alpha-glucosidase inhibitor and
insulin on glucose metabolism and lipid profiles in non-insulin-dependent diabetes mellitus. J Int Med Res
1996;24:438-47.
Okada S, Ishii K, Tanokuchi S, Hamada H, Ichiki K, Ota Z. Effect of alpha-glucosidase inhibitor in combination
with sulphonylurea compounds on lipid profile in patients with non-insulin-dependent diabetes mellitus. J Int
Med Res 1995;23:492-6.
Okada S, Miyai Y, Ichiki K, Sato K, Masaki Y, Higuchi T, Ogino Y, Ota Z. Clinofibrate therapy raises highdensity lipoprotein levels and lowers atherogenic index in diabetes mellitus patients. J Int Med Res
1989;17:521-5.
Okubo M, Murase T. Hypertriglyceridemia and low HDL cholesterol in Japanese patients with NIDDM.
Diabetes 1996;45(Suppl 3):S123-5.
O'Neal DN, Lewicki J, Ansari MZ, Matthews PG, Best JD. Lipid levels and peripheral vascular disease in
diabetic and non-diabetic subjects. Atherosclerosis 1998;136:1-8.
Onuma T, Kikuchi T, Tsutsui M, Shimura S, Matsui J, Boku A, Takebe K. High incidence of diabetic
nephropathy in non-insulin-dependent diabetic patients with heterozygous familial hypercholesterolemia. Curr
Ther Res 1994;55:532-6.
Orchard TJ. Dyslipoproteinemia and diabetes. Endocrinol Metab Clin North Am 1990;19:361-80.
Orloff DG, Blazing MA, O'Connor CM. Atherosclerosis disease in non-insulin-dependent diabetes mellitus: role
of abnormal lipids and the place for lipid-altering therapies. Am Heart J 1999;138:S406-12.
Ostgren CJ, Lindblad U, Bog-Hansen E, Ranstam J, Melander A, Rastam L. Differences in treatment and
metabolic abnormalities between normo- and hypertensive patients with Type 2 diabetes: the Skaraborg
Hypertension and Diabetes Project. Diabetes Obes Metab 1999;1:105-12.
Owens D, Stinson J, Collins P, Johnson A, Tomkin GH. Improvement in the regulation of cellular
cholesterologenesis in diabetes: the effect of reduction in serum cholesterol by simvastatin. Diabet Med
1991;8:151-6.
Ozdemirler G, Mehmetcik G, Oztezcan S, Toker G, Sivas A, Uysal M. Peroxidation potential and antioxidant
activity of serum in patients with diabetes mellitus and myocardial infarction. Horm Metab Res 1995;27:194-6.
Page RCL, Harnden KE, Walravens NKN, Onslow C, Sutton P, Levy JC, Hockaday DTR, Turner RC. 'Healthy
living' and sulphonylurea therapy have different effects on glucose tolerance and risk factors for vascular disease
in subjects with impaired glucose tolerance. Quart J Med 1993;86:145-54.
Paisey R, Elkeles RS, Hambley J, Magill P. The effects of chlorpropamide and insulin on serum lipids,
lipoproteins and fractional triglycerides removal. Diabetelogia 1978;15:81-5.
Paisey RB, Harvey P, Rice S, Belka I, Bower L, Dunn M, Taylor P, Paisey RM, Frost J, Ash I. An intensive
weight loss programme in established type 2 diabetes and controls: effects on weight and atherosclerosis risk
factors at 1 year. Diabet Med 1998;15:73-9.
Paisey RB, Frost J, Harvey P, Paisey A, Bower L, Paisey RM, Taylor P, Belka I. Five year results of a
prospective very low calorie diet or conventional weight loss programme in type 2 diabetes. J Hum Nutr Dietet
2002;15:121-7.
Palin SL, Kumar S, Sturdee DW, Barnett AH. HRT in women with diabetes - review of the effects on glucose
and lipid metabolism. Diabetes Res Clin Pract 2001;54:67-77.
Palumbo PJ. Metformin: effects on cardiovascular risk factors in patients with non-insulin-dependent diabetes
mellitus. J Diabetes Complications 1998;12:110-9.
210
Pan XR, Walden CE, Warnick GR, Hu SX, Albers JJ, Cheung M, Bierman EL. Comparison of plasma
lipoproteins and apoproteins in Chinese and American non-insulin-dependent diabetic subjects and controls.
Paolisso G, Sgambato S, De Riu S, Gambardella A, Verza M, Varricchio M, D'Onofrio F. Simvastatin reduces
plasma lipid levels and improves insulin action in elderly, non-insulin dependent diabetics. Eur J Clin
Pharmacol 1991;40:27-31.
Papadakis JA, Milionis HJ, Press M, Mikhailidis DP. Treating dyslipidaemia in non-insulin-dependent diabetes
mellitus - a special reference to statins. J Diabetes Complications 2001;15:211-26.
Parfitt VJ, Hopton M, Taberner J, Bolton C, Hartog M. The effects of high monounsaturated and
polyunsaturated fat diets on vascular endothelium and the coagulation system in non-insulin dependent diabetes
mellitus--related to changes in lipid peroxidation? Biochem Soc Trans 1993;21:S103.
Parillo M, Rivellese AA, Ciardullo AV, Capaldo B, Giacco A, Genovese S, Riccardi G. A highmonounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent
diabetic patients. Metabolism 1992;41:1373-8.
Parving HH, Gall MA, Nielsen FS. Dyslipidaemia and cardiovascular disease in non-insulin-dependent diabetic
patients with and without diabetic nephropathy. J Intern Med 1994;236(Suppl 736):89-94.
Pascale RW, Wing RR, Butler BA, Mullen M, Bononi P. Effects of a behavioral weight loss program stressing
calorie restriction versus calorie plus fat restriction in obese individuals with NIDDM or a family history of
Patel J, Anderson RJ, Rappaport EB. Rosiglitazone monotherapy improves glycaemic control in patients with
type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diabetes Obes Metab 1999;1:165-72.
Patti L, Maffettone A, Iovine C, Marino LD, Annuzzi G, Riccardi G, Rivellese AA. Long-term effects of fish oil
on lipoprotein subfractions and low density lipoprotein size in non-insulin-dependent diabetic patients with
hypertriglyceridemia. Atherosclerosis 1999;146:361-7.
Pauciullo P, Mancini M. Treatment challenges in hypercholesterolemia. Cardiovasc Drugs Ther 1998;12:32537.
Pekkanen J, Linn S, Heiss G, Suchindran CM, Leon A, Rifkind BM, Tyroler HA. Ten-year mortality from
cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular
disease. N Engl J Med 1990;322:1700-7.
Pelikanova T, Kohout M, Valek J, Kazdova L, Base J. Metabolic effects of omega-3 fatty acids in type 2 (noninsulin-dependent) diabetic patients. Ann NY Acad Sci 1993;683:272-8.
Perez A, Carreras G, Caixas A, Castellvi A, Caballero A, Bonet R, Ordonez-Llanos J, DeLeiva A. Plasma
lipoprotein (a) levels are not influenced by glycemic control in Type 1 diabetes. Diabetes Care 1998;21:151720.
Perriello G, Misericordia P, Volpi E, Santucci A, Santucci C, Ferrannini E, Ventura MM, Santeusanio F,
Brunetti P, Bolli GB. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression
of lipid oxidation and hepatic glucose production. Diabetes 1994;43:920-8.
Peterson DB, Fisher K, Carter RD, Mann J. Fatty acid composition of erythrocytes and plasma triglyceride and
cardiovascular risk in Asian diabetic patients. Lancet 1994;343:1528-30.
Pfeffer MA, Keech A, Sacks FM, Cobbe SM, Tonkin A, Byington RP, Davis BR, Friedman CP, Braunwald E.
Safety and tolerability of pravastatin in long-term clinical trials. Prospective Pravastatin Pooling (PPP) Project.
Circulation 2002;105:2341-6.
Pfeifer MA, Brunzell JD, Best JD, Judzewitsch RG, Halter JB, Porte D Jr. The response of plasma triglycerides,
cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial
hypertriglyceridemia. Diabetes 1983;32:525-31.
211
Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, Salzman A; Rosiglitazone Clinical Trials
Study Group. Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2
Picard S, Talussot C, Serusclat A, Ambrosio N, Berthezene F. Minimally oxidised LDL as estimated by a new
method increase in plasma of type 2 diabetic patients with atherosclerosis or nephropathy. Diabetes Metab
1996;22:25-30.
Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick
LS. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin
versus Revascularization Treatment Investigators. N Engl J Med 1999;341:70-6.
Pontiroli AE, Calderara A, Bonisolli L, De Pasqua A, Maffi P, Margonato A, Radaelli G, Gallus G, Pozza G.
Risk factors for micro- and macroangiopathic complications in Type 2 diabetes: lack of association with
acetylator phenotype, chlorpropamide alcohol flush and ABO and Rh blood groups. Diabete Metab
1987;13:444-9.
Pontrelli L, Parris W, Adeli K, Cheung RC. Atorvastatin treatment beneficially alters the lipoprotein profile and
increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting
glucose/type 2 diabetes. Metabolism 2002;51:334-42.
Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density
lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronaryartery bypass grafts. N Engl J Med 1997;336:153-62.
Prince MJ, Deeg MA. Do n-3 fatty acids improve glucose tolerance and lipemia in diabetics? Curr Opin Lipidol
1997;8:7-11.
Purnell JQ, Brunzell JD. Effect of intensive diabetes therapy on diabetic dyslipidemia. Diabetes Rev
1997;5:434-44.
Pyorala K, Steiner G. Will correction of dyslipoproteinaemia reduce coronary heart disease risk in patients with
non-insulin-dependent diabetes? Need for trial evidence. Ann Med 1996;28:357-62.
Rabkin SW, Boyko E, Streja DA. Changes in high density lipoprotein cholesterol after initiation of insulin
therapy in non-insulin-dependent diabetes mellitus: relationship to changes in body weight. Am J Med Sci
1983;285:14-20.
Raeini-Sarjaz M, Vanstone CA, Papamandjaris AA, Wykes LJ, Jones PJ. Comparison of the effect of dietary fat
restriction with that of energy restriction on human lipid metabolism. Am J Clin Nutr 2001;73:262-7.
Rains SG, Wilson GA, Richmond W, Elkeles RS. The reduction of low density lipoprotein cholesterol by
metformin is maintained with long-term therapy. J Roy Soc Med 1989;82:93-4.
Rainwater DL, MacCluer JW, Stern MP, VandeBerg JL, Haffner SM. Effects of NIDDM on lipoprotein (a)
concentration and apolipoprotein (a) size. Diabetes 1994;43:942-6.
Ramirez LC, Arauz-Pacheco C, Lackner C, Albright G, Adams BV, Raskin P. Lipoprotein (a) levels in diabetes
mellitus: relationship to metabolic control. Ann Intern Med 1992;117:42-7.
Raskin P, Ganda OP, Schwartz S, Willard D, Rosenstock J, Lodewick PA, Cressman MD, Phillipson B, Weiner
B, McGovern ME. Norton JM, Cucinotta GG, Behounek BD. Efficacy and safety of pravastatin in the treatment
of patients with type 1 or type 2 diabetes mellitus and hypercholesterolemia. Am J Med 1995;99:362-9.
Raskin P, Rappaport EB, Cole ST, Yan Y, Patwardhan R, Freed MI. Rosiglitazone short-term monotherapy
lowers fasting and post-prandial glucose in patients with type 2 diabetes. Diabetologia 2000;43:278-84.
Rasmussen OW, Thomsen C, Hansen KW, Vesterlund M, Winther E, Hermansen K. Effects on blood pressure,
glucose, and lipid levels of a high-monounsaturated fat diet compared with a high-carbohydrate diet in NIDDM
subjects. Diabetes Care 1993;16:1565-71.
Ravid M, Neumann L, Lishner M. Plasma lipids and the progression of nephropathy in diabetes mellitus type II:
effect of ACE inhibitors. Kidney Int 1995;47:907-10.
212
Raz I, Hauser E, Bursztyn M. Moderate exercise improves glucose metabolism in uncontrolled elderly patients
with non-insulin-dependent diabetes mellitus. Isr J Med Sci 1994;30:766-70.
Reavan GM. Beneficial effect of moderate weight loss in older patients with non- insulin dependent diabetes
mellitus poorly controlled with insulin. J Am Geriatr Soc 1985;33:93-5.
Reaven GM. Effect of metformin on various aspects of glucose, insulin and lipid metabolism in patients with
non-insulin-dependent diabetes mellitus with varying degrees of hyperglycemia. Diabetes Metab Rev
1995;11(Suppl 1):97-108.
Reaven P. Dietary and pharmacologic regimens to reduce lipid peroxidation in non-insulin-dependent diabetes
mellitus. Am J Clin Nutr 1995;62(Suppl 6):S1483-9.
Reaven P, Grasse B, Barnett J. Effect of antioxidants alone and in combination with monounsaturated fatty acidenriched diets on lipoprotein oxidation. Arterioscler Thromb Vasc Biol 1996;16:1465-72.
Reaven GM, Johnston P, Hollenbeck CB, Skowronski R, Zhang JC, Goldfine ID, Chen YD. Combined
metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic
control. J Clin Endocrinol Metab 1992;74:1020-6.
Relimpio F, Pumar A, Losada F, Molina J, Maynar A, Acosta D, Astorga R. Urinary albumin excretion rate and
cardiovascular disease in Spaniard type 2 diabetic patients. Diabetes Res Clin Pract 1997;36:127-34.
Relimpio F, Pumar A, Losada F, Montilla C, Morales F, Acosta D, Astorga R. Lack of association of lipoprotein
(a) with coronary heart disease in Spaniard type 2 diabetic patients. Diabetes Res Clin Pract 1997;35:135-41.
Reverter JL, Senti M, Rubies-Prat J, Lucas A, Salinas I, Pizarro E, Pedro-Botet J, Romero R, Sanmarti A.
Relationship between lipoprotein profile and urinary albumin excretion in type II diabetic patients with stable
metabolic control. Diabetes Care 1994;17:189-94.
Riccardi G, Genovese S, Saldalamacchia G, Patti L, Marotta G, Postiglione A, Rivellese A, Capaldo B, Mancini
M. Effects of bezafibrate on insulin secretion and peripheral insulin sensitivity in hyperlipidemic patients with
and without diabetes. Atherosclerosis 1989;75:175-81.
Riccardi G, Parillo M. Comparison of the metabolic effects of fat-modified vs low fat diets. Ann NY Acad Sci
1993;683:192-8.
Riccardi G, Rivellese AA. Effects of dietary fiber and carbohydrate on glucose and lipoprotein metabolism in
diabetic patients. Diabetes Care 1991;14:1115-25.
Riegger G, Abletshauser C, Ludwig M, Schwandt P, Widimsky J, Weidinger G, Welzel D. The effect of
fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment.
Ritz E. Why are lipids not predictive of cardiovascular death in the dialysis patient? Miner Electrolyte Metab
1996;22:9-12.
Rivellese AA, Auletta P, Marotta G, Saldalamacchia G, Giacco A, Mastrilli V, Vaccaro O, Riccardi G. Long
term metabolic effects of two dietary methods of treating hyperlipidaemia. BMJ 1994;308:227-31.
Rivellese AA, De Natale C, Lilli S. Type of dietary fat and insulin resistance. Ann NY Acad Sci 2002;967:32935.
Rivellese AA, Giacco R, Genovese S, Patti L, Marotta G, Pacioni D, Annuzzi G, Riccardi G. Effects of
changing amount of carbohydrate in diet on plasma lipoproteins and apolipoproteins in Type II diabetic patients.
Rivellese AA, Maffettone A, Iovine C, Di Marino L, Annuzzi G, Mancini M, Riccardi G. Long-term effects of
fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes
Care 1996;19:1207-13.
213
Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, Collins D; Veterans Affairs HDL
Intervention Trial (VA-HIT). Insulin resistance and cardiovascular events with low HDL cholesterol: the
Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care 2003;26:1513-7.
Robinson AC, Burke J, Robinson S, Johnston DG, Elkeles RS. The effects of metformin on glycemic control
and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care
1998;21:701-5.
Romano G, Patti L, Innelli F, Di Marino L, Annuzzi G, Iavicoli M, Coronel GA, Riccardi G, Rivellese AA.
Insulin and sulfonylurea therapy in NIDDM patients. Are the effects on lipoprotein metabolism different even
with similar blood glucose control?. Diabetes 1997;46:1601-6.
Roselli della Rovere G, Lapolla A, Sartore G, Rossetti C, Zambon S, Minicuci N, Crepaldi G, Fedele D,
Manzato E. Nutr Metab Cardiovasc Dis 2003;13:46-51.
Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 1990;13:610-30.
Rubies-Prat J, Reverter JL, Senti M, Pedro-Botet J, Salinas I. Lucas A, Nogues X, Sanmarti A. Calculated lowdensity lipoprotein cholesterol should not be used for management of lipoprotein abnormalities in patients with
diabetes mellitus. Diabetes Care 1993;16:1081-6.
Rubinstein A, Maritz FJ, Soule SG, Markel A, Chajek-Shaul T, Maislos M, Tal S, Stolero D. Efficacy and
safety of cerivstatin for type 2 diabetes and gypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus
investigators. J Cardiovasc Risk 1999;6:399-403.
Ruderman N, Horton E, Kemmer F, Berger M. The lost symposium. Diabetes and exercise 1990. Diabetes Care
1993;16:959-60.
Rustemeijer C, Schouten JA, Janssens EN, Spooren PF, van Doormaal JJ. Pravastatin in diabetes-associated
hypercholesterolemia. Acta Diabetol 1997;34:294-300.
Salonen R, Nyyssonen K, Porkkala E, Rummukainen J, Belder R, Park JS, Salonen JT. Kuopio Atherosclerosis
Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on
atherosclerotic progression in carotid and femoral arteries. Circulation 1995;92:1758-64.
Saloranta C, Groop L, Ekstrand A, Franssila-Kallunki A, Eriksson J, Taskinen MR. Different acute and chronic
effects of acipimox treatment on glucose and lipid metabolism in patients with type 2 diabetes. Diabet Med
1993;10:950-7.
Samaras K, Hayward CS, Sullivan D, Kelly RP, Campbell LV. Effects of postmenopausal hormone replacement
therapy on central abdominal fat, glycaemic control, lipid metabolism, and vascular factors in Type 2 diabetes.
A prospective study. Diabetes Care 1999;22:1401-7.
Sarkkinen ES, Uusitupa MI, Gylling H, Miettinen TA. Fat-modified diets influence serum concentrations of
cholesterol precursors and plant sterols in hypercholesterolemmic subjects. Metabolism 1998;47:744-50.
Sarlund H, Pyorala K, Penttila I, Laakso M. Early abnormalities in coronary heart disease risk factors in
relatives of subjects with non-insulin-dependent diabetes. Atheroscler Thomb 1992;12:657-63.
Sartor G, Ursing D, Nilsson-Ehle P, Wahlin-Boll E, Melander A. Lack of primary effect of sulphonylurea
(glipizide) on plasma lipoproteins and insulin action in former Type 2 diabetics with attenuated insulin
secretion. Eur J Clin Pharmacol 1987;33:279-82.
Sasaki A, Horiuchi N, Hasegawa K, Uehara M. Mortality from coronary heart disease and cerebrovascular
disease and associated risk factors in diabetic patients in Osaka District, Japan. Diabetes Res Clin Pract
1995;27:77-83.
Sattar N, McKenzie J, MacCuish AC, Jaap AJ. Hormone replacement therapy in type 2 diabetes mellitus: a
cardiovascular perspective. Diabet Med 1998;15:631-3.
Sawayama Y, Shimizu C, Maeda N, Tatsukawa M, Kinukawa N, Koyanagi S, Kashiwagi S, Hayashi J. Effects
of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic
hypercholesterolemia. Fukuoka Atherosclerosis Trial (FAST). J Am Coll Cardiolo 2002;39:610-6.
214
Scanu AM. Genetic basis and pathophysiological implications of high plasma Lp(a) levels. J Intern Med
1992;231:679-83.
Schaper NC. Early atherogenesis in diabetes mellitus. Diabet Med 1996;13(Suppl):S23-5.
Schartl M, Bocksch W, Koschyk DH, Voelker W, Karsch KR, Kreuzer J, Hausmann D, Beckmann S, Gross M.
Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque
volume and composition in patients with coronary artery disease. Circulation 2001;104:387-92.
Schectman G, Kaul S, Cherayil GD, Lee M, Kissebah A. Can the hypotriglyceridemic effect of fish oil
concentrate be sustained? Ann Intern Med 1989;110:346-52.
Schectman G, Kaul S, Kissebah AH. Effect of fish oil concentrate on lipoprotein composition in NIDDM.
Diabetes 1988;37:1567-73.
Schernthaner G. Cardiovascular mortality and morbidity in type-2 diabetes mellitus. Diabetes Res Clin Pract
1996;31(Suppl 1):S3-13.
Schleiffer T, Hellstern P, Freitag M, Brass H. Plasminogen activator inhibitor 1 activity and lipoprotein(a) in
nephropathic patients with non-insulin-dependent diabetes mellitus versus patients with nondiabetic
nephropathy. Haemostasis 1994;24:49-54.
Schonfeld G. Hypertriglyceridemia in noninsulin dependent diabetes mellitus. Semin Thromb Hemost
1988;14:184-8.
Schranz AG. Abnormal glucose tolerance in the Maltese. A population-based longitudinal study of the natural
history of NIDDM and IGT in Malta. Diabetes Res Clin Pract 1989;7:7-16.
Schwandt P. Very low density lipoproteins in Type II diabetes mellitus and risk of atherosclerosis. Horm Metab
Res 1985;15:80-3.
Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S,
Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study
Investigators. Effects of atorvastatin on early recurrent ischaemic events in acute coronary syndromes: the
MIRACL study: a randomized controlled trial. JAMA 2001;285:1711-8.
Schwenke DC, D'Agostino RB Jr, Goff DC Jr, Karter AJ, Rewers MJ, Wagenknecht LE. Insulin resistance
atherosclerosis study. Differences in LDL oxidizability by glycemic status: the insulin resistance atherosclerosis
study. Diabetes Care 2003;26:1449-55.
Scott RS, Florkowski CM, Lipid and Diabetes Research Group. Noninsulin dependent diabetes mellitus: the
importance of dyslipidaemia. NZ Med J 1994;107:155-6.
Seghieri G, Alviggi L, De Giorgio LA, Breschi C, Gironi A, Niccolai M, Bartolomei GC. Serum lipids and
lipoproteins in Type 2 diabetic patients with persistent microalbuminuria. Diabet Med 1990;7:810-4.
Serruys PW, Foley DP, Jackson G, Bonnier H, Macaya C, Vrolix M, Branzi A, Shepherd J, suryapranata H, de
Feyter PJ, Melkert R, van Es GA, Pfister PJ. A randomised placebo-controlled trial of fluvastatin for prevention
of restenosis after successful coronary bollon angioplasty. Euro Heart J 1999;20:58-69.
Sheffield JVL. General medicine update: NIDDM, prevention of CAD, and risks and benefits of hormone
replacement therapy. Compr Ther 1997;23:303-9.
Shen DC, Fuh MM, Shieh SM, Chen YD, Reaven GM. Effect of gemfibrozil treatment in sulphonylurea-treated
patients with non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1991;73:503-10.
Shepherd J, Packard CJ, Patsch JR, Gotto AM Jr, Taunton OD. Effects fo dietary polyunsaturated and saturated
fat on the properties of high-density lipoprotein and the metabolism of apoliporotein A-1. J Clin Invest
1978;61:1582-92.
215
Shih KC, Kwok CF, Hwu CM, Hsiao LC, Li SH, Liu YF, Ho LT. Acipimox attenuates hypertriglyceridemia in
dyslipidemic noninsulin dependent diabetes mellitus patients without perturbation of insulin sensitivity and
glycemic control. Diabetes Res Clin Pract 1997;36:113-9.
Simonson DC, Kourides IA, Feinglos M, Shamoon H, Fischette CT. Efficacy, safety, and dose-response
characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in
NIDDM. Results of two multicenter, randomized, placebo-controlled clinical trials. The Glipizide
Gastrointestinal Therapeutic System Study Group. Diabetes Care 1997;20:597-606.
Simopoulos A. n-3 fatty acids in the prevention-management of cardiovascular disease. Can J Physiol
Pharmacol 1997;75:234-9.
Simpson RW, Mann JI, Hockaday TD, Hockaday JM, Turner RC, Jelfs R. Lipid abnormalities in untreated
maturity-onset diabetes and the effect of treatment. Diabetologia 1979;16:101-6.
Sinha R, Ismail A, Herbert S, Hoyte R, Gill G. Effect of diet and fenofibrate on lipid and glycaemic control in
type 2 diabetes. Pract Diabetes Int 2001;18:269-73.
Sironi AM, Vichi S, Gastaldelli A, Pecori N, Anichini R, Foot E, Seghieri G, Ferrannini E. Effects of
troglitazone on insulin action and cardiovascular risk factors in patients with non-insulin-dependent diabetes.
Clin Pharmacol Ther 1997;62:194-202.
Sirtori CR, Crepaldi G, Manzato E, Mancini M, Rivellese A, Paoletti R, Pazzucconi F, Pamparana F, Stragliotto
E. One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose
intolerance: reduced triglyceridemia, total cholesterol and increased HDL-C without glycemic alterations.
Smellie WSA, Sandler D, O'Donnell J. Hyperlipidaemia and diabetes. Ann Clin Biochem 1993;30:331-2.
Smellie WS, Sandler D, O'Donnell J, MacCuish AC. Screening and treatment for hyperlipidaemia in noninsulin-dependent diabetes: a prospective assessment of 350 patients. Br J Clin Pract 1995;49:83-5.
Smud R, Sermukslis B. Bezafibrate and fenofibrate in type II diabetics with hyperlipoproteinaemia. Curr Med
Res Opin 1987;10:612-24.
Sobel BE. Altered fibrinolysis and platelet function in the development of vascular complications of diabetes.
Curr Opin Endocrinol Diabetes 1996;3:355-60.
Solomon CG. Reducing cardiovascular risk in Type 2 diabetes. N Engl J Med 2003;348:457-9.
Solomon CG, Hu FB, Stampfer MJ, Colditz GA, Speizer FE, Rimm EB, Willett WC, Manson JE. Moderate
alcohol consumption and risk of coronary heart disease among women with type 2 diabetes mellitus. Circulation
2000;102:494-9.
Sosenko JM, Kato M, Soto R, Goldberg RB. Plasma lipid levels at diagnosis in Type 2 diabetic patients. Diabet
Med 1993;10:814-9.
Sotaniemi EA, Haapakoski E, Rautio A. Ginseng therapy in non-insulin-dependent diabetic patients. Effects on
psychophysical performance, glucose homeostasis, serum lipids, serum aminoterminalpropeptide concentration,
and body weight. Diabetes Care 1995;18:1373-5.
Sprecher DL, Watkins TR, Behar S, Brown WV, Rubins HB, Schaefer EJ. Importance of high-density
lipoprotein cholesterol and triglyceride levels in coronary heart disease. Am J Cardiol 2003;91:575-80.
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of lowdensity lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-24.
Steiner G. The Diabetes Atherosclerosis Intervention Study (DAIS): A study conducted in cooperation with the
World Health Organization. Diabetologia 1996;39:1655-61.
Steiner G. Altering triglycerides concentrations changes insulin-glucose relationships in hypertriglyceridemic
patients. Double-blind study with gemfibrozil with implications for atherosclerosis. Diabetes Care
1991;14:1077-81.
216
Steiner G. Intermediate-density lipoproteins, diabetes and coronary artery disease. Diabetes Res Clin Pract
1998;40(Suppl 1):S29-33.
Steiner G. Risk factors for macrovascular disease in Type 2 diabetes. Diabetes Care 1999;22(Suppl 3):C6-9.
Steiner G, Stewart D, Hosking JD. Baseline characteristics of the study population in the Diabetes
Atherosclerosis Intervention Study (DAIS). World Health Organization Collaborating Centre for the Study of
Atherosclerosis in Diabetes. Am J Cardiol 1999;84:1004-10.
Steiner G, Tkac I, Uffelman KD, Lewis GF. Important contribution of lipoprotein particle number to plasma
triglycerides concentration in type 2 diabetes. Atherosclerosis 1998;137:211-4.
Stern MP. Diabetes and cardiovascular disease. The "Common Soil" hypothesis. Diabetes 1995;44:369-74.
Stern MP, Haffner SM. Dyslipidemia in type II diabetes. Implications for therapeutic intervention. Diabetes
Care 1991;14:1144-59.
Stewart JM, Kilpatrick ES, Cathcart S, Small M, Dominiczak MH. Low-density lipoprotein particle size in type
2 diabetic patients and age matched controls. Ann Clin Biochem 1994;31:153-9.
Stewart MW, Dyer RG, Alberti KGMM, Laker MF. The effects of lipid lowering drugs on metabolic control
and lipoprotein composition in type 2 diabetic patients with mild hyperlipidaemia. Diabet Med 1995;12:250-7.
Stewart MW, Laker MF, Alberti KGMM. The contribution of lipids to coronary heart disease in diabetes
mellitus. J Int Med 1994;236(Suppl 736):41-6.
Stewart MW, Laker MF, Dyer RG, Game F, Mitcheson J, Winocour PH, Alberti KG. Lipoprotein compositional
abnormalities and insulin resistance in type II diabetic patients with mild hyperlipidemia. Arterioscler Thromb
1993;13:1046-52.
Steyn K, Weich HFH, Bonnici F, Kotze TJW, Stander I, Vermaak WJH, Lourens W, Van Lathem J, Omar
MAK, Fourie J. Simvastatin in non-insulin-dependent diabetic patients with hypercholesterolaemia. S Afr Med J
1992;82:402-6.
Storm H, Thomsen C, Pedersen E, Rasmussen O, Christiansen C, Hermansen K. Comparison of a carbohydraterich diet and diets rich in stearic or palmitic acid in NIDDM patients: Effects on lipids, glycemic control, and
diurnal blood pressure. Diabetes Care 1997;20:1807-13.
Syvanne M, Taskinen MR. Lipids and lipoproteins as coronary risk factors in non-insulin-dependent diabetes
mellitus. Lancet 1997;350(Suppl 1):SI20-3.
Syvanne M, Vuorinen-Markkola H, Hilden H, Taskinen MR. Gemfibrozil reduces postprandial lipemia in noninsulin-dependent diabetes mellitus. Arteriosclerosis Thrombosis 1993;13:286-95.
Tallis GA, Beng C, Popplewell P, Phillips P. Sugar and fat, a recipe for disaster. New guidelines for the
pharmacological management of diabetic dyslipidaemia. Aust Fam Phys 1995;24:1638-49.
Tan CE, Chew LS, Tai ES, Chio LF, Lim HS, Loh LM, Shepherd J. Benefits of micronised fenofibrate in Type
2 diabetes mellitus subjects with good glycaemic control. Atherosclerosis 2001;154:469-74.
Tan CE, Chew LS, Chio LF, Tai ES, Lim HS, Lim SC, Jayakumar L, Eng HK, Packard CJ. Cardiovascular risk
factors and LDL subfraction profile in Type 2 diabetes mellitus subjects with good glycaemic control. Diabetes
Res Clin Prac 2001;51:107-14.
Tan KC, Cooper MB, Ling KL, Griffin BA, Freeman DJ, Packard CJ, Shepherd J, Hales CN, Betteridge DJ.
Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent
diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species
and insulin resistance. Athersclerosis 1995;113:273-87.
Tan KC, Shiu SW, Wong Y. Plasma phospholipid transfer protein activity and small, dense LDL in type 2
diabetes mellitus. Eur J Clin Invest 2003;33:301-6.
217
Taskinen MR. Hyperlipidaemia in diabetes. Baillieres Clin Endocrinol Metab 1990;4:743-75.

Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003;46:733-49.
Taskinen MR. Quantitative and qualitative lipoprotein abnormalities in diabetes mellitus. Diabetes
1992;41(Suppl 2):12-7.
Taskinen MR. Criteria for metabolic control and intervention in diabetes. Diabetes 1996;45(Suppl 3):S120-2.
Taskinen MR. Triglycerides is the major atherogenic lipid in NIDDM. Diabetes Metab Rev 1997;13:93-8.
Taskinen MR, Beltz WF, Harper I, Fields RM, Schonfeld G, Grundy SM, Howard BV. Effects of NIDDM on
very-low-density lipoprotein triglycerides and apolipoprotein B metabolism. Studies before and after
sulfonylurea therapy. Diabetes 1986;35:1268-77.
Taskinen MR, Lahdenpera S, Syvanne M. New insights into lipid metabolism in non-insulin-dependent diabetes
mellitus. Ann Med 1996;28:335-40.
Taskinen MR, Smith U. Lipid disorders in NIDDM: implications for treatment. J Intern Med 1998;244:361-70.
Taskinen MR, Kuusi T, Helve E, Nikkila EA, Yki-Jarvinen H. Insulin therapy induces antiatherogenic changes
of serum lipoproteins in noninsulin-dependent diabetes. Arteriosclerosis 1988;8:168-77.
Taskinen MR, Packard CJ, Shepherd J. Effect of insulin therapy on metabolic fate of apolipoprotein Bcontaining lipoproteins in NIDDM. Diabetes 1990;39:1017-27.
Temelkova-Kurktschiev T, Hanefeld M, Leonhardt W. Small dense low-density lipoprotein (LDL) in noninsulin-dependent diabetes mellitus (NIDDM). Impact of hypertriglyceridemia. Ann NY Acad Sci
1997;827:279-86.
Tetrault GA, Miller WG, Chinchilli VM, Brown B, Balby T, Rooney P, Bennett S, Seckman V, Dickens M,
Johnson J, Ligon D, Hull B, Carpenter R, Steinmetz W, Mason L, Freude K, St Charles C, Huffington B,
Rosendale AM. Regional interlaboratory standardization of determinations of cholesterol, high-density
lipoprotein cholesterol, and triglycerides. Clin Chem 1990;36:145-9.
The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients
with coronary heart disease. The Bezafibrate Prevention (BIP) study. Circulation 2000;102:21-7.
Thorburn AW, Crapo PA, Beltz WF, Wallace P, Witztum JL, Henry RR. Lipid metabolism in non-insulindependent diabetes: Effects of long-term treatment with fructose-supplemented mixed meals. Am J Clin Nutr
1989;50:1015-22.
Tian H, Han L, Ren Y, Li X, Liang J. Lipoprotein(a) level and lipids in Type 2 diabetic patients and their
normoglycaemic first-degree relatives in Type 2 diabetic pedigrees. Diabetes Res Clin Pract 2003;59:63-9.
Tilly-Kiesi M, Syvanne M, Kuusi T, Lahdenpera S, Taskinen M-R. Abnormalities of low density lipoproteins in
normolipidemic type II diabetic and nondiabetic patients with coronary artery disease. J Lipid Res 1992;33:33342.
Tilly-Kiesi M, Knudsen P, Groop L, Taskinen M-R, Nissen M, Forsen B, Snickars B, Ehrnstrom B-O, Isomaa
B, Lahti K, Forsblom C, Tuomi T, Lehto M, Haggblom M, Akerma L, Eklof G, Paulaharju S, Gullstrom M,
Stenbeck I- B. Hyperinsulinemia and insulin resistance are associated with multiple abnormalities of lipoprotein
subclasses in glucose-tolerant relatives of NIDDM patients. J Lipid Res 1995;37:1569-78.
Tomlinson BT, Mak TWL, Tsui JYY, Woo J, Shek CC, Critchley JAJH, Masarei JRL. Effects of Fluvastatin on
lipid profile and apolipoproteins in Chinese patients with hypercholesterolemia. Am J Cardiol 1995;76:136-9.
Tonolo G, Ciccarese M, Brizzi P, Puddu L, Secchi G, Calvia P, Atzeni MM, Melis MG, Maioli M. Reduction of
albumin excretion rate in normotensive microalbuminuric Type 2 diabetic patients during long-term simvastatin
treatment. Diabetes Care 1997;20:1891-5.
218
Torjesen PA, Birkeland KI, Anderssen SA, Hjermann I, Holme I, Urdal P. Lifestyle changes may reverse
development of the insulin resistance syndrome: the Oslo Diet and Exercise Study: a randomized trial. Diabetes
Care 1997;20:26-31.
Torremocha F, Hadjadj S, Carrie F, Rosenberg T, Herpin D, Marechaud R. Prediction of major coronary events
by coronary risk profile and silent myocardial ischaemia: Prospective follow-up study of primary prevention in
72 diabetic. Diabetes Metab 2001;27:49-57.
Tschope W, Koch M, Thomas B, Ritz E. Serum lipids predict cardiac death in diabetic patients on maintenance
hemodialysis. Results of a prospective study. Nephron 1993;64:354-8.
UKPDS 13. United Kingdom Prospective Diabetes Study (UKPDS) 13: Relative efficacy of randomly allocated
diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes
followed for three years. BMJ 1995;310:83-8.
UKPDS 27. UK Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age
and sex. Diabetes Care 1997;20:1683-7.
UKPDS 28. UKPDS 28: A randomised trial of efficacy of early addition of metformin in sulfonylurea-treated
Type 2 diabetes. Diabetes Care 1998;21:87-92.
Umeda F, Watanabe J, Inoue K, Hisatomi A, Mimura K, Yamauchi T, Sako Y, Kunisaki M, Tajiri Y, Nawata H.
Effect of pravastatin on serum lipids, apolipoproteins and lipoprotein (a) in patients with non-insulin dependent
diabetes mellitus. Endocrinol Japan 1992;39:45-50.
Uusitupa M, Laakso M, Sarlund H, Majander H, Takala J, Penttila I. Long term effects of a very low calorie diet
on metabolic control and cardiovascular risk factors in the treatment of obese non-insulin dependent diabetics.
Int J Obes 1989;13(Supp 2):163-4.
Uusitupa M, Laitinen J, Siitonen O, Vanninen E, Pyorala K. The maintenance of improved metabolic control
after intensified diet therapy in recent type 2 diabetes. Diabetes Res Clin Pract 1993;19:227-38.
Uusitupa M, Siitonen O, Pyorala K, Aro A, Hersio K, Penttila I, Voutilainen E. The relationship of
cardiovascular risk factors to the prevalence of coronary heart disease in newly diagnosed type 2 (non-insulindependent) diabetes. Diabetologia 1985;28:653-9.
Uusitupa MIJ. Fructose in the diabetic diet. Am J Clin Nutr 1994;59(Suppl 1):S753-7.
Uusitupa MIJ, Laakso M, Sarlund H, Majander H, Takala J, Penttila I. Effects of a very-low-calorie diet on
metabolic control and cardiovascular risk factors in the treatment of obese non-insulin-dependent diabetics. Am
J Clin Nutr 1990;51:768-73.
Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. 5-Year incidence of atherosclerotic vascular
disease in relation to general risk factors, insulin level, and abnormalities in lipoprotein composition in noninsulin-dependent diabetic and nondiabetic subjects. Circulation 1990;82:27-36.
Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. Ten year cardiovascular mortality in relation
to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and nondiabetic subjects. Diabetologia 1993;36:1175-84.
Vaag AA, Beck-Nielsen H. Effects of prolonged acipimox treatment on glucose and lipid metabolism and on in
vivo insulin sensitivity in patients with non-insulin dependent diabetes mellitus. Acta Endocrinol 1992;127:34450.
Vakkilainen J, Steiner G, Ansquer JC, Perttunen-Nio H, Taskinen MR. Fenofibrate lowers plasma triglycerides
and increases LDL particle diameter in subjects with Type 2 diabetes. Diabetes Care 2002;25:627-8
Valmadrid CT, Klein R, Moss SE, Klein BEK, Cruickshanks KJ. Alcohol intake and the risk of coronary heart
disease mortality in persons with older-onset diabetes mellitus. JAMA 1999;282:239-46.
Vaverkova H, Chlup R, Ficker L, Novotny D, Bartek J. Complimentary insulin therapy improves blood glucose
and serum lipid parameters in type 2 (non-insulin-dependent) diabetic patients. II. Effects on serum lipids,
lipoproteins and apoproteins. Exp Clin Endocrinol Diabetes 1997;105(Suppl 2):74-7.
219
Velazquez E, Winocour PH, Kesteven P, Alberti KGMM, Laker MF. Relation of lipid peroxides to
macrovascular disease in Type 2 diabetes. Diabet Med 1991;8:752-8.
Velussi M. Long-term (18-month) efficacy of atorvastatin therapy in Type 2 diabetics at cardiovascular risk.
Nutr Metab Cardiovasc Dis 2002;12:29-35.
Verity LS, Ismail AH. Effects of exercise on cardiovascular disease risk in women with NIDDM. Diabetes Res
Clin Pract 1989;6:27-35.
Vessby B. Effects of omega 3 fatty acids on glucose and lipid metabolism in non-insulin-dependent diabetes
mellitus. World Rev Nutr Diet 1991;66:407-16.
Vessby B, Boberg M. Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients
with non-insulin-dependent diabetes mellitus. J Intern Med 1990;228:165-71.
Vignati L, Anderson JH Jr, Iversen PW. Efficacy of insulin lispro in combination with NPH human insulin
twice per day in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. Clin Ther
1997;19:1408-21.
Vlajinac H, Ilic M, Marinkovic J. Cardiovascular risk factors and prevalence of coronary heart disease in Type 2
(non-insulin-dependent) diabetes. Eur J Epidemiol 1992;8:783-8.
Walden CE, Knopp RH, Wahl PW, Beach KW, Strandness E Jr. Sex differences in the effect of diabetes
mellitus on lipoprotein tryglyceride and cholesterol concentrations. N Engl J Med 1984;311:953-9.
Walker WG. Relation of lipid abnormalities to progression of renal damage in essential hypertension, insulindependent and non insulin-dependent diabetes mellitus. Miner Electolyte Metab 1993;19:137-43.
Wallberg-Henriksson H, Rincon J, Zierath JR. Erratum: Exercise in the management of non-insulin-dependent
diabetes mellitus. Sports Med 1998;25:25-35.
Wasada T, Kuroki H, Arii H, Maruyama A, Aoki K, Katsumori K, Saito S, Hanada H, Omori Y. Relationship
between insulin resistance and risk factors for cardiovascular disease in Japanese non-insulin-dependent diabetic
patients. Diabetes Res Clin Pract 1994;25:191-8.
Wassef N, Sidhom G, Zakareya el-K, Mohamed el-K. Lipoprotein (a) in android obesity and NIDDM. Diabetes
Care 1997;20:1693-6.
Watanabe J, Kobayashi K, Umeda F, Yamauchi T, Mimura K, Nakashima N, Masakado M, Hiramatsu S,
Nawata H. Apolipoprotein E polymorphism affects the response to pravastatin on plasma apolipoproteins in
diabetic patients. Diabetes Res Clin Pract 1993;20:21-7.
Watts NB, Spanheimer RG, DiGirolamo M, Gebhart SS, Musey VC, Siddiq YK, Phillips LS. Prediction of
glucose response to weight loss in patients with non- insulin dependent diabetes mellitus. Arch Intern Med
1990;150:803-6.
Weber P, Schrezenmeir J, Fenselau S, Ausieker S, Probst R, Zuchhold HD, Prellwitz W, Beyer J. Prolonged
postprandial increment in triglycerides and decreased postprandial response of very low density lipoproteins in
type 2 diabetics following an oral lipid load. Ann NY Acad Sci 1993;683:315-21.
Weintraub WS, Boccuzzi SJ, Klein JL, Kosinski AS, King III SB, Ivanhoe R, Cedarholm JC, Stillabower ME,
Talley JD, DeMaio SJ, O'Neill WW, Frazier II JE, Cohen-Bernstein CL, Robbins DC, Brown III CL, Alexander
RW, Mitchel YB, Hirsch JJ, Melino MR. Lack of effect of lovastatin on restenosis after coronary angioplasty. N
Engl J Med 1994;331:1331-7.
Westerveld HT, de Graaf JC, van Breugel HH, Akkerman JW, Sixma JJ, Erkelens DW, Banga JD. Effects of
low-dose EPA-E on glucemic control, lipid profile, lipoprotein (a), platelet aggregation, viscosity, and platelet
and vessel wall interaction in NIDDM. Diabetes Care 1993;16:683-8.
Wilson PWF. Lower diabetes risk with hormone replacement therapy: An encore for estrogen? Ann Intern Med
2003;138:69-70.
220
Wing RR, Shoemaker M, Marcus MD, McDermott M, Gooding W. Variables associated with weight loss and
improvements in glycemic control in type II diabetic patients in behavioral weight control programs. Int J Obes
1990;14:495-503.
Wing RR, Epstein LH, Nowalk MP, Koeske R, Hagg S. Behaviour changes, weight loss and physiological
improvements in Type II diabetic patients. J Consult Clin Psychol 1985;53:111-22.
Wing RR, Koeske R, Epstein LH, Nowalk MP, Gooding W, Becker D. Long-term effects of modest weight loss
in type II diabetic patients. Arch Intern Med 1987;147:1749-53.
Winocour PH, Bhatnagar D, Ishola M, Arrol S, Durrington PN. Lipoprotein (a) and microvascular disease in
type 1 (insulin-dependent) diabetes. Diabet Med 1991;8:922-7.
Wirta O, Pasternack A, Mustonen J, Laippala P. Renal and cardiovascular predictors of 9-year total and sudden
cardiac mortality in non-insulin-dependent diabetic subjects. Nephrol Dial Transplant 1997;12:2612-17.
Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest
1991;88:1785-92.
Wolever TM, Jenkins DJ, Vuksan V, Jenkins AL, Buckley GC, Wong GS, Josse RG. Beneficial effect of a low
glycaemic index diet in Type 2 diabetes. Diabet Med 1992;9:451-8.
Wolffenbuttel BH, Gomis R, Squatrito S, Jones NP, Patwardhan RN. Addition of low-dose rosiglitazone to
sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. Diabet Med 2000;17(1):40-7.
Wolffenbuttel BH, Leurs PB, Sels JP, Rondas-Colbers GJ, Menheere PP, Nieuwenhuijzen Kruseman AC.
Improved blood glucose control by insulin therapy in type 2 diabetic patients has no effect on lipoprotein(a)
levels. Diabet Med 1992;10:427-30.
Wolffenbuttel BH, Sels JP, Heesen BJ, Menheere PP, Kruseman AC. Lipoprotein (a) levels and diabetes
control. Diabetes Care 1992;15:941.
Wolffenbuttel BH, Weber RF, Van Koetsveld PM, Verschoor L. Limitations of diet therapy in patients with
non- insulin dependent diabetes mellitus. Int J Obes 1989;13:173-82.
Wollesen F, Dahlen G, Berglund L, Berne C. Peripheral atherosclerosis and serum lipoprotein (a) in diabetes.
Wu M-S, Johnston P, Sheu WH-H, Hollenbeck CB, Jeng C-Y, Goldfine ID, Chen Y-DI, Reaven GM. Effect of
metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990;13:1-8.
Yamada N, Yoshinaga H, Gotoda T, Harada K, Shimada M, Ohsuga J-C, Akanuma Y, Murase T. Plasma lipid
abnormalities and risk factors for coronary artery disease in Japanese subjects with diabetes mellitus and glucose
intolerance. Diabetes Res Clin Pract 1994;24(Suppl 1):S215-20.
Yamamoto M, Egusa G, Yamakido M. Carotid atherosclerosis and serum lipoprotein(a) concentrations in
patients with NIDDM. Diabetes Care 1997;20:829-31.
Yoshinari M, Asano T, Kaori S, Shi AH, Wakisaka M, Iwase M, Fujishima M. Effect of gemfibrozil on serum
levels of prostacyclin and precursor fatty acids in hyperlipidemic patients with Type 2 diabetes. Diabetes Res
Clin Pract 1998;42:149-54.
Yoshinari M, Yamamoto M, Wakisaka M, Iwase M, Takano K, Fujishima M. Effect of bezafibrate on
hypercoagulability assessed by fluorogenic prothrombin time in hyperlipidemic patients with non-insulindependent diabetes mellitus. Thrombosis Res 1997;86:443-51.
Yoshino G, Hirano T, Kazumi T. Dyslipidemia in diabetes mellitus. Diabetes Res Clin Pract 1996;33:1-14.
Yoshino G, Kazumi T, Iwai M, Matsushita M, Matsuba K, Uenoyama R, Iwatani I, Baba S. Long-term
treatment of hypercholesterolemic non-insulin dependent diabetics (NIDDM) with pravastatin (CS-514).
Yudkin JS. Lipids, thrombosis and cardiovascular disease in diabetes. Proc Nutr Soc 1997;56:273-80.
221
Zambon S, Friday KE, Childs MT, Fujimoto WY, Bierman EL, Ensinck JW. Effect of glyburide and omega3
fatty acid dietary supplements on glucose and lipid metabolism in patients with non-insulin-dependent diabetes
mellitus. Am J Clin Nutr 1992;56:447-54.
Zambon S, Lapolla A, Sartore G, Gherardingher C, Cortella A, Manzato E, Crepaldi G, Fedele D. Long-term
treatment with simvastatin in hypercholesterolemic non-insulin-dependent diabetic patients. Curr Ther Res
1992;52:221-9.
Zierath JR, Wallberg-Henriksson H. Exercise training in obese diabetic patients. Special considerations. Sports
Med 1992;14:171-89.
Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:473-85.
Zimetbaum P, Frishman WH, Kahn S. Effects of gemfibrozil and other fibric acid derivatives on blood lipids
and lipoproteins. J Clin Pharmacol 1991;31:25-37.
222
2.5
Lipid Guideline Search Strategy and Yield
Electronic Databases Searched:

Medline
EMBASE
CINAHL
Cochrane
Terms used to search the databases:

Detailed within the table below.
Search Inclusion Criteria:

Where possible the searches were limited by the English language and human research. The databases were searched for the following years of publication: Medline 1985 - August 2003; EMBASE 1988 - August 2003;
CINAHL 1985 - August 2003; Cochrane 1993 - August 2003. Unless other year ranges are specified on the table.
Other searching:
Reference lists at the end of review articles of particular relevance were hand searched.
Relevant articles were solicited from expert colleagues and organisations.
Local and international clinical practice guidelines were reviewed for relevant references.
Abbreviations:
The database searched has been indicated next to each set of keywords using the following abbreviations. M= Medline, EM= EMBASE, CO= Cochrane and CI= CINAHL. All EMBASE and Medline searches were done
using English language En.La and human as a limit. Other abbreviations used were NIDDM= non-insulin-dependent diabetes mellitus; CVD = cardiovascular disease; CBD = cerebrovascular disease; MI = myocardial
infarction; CHD = coronary heart disease; CAD = coronary artery disease; dh = diet therapy; dt = drug therapy; th = therapy, ae = adverse effects, du = diagnostic use, st = standards, cl = classification, co = complications,
di = diagnosis, TG = triglycerides; HRT = hormone replacement therapy; FA = fatty acid/s; LDL = low density lipoprotein; HDL = high density lipoprotein; VLDL = very low density lipoprotein;
Identified = number of articles which matched the MeSH terms listed OR contained the text terms in each particular database.
Relevant = those articles considered relevant to the questions being asked after viewing titles OR abstracts.
Articles identified by other strategies = articles identified by hand searching, other searches for other questions, OR from colleagues.
Total for Review = Those articles which were relevant to the question, contained original data OR were systematic reviews of original articles and met the following criteria.
223
Criteria used to determine the suitability of articles for review

1.
Appropriate patient population for question being addressed (epidemiology, specific diet)
2.
The paper was published in the English language
3.
Articles with original data
4.
Review articles on lipids where diabetes is a major focus OR on diabetes where lipids are a major focus
5.
Review articles that cover lipids in patients with diabetes
6.
Articles based on human studies not those with hypothesis/mechanism/in vitro study/ animal study, detailed compositional analysis of lipids/lipoproteins or genetic studies that are clinically
inapplicable
7.
Articles were obtained from journals able to be accessed within our Library network, ordered through an interlibrary loan or obtained via other sources.
224
QUESTIONS
KEY WORDS
Total for Question

1. What lipid
NIDDM/ AND (Lipids/ OR
abnormalities are
hypercholesterolemia/ OR
associated with
TG/ OR hyperlipidemia/
Type 2 diabetes and OR cholesterol/ OR
lipoproteins/) CI 85-03
what are the
AND limit to review
consequences?
articles M 85-99
AND limit to review
articles OR RCT/ OR metaanalysis/ OR cohort/ M 9903
(Lipoproteins/ae,du OR
Lipoproteins, HDL
cholesterol/ae,st,du OR
Lipoproetins, LDL
cholesterol/ae,st,du, OR
hypercholesterolemia/cl,co,
di,th OR hyperlipidemia/cl,
di OR Lipids/ae,st,du OR
cholesterol/ae,st,du) AND
(Diagnostic tests, routine/
OR chemistry, clinical/ OR
hematologic tests/ OR risk
assessment/ OR methods/)
AND frequency.mp M, CI
85-03
(Lipoproteins/ OR
Lipoproteins, HDL
cholesterol/ OR
Lipoproetins, LDL
cholesterol/ OR
hyperlipidemia/ OR Lipids/
OR cholesterol/ OR
triglycerides/) AND
(Diagnosis, laboratory/ OR
chemistry, clinical/ OR
assessment/ OR sampling
methods/) AND
frequency.mp M, CI 85-03
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
20479
362
25
278
220
294
84 (M)
5 (CI)
176 (M)
9 (CI)
225
TOTAL
FOR
REVIEW
260
LEVEL I
LEVEL II
LEVEL
III
77
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
86
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
1. What lipid
abnormalities are
associated with
Type 2 diabetes and
what are the
consequences?
(Lipoproteins/ OR
Lipoproteins, HDL cholesterol/
OR Lipoproetins, LDL
cholesterol/ OR
hyperlipidemia/ OR Lipids/ OR
cholesterol/ OR triglycerides/)
AND (laboratory techniques
and procedures/ OR chemistry,
clinical/ OR hematologic tests/
OR risk assessment/ OR
sampling methods.mp) AND
frequency.mp M 99-03
(Laboratory assessment.mp OR
predictive value of tests/ OR
diagnostic tests, routine/ OR
clinical chemistry tests/ OR
AND (lipids/ OR cholesterol/
OR hypercholesterolemia/ OR
hyperlipidemia/ OR
triglycerides/ OR lipoproteins/)
M, CI 85-03
AND limit review articles M
85-99
(Laboratory assessment.mp OR
predictive value of tests/ OR
diagnostic tests, routine/ OR
clinical chemistry tests/ OR
AND (lipids/ OR cholesterol/
hyperlipidemia/ OR
triglycerides/ OR lipoproteins/)
AND
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
10
585 (M)
445 (CI)
45 (M)
91
226
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
1. What lipid
abnormalities are
associated with
Type 2 diabetes and
what are the
consequences?
NIDDM/ M 85-03
NIDDM/ AND: TG/
Cholesterol/
Dyslipid emia/
High density cholesterol/
Hyperlipidemia/
Lipid/
Lipid blood level/
Low density lipoprotein/
Lipid metabolism/ EM 8899
limit to review/ OR
metaanalysis/ OR cohort
analysis/ OR cohort
study.mp systematic
review.mp EM 99-03
Freguency AND
(Lipoprotein/ OR LDL/ OR
HDL/ OR Triacylglycerol/
OR hypercholesterolemia/
OR hyperlipidemia/ OR
lipid/ OR cholesterol/) EM
88-99, CI 85-99
AND NIDDM/ EM 99-03
NO. ARTICLES
IDENTIFIED
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
806
557
221
315
137
672
303
229
458
767 (EM)
604 (EM)
43 (CI)
72
Diabetes mellitus.mp AND

Lipids.mp CO 93-03
854
Risk assessment.mp AND

lipid.mp CO 93-03
75
NIDDM.mp AND: TG.mp

Cholesterol.mp
Hypercholesterolemia.mp
(Hyperlipidaemia.mp OR
Hyperlipidemia.mp)
Lipids.mp
Lipoproteins.mp CO 93-99
NO RELEVANT
ARTICLES
180
236
19
25
132
121
227
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
1. What lipid
abnormalities are
associated with
Type 2 diabetes and
what are the
consequences?
NIDDM.mp AND (TG.mp OR

Cholesterol.mp OR
OR Hyperlipidaemia.mp OR
Hyperlipidemia.mp OR
Lipids.mp OR
Lipoproteins.mp) CO 99-03
306
(Lipids.mp OR lipoproteinsLDL-cholesterol.mp OR
triglycerides.mp OR
lipoproteins.mp) AND:
(diagnostic-techniques-andprocedures.mp OR riskassessment.mp OR diagnostictests-routine.mp OR chemicaltest.mp OR diagnostic-tests.mp
OR clinical-chemistry-test.mp)
Frequency CO 93-99
(Lipids.mp OR lipoproteinsLDL-cholesterol.mp OR
triglycerides.mp OR
lipoproteins.mp) AND
(diagnostic-techniques-andprocedures.mp OR riskassessment.mp OR diagnostictests-routine.mp OR chemicaltest.mp OR diagnostic-tests.mp
OR clinical-chemistry-test.mp)
Frequency CO 99-03
NIDDM/ AND (cholesterol/
hyperlipidemia/ OR TG/ OR
lipoproteins/) CI 85-03
AND limit to review articles M
85-99
AND (RCT/ OR meta-analysis/
OR cohort/) M 99-03
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
229
82
278
220
294
228
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
1. What lipid
abnormalities are
associated with
Type 2 diabetes and
what are the
consequences?
NIDDM/ AND Lipids.mp/

AND (coronary disease/ OR
coronary heart disease.mp OR
CBD.mp/ OR PVD.mp/) M 9103
lipoproteins/) AND (CBD/ OR
myocardial
ischemia/
OR
coronary disease/ OR CVD/
OR vascular disease/ OR MI/)
M, CI 85-03
lipoproteins/) AND (diabetic
retinopathy/
OR
diabetic
neuropathies/ OR diabetic
nephropathies/
OR
neuropathy.mp/
OR
retinopathy.mp/
OR
nephropathy.mp/) M, CI 85-03
NIDDM/ AND: Lipid/
Cholesterol/
Dyslipidemia/
Hyperlipidemia/
Lipid blood level/
Lipid metabolism/
TG/
CHD/
CVD lipid/
Cholesterol risk factor/
Coronary risk/
Cerebrovascular disease/
HRT Lipid/
Ischemic heart disease/
Risk assessment/
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
165
558 (M)
80 (CI)
288 (M)
20 (CI)
672
557
221
315
137
303
458
229
806
3
152
17
177
53
3
199
199
229
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
1. What lipid
abnormalities are
associated with
Type 2 diabetes and
what are the
consequences?
Stroke/
Vascular/ EM 88-99
AND review/ OR randomised
controlled trial/ OR metaanalysis/ EM 99-03
lipoproteins/) AND (heart
infarction/ OR ischemic heart
disease/ OR retinopathy/ OR
myocardial ischemia.mp OR
diabetic neuropathy/ OR
diabetic retinopathy/ OR
neuropathy/ OR MI.mp OR
diabetic nephropathy/ OR
coronary disease.mp OR CVD/
OR nephropathy.mp OR
vascular disease/ OR
microvascular.mp) EM 88-03
Lipids.mp CO 93-03
NIDDM.mp AND: TG.mp
Cholesterol.mp
Hyperlipidemia.mp)
Lipoproteins.mp CO
NIDDM.mp AND (TG.mp OR
Cholesterol.mp OR
OR Hyperlipidaemia.mp OR
Hyperlipidemia.mp OR
Lipoproteins.mp) CO 93-03
NIDDM.mp AND lipids.mp
AND:
Cardiovascular disease.mp
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
190
140
978
958
854
180
236
19
25
121
306
132
15
230
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
NO. ARTICLES
IDENTIFIED
1. What lipid
abnormalities are
associated with
Type 2 diabetes and
what are the
consequences?
Cerebrovascular disease.mp
Coronary heart disease.mp
Diabetic nephropathies.mp
Diabetic neuropathies.mp
Diabetic retinopathy.mp
Macrovascular.mp
Myocardial infarction.mp
Myocardial ischemia.mp
Nephropathy.mp
Neuropathy.mp
Retinopathy.mp
Stroke.mp
Vascular disease.mp CO
93-99
2
10
3
0
4
3
6
1
4
4
4
3
0

AND (Cardiovascular
disease.mp OR
Cerebrovascular disease.mp
OR
Coronary heart disease.mp
OR Diabetic
nephropathies.mp OR
Diabetic neuropathies.mp
OR
Diabetic retinopathy.mp OR
Macrovascular.mp OR
Myocardial infarction.mp
OR
Myocardial ischemia.mp
OR
Nephropathy.mp OR
Neuropathy.mp OR
Retinopathy.mp OR
Stroke.mp OR
Vascular disease.mp) CO
99-03
181 (CO)
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
231
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
2. What are the effects Total for Questions

of diet and exercise NIDDM/ AND (Cholesterol/
on lipids in people OR Hypercholesterolemia/ OR
OR TG/ OR
with
Type
2 Hyperlipidemia/
Lipoproteins/) CI 85-03
AND limit to review articles M
diabetes?
85-99
AND (RCT/ OR cohort/ OR
metaanalysis/) M99-03
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
7603
491
10
278
220
294
Phytosterols/ AND
(Cholesterol/ OR Lipoprotien,
hdl cholesterol/ OR
Lipoprotein., ldl cholesterol/
OR Lipoproteins, vldl
cholesterol/) M 85-99, EM 8899
109 (M)
117 (EM)
Phytosterols/ AND
(Cholesterol/ OR Lipoprotien,
hdl cholesterol/ OR
Lipoprotein., ldl cholesterol/
OR Lipoproteins, vldl
cholesterol/) AND NIDDM/ M
99-03
105
NIDDM/ AND lipids.mp/ AND

Antioxidants.mp/ M (99-03)
17
NIDDM/ AND (Cholesterol/

lipoproteins/) AND (diabetic
diet/ OR exercise/ OR diet/ OR
exercise therapy/ OR diet
therapy/ OR antioxidants/) M,
CI
85-03
270 (M)
42 (CI)
232
TOTAL
FOR
REVIEW
208
LEVEL I
LEVEL II
80
LEVEL
III
42
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
129
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
2. What are the

effects of diet and
exercise on lipids in
people with Type 2
diabetes?
NIDDM/ AND:
(Dietary fats/ OR saturated
fat.mp) AND (Cholesterol/
OR HDL cholesterol OR
LDL cholesterol) M 85-03
63
(Dietary fats/ OR fatty

acids, saturated/) AND
(Cholesterol/ OR HDL
cholesterol
OR
LDL
cholesterol) CI 85-03
12
(Fat intake/ OR saturated

fatty
acid/)
AND
(cholesterol/ OR HDL
cholesterol/
OR
LDL
cholesterol/ OR VLDL
cholesterol/) EM 88-99
59
Saturated fat.mp AND

cholesterol.mp CO 93-03
12
NIDDM/
AND
triglycerides/ AND:
Alcohol
drinking/
OR
alcoholic beverages/ OR
ethanol/ M 85-99
23
Alcoholic beverages/ OR
alcohol drinking/ CI 85-03
16
Alcohol/
OR
alcohol
consulmption/ EM 88-99
21
Alcohol/ CO 93-03
22
Phytosterols.mp CI 85-03,
CO 93-03
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
20 (CI)
350 (CO)
233
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
2. What are the

effects of diet and
exercise on lipids in
people with Type 2
diabetes?
NIDDM.mp AND: TG.mp

Cholesterol.mp
Hyperlipidemia.mp)
Lipoproteins.mp CO 93-99
180
236
19
25
121

Lipids.mp CO 93-99
385
NIDDM/ AND : TG/

Cholesterol/
Dyslipidemia/
Hidensity cholesterol/
Hyperlipidemia/
Lipid/
Lipid blood level/
Lipid metabolism/
Antioxidant/
Diet/
Diet and lipid/ CO 93-99
806
557
221
315
137
672
303
458
229
27
122
245
Exercise/ EM 88-99
AND review/ or randomised
controlled trial/ or metaanalysis/ or systematic
review.mp EM 99-03
104
??
NIDDM AND LIPIDS:

Antioxidant/
Diet/
Exercise/
Glycaemic control/ Glycemic
control/ CO 93-99
132
0
56
9
10
49
NIDDM AND (LIPIDS OR

Antioxidant/ OR Diet/ OR
Exercise/ OR Glycaemic
control/ OR Glycemic control/
) CO 93-99
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
135
234
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
3.
Total for Question
What is the effect

of improved blood
glucose control on
lipids in Type 2
diabetes?
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
8487
276
21

hyperlipidaemia/ OR HDL OR
Hyperlipidemia/ OR TG/) CI
85-03
Limit to review articles M 8599
OR RCT/ OR metaanalysis/
OR cohort/ M 99-03
278 (CI)
As Above AND (glycemic

control.mp OR glycaemic
control.mp OR blood glucose/
OR
hemoglobin
a,
glycosylated/ OR insulin/ OR
hypoglycemic agents/) M, CI
85-03
1543 (M)
117 (CI)
NIDDM.mp AND Lipids.mp

AND: Diet.mp
Glycaemic control.mp
Glycemic control.mp CO 93-99
132
diabetes mellitus non-insulin

dependent/ AND (lipids/ OR
diet/) CO 99-03
188
NIDDM/
AND:
Lipid/
Cholesterol/
Dyslipidemia/
Hyperlipidemia/
Lipid blood level/
Lipid metabolism/
TG/
Antioxidant/ EM 88-99
(antibiabetic
agent/
OR
glycosylated hemoglobin/ OR
glucose blood level/ OR
hemoglobin A1C/) EM 99-03
672
557
221
315
137
303
458
229
806
27
958
220 (M)
294 (M)
56
10
235
TOTAL
FOR
REVIEW
107
LEVEL I
LEVEL II
31
LEVEL
III
LEVEL
IV
21
13
TOTAL
NO.
REVIEWED
AND GRADED
65
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
3.
Diabetes Mellitus.mp AND

Lipids.mp CO 93-99
385
NIDDM.mp AND: TG.mp

Hyperlipidemia.mp)
Lipoproteins.mp
Cholesterol.mp CO 93-99
180
19
25
4.
What is the effect

of improved blood
glucose control on
lipids in Type 2
diabetes?
What are the

effects on lipids of
treatment with
lipid modifying
agents and HRT in
Type 2 diabetes?
Total For Question
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
660
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
72
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
121
236
8018
NIDDM/dh,dt,th,
AND
(lipids
OR
hypertriglyceridemia/ OR
TG/ OR hyperlipidaemia/
cholesterol/) M, CI 85-03
827 (M)
95 (CI)

OR hyperlipidaemia/ OR
TG/
OR
hyperlipidemia/ CI 85-99
(Limit to review articles) M
85-99
101
(hypercholesterolemia/ OR
TG/
OR
hypertriglyceridemia/OR
hyperlipidaemia/
OR
hyperlipidemia/
OR
cholesterol/ OR lipids/)
AND
NIDDM/
AND
Antilipemic agents/ M, CI
85-03, EM 88-99
149 (M)
11 (CI)
7 (EM)
NIDDM/ AND HRT/ M 8599, CI 85-03, EM 88-99
0 (M)
18 (CI)
4 (EM)
220
236
164
14
97
QUESTIONS
KEY WORDS
4.
HRT/ M, CI 85-99
7 (M)
39 (CI)
NIDDM/ AND Antilipemic

agents/ AND Lipids/ M, CI
85-99
23 (M)
0 (CI)
(Bezafibrate/ OR
gemfibrozil/ OR fibric
acid.mp/ OR acipimox.mp/
OR nicotinic acid.mp/ OR
niacin/ OR
hydroxymethylglutaryl-coa
reductase inhibitors/ OR
bile acid sequestrants.mp/
OR statins.mp OR
atorvastatin.mp/ OR fish
oils/ OR cholestyramine/
OR FA, omega-3/ OR
fluvastatin.mp/ OR
cholestipol.mp/ OR
Lovastatin/ OR pravastatin/
OR probucol/) M, CI 85-03
220 (M)
21 (CI)
NIDDM/ AND
(Acipimox.mp/ OR
antilipedic agents/ OR
HRT/ OR niacin/ OR
bezafibrate/ OR
gemfibrozil/ OR fibric
acid.mp/ OR
reductase inhibitors/ OR
nicotinic acid.mp/ OR
cholestyramine/ OR bile
acid sequestrants.mp/ OR
probucol/ OR
fluvastatin.mp/ OR fish oils/
OR statins.mp OR
atorvastatin.mp/ OR
lovastatin/ OR
cholestipol.mp/ OR FA,
omega-3/ OR pravastatin/)
148 (M)
9 (CI)
What are the

treatment with
lipid modifying
agents and HRT in
Type 2 diabetes?
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
237
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
4.
AND
(Hemoglobin
a,
glycosylated/
OR
hypoglycemic agents/ OR
insulin/
OR
glycaemic
control.mp.
OR
glycemic
control.mp OR blood glucose/)
M, CI 85-99
What
are
the
treatment
with
lipid
modifying
agents and HRT in
Type 2 diabetes?
NIDDM/ AND (fishes/ OR

fish.mp) AND (Cholesterol/
OR
lipoproteins,
hdl
cholesterol/ OR lipoproteins ldl
cholesterol/ OR Lipoproteins,
vldl cholesterol/) M 85-03
NIDDM/ AND (lipoproteins,
HDL
cholesterol/
OR
cholesterol/ lipoproteins, LDL
cholesterol/) AND (fish/ or fish
oils/) CI 85-03, EM 88-03
NIDDM.mp AND fish.mp
AND cholesterol.mp CO 93-99
NIDDM/ AND :
Cholesterol/
Dyslipidemia/
Hyperlipidemia/
Lipid/
Lipid blood level/
Lipid metabolism/
TG/
Estrogen/
(probucol/ OR acipimox/ OR
pravastatin/ OR colestyramine/
OR
atorvastatin/
OR
lovastatin.mp OR colestipol/
OR
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
30
8 (CI)
35 (EM)
25
557
221
315
137
672
303
458
229
806
51
149
238
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
4.
hydroxymethylglutaryl-Co A
reductase inhibitors.mp OR
fluindostatin/ OR statin/) EM
88-99
What are the

treatment with
lipid modifying
agents and HRT in
Type 2 diabetes?
NIDDM/ AND (Cholesterol/

OR Dyslipidemia/ OR
High density cholesterol/ OR
Hyperlipidemia/ OR Lipid/ OR
Lipid blood level/ OR Lipid
metabolism/ OR
Low density lipoprotein/ OR
TG/ OR Estrogen/) EM 99-03
hudroxymethyglutaryl-co
A
reductase inhibitors/ AND
(RCT/ OR review/ OR metaanalysis/
OR
systematic
review.mp EM 99-03
NIDDM/ AND (Antidiabetic
agent/ OR blood glucose
monitoring/
OR
oral
antidiabetic
agent/
OR
glycemic
control.mp
OR
glucose/ OR glucose blood
level/
OR
glycaemic
control.mp OR insulin/) AND:
Antilipemic agents/
HRT.mp.
(Fibric acid.mp OR bezafibrate/
OR gemfibrozil/ OR bile acid
sequestrant/ OR fish oil/ OR
omega 3 FA/ OR nicotinic acid/
OR niacin.mp. OR probucol/
OR acipimox/ OR pravastatin/
OR
colestyramine/
OR
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
81
214
61
5
203
atorvastatin/ OR
239
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
4.
lovastatin.mp OR colestipol/
OR hydroxymethylglutaryl-Co
A reductase inhibitors.mp OR
fluindostatin/ OR statin/) EM
88-99
What are the

treatment with
lipid modifying
agents and HRT in
Type 2 diabetes?
NIDDM/ AND
(hyperlipidemia/ OR
hyperlipidaemia/ OR
cholesterol/ OR
hypertriglyceridemia/ OR TG/)
AND:
(bezafibrate/ OR gemfibrozil/
OR nicotinic acid/ OR
niacin.mp OR fibric acid.mp
OR acipimox/ OR
colestyramine/ OR Omega 3
FA/ OR
reductase inhibitors.mp OR bile
acid sequestrant/ OR statin/ OR
probucol/ OR colestipol/ OR
atorvastatin/ OR fish oil/ OR
pravastatin/ OR fluindostatin/
OR lovastatin.mp) EM 88-99
NIDDM/ AND
(hyperlipidemia/ OR
cholesterol/ OR
hyperlipidaemia/ OR
hypertriglyceridemia/ OR TG/)
AND Antilipemic agents/ EM
88-99
NIDDM.mp AND
Antilipemic agents.mp
AND: Lipids.mp
Cholesterol.mp
TG.mp
Hyperlipidemia.mp
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
208
49
9
14
14
7
240
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
4.
Hypertriglyceridemia.mp
Glycaemic.mp
OR
glycemic control.mp
Estrogen.mp CO 93-99
What are the

treatment with
lipid modifying
agents and HRT in
Type 2 diabetes?
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
3
1
5
2

Lipids.mp CO 93-99
NIDDM.mp AND HRT.mp
AND:Lipids.mp
Cholesterol.mp
(TG.mp OR glycaemic.mp
OR glycemic control.mp
OR hyperlipidemia.mp OR
hypercholesterolemia.mp
OR
hypertriglyceridemia.mp)
CO 93-99
1
1
0

Lipids.mp CO 93-99
385

AND: Cholesterol.mp
Glycaemic control.mp
Glycemic control.mp CO
93-99
132
98
10
49
NIDDM.mp AND: TG.mp

Cholesterol.mp
Lipoproteins.mp
Hyperlipidemia.mp) CO 9399
180
236
19
121
25
241
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
5.
Total For Question
Does treatment
with lipid
modifying agents or
HRT improve
outcomes in Type 2
diabetes
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
7976
81
32
NIDDM/
AND
(hyperlipidemia/
OR
hyperlipidaemia/ OR lipids/
OR
TG/
OR
hypertriglyceridemia/
cholesterol/) CI 85-99
limit to review articles M
85-99
101 (CI)
(hypercholesterolemia/ OR
TG/ OR hyperlipidaemia/
cholesterol/
OR
lipids/) AND (CVD/ OR
Coronary
disease/
OR
Risk/)
AND: NIDDM/ M, CI 8503, EM 88-99
(triglycerides.mp
OR
triaclyglycerol/ OR lipid/
OR coronary artery disease/
OR cardiovascular risk/ OR
coronary
risk/)
AND
(review/ OR RCT/ OR
meta-analysis/ OR clinical
trial/) EM 99-03
325(M)
2 (CI)
81 (EM)
NIDDM/dh,dt,th, M 85-03,
CI 85-99, EM 88-03
128 (M)
5 (CI)
382 (EM)
NIDDM AND:
Cholesterol/
Hypercholesterolemia/
(Hyperlipidaemia
OR
Hyperlipidemia/)
Lipoproteins/
TG/ CO 93-99
220 (M)
269
236
19
25
121
180
242
TOTAL
FOR
REVIEW
93
LEVEL I
LEVEL II
46
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
60
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
5.
NIDDM/
AND
(hyperlipidemia/
OR
hypercholesterolemia/
OR
hypertriglyceridemia/ OR TG/
OR
hyperlipidaemia/
OR
cholesterol/) AND:
Antilipemic agents/ M, CI 8599
Does treatment
with lipid
modifying agents or
HRT improve
outcomes in Type 2
diabetes
HRT/ M 85-99, CI 85-03, EM

94-99
estrogen therapy/ OR HRT.mp
EM 99-03
OR
nicotinic
acid/
OR
niacin.mp. OR fibric acid.mp
OR
acipimox/
OR
FA/
OR
reductase inhibitors.mp. OR
bile acid sequestrant/ OR statin/
OR probucol/ OR colestipol/
OR atorvastatin/ OR fish oil/
OR
pravastatin/
OR
fluindostatin/
OR
lovastatin.mp) M, CI 85-99
NIDDM/ AND Antilipemic
agents/ AND HRT/ AND
OR
nicotinic
acid/
OR
niacin.mp. OR fibric acid.mp
OR
acipimox/
OR
FA/
OR
reductase inhibitors.mp. OR
bile acid sequestrant/ OR statin/
OR probucol/ OR
NO. ARTICLES
IDENTIFIED
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
56 (M)
6 (CI)
0(M)
5(CI)
4 (EM)
24 (EM)
137(M)
6(CI)
32
243
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
5.
colestipol/ OR atorvastatin/
OR fish oil/ OR pravastatin/
OR
fluindostatin/
OR
lovastatin.mp) M 85-99
Does treatment
with lipid
modifying agents or
HRT improve
outcomes in Type 2
diabetes
NO. ARTICLES
IDENTIFIED
NIDDM/ AND : TG/

Cholesterol/
Dyslipidemia/
Hyperlipidemia/
806
557
221
315
137
Lipid/
672
Lipid blood level/

Lipid metabolism/
CHD/
CVD lipid/
Cholesterol risk factor/
Coronary risk/
HRT Lipid/
Ischemic heart disease/
Risk assessment/
Stroke/
Vascular/ EM 93-99
303
458
229
3
152
17
177
53
3
199
128
190
140
NIDDM AND
risk/ EM 99-03
96
coronary
Diabetes Mellitus
Lipids/ CO 93-99
AND
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
385
244
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
5.
NIDDM/ AND Lipids/

AND: Cholesterol/
Cardiovascular disease/
Coronary heart disease/
Diabetic nephropathies/
Diabetic neuropathies/
Diabetic retinopathy/
Macrovascular/
Myocardial infarction/
Myocardial ischemia/
Nephropathy/
Neuropathy/
Retinopathy/
Stroke/
Vascular disease/
Estrogen/ CO 93-99
132
98
15
2
10
3
0
4
3
6
1
4
4
4
3
0
2
NIDDM.mp
AND
cardiovascular diseases.mp
AND: HRT.mp
Antilipemic agents.mp CO
93-03
41
Does treatment
with lipid
modifying agents or
HRT improve
outcomes in Type 2
diabetes
NO. ARTICLES
IDENTIFIED
NIDDM/ AND estrogen/

CO 93-03
14
NIDDM/
AND
hydroxymethylglutarylCoA reductase inhibitors/
AND (costs and cost
analysis/ OR cost-benefit
analysis
OR
costeffectiveness.mp) M 85-03
NIDEM/ AND statins/

AND (cost benefit analysis
OR cost.mp) CI 85-03
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
245
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE
QUESTIONS
KEY WORDS
NO. ARTICLES
IDENTIFIED
NIDDM/ AND (statins.mp

5. Does treatment
OR hydroxymethylglutarylwith lipid
CoA reductase inhibitors/)
modifying agents or AND (cost benefit
analysis/ OR cost
HRT improve
outcomes in Type 2 effectiveness analysis/
OR cost/) EM 88-03
diabetes
15
NIDDM.mp AND
(statins.mp OR
hydroxymethylglutarylCoA reductase inhibitors/)
AND (cost effectiveness.mp
OR cost.mp OR cost-benefit
analysis/) CO 93-03
NO RELEVANT
ARTICLES
ARTICLES
IDENTIFIED BY
OTHER
STRATEGIES
246
TOTAL
FOR
REVIEW
LEVEL I
LEVEL II
LEVEL
III
LEVEL
IV
TOTAL
NO.
REVIEWED
AND GRADED
HIGHEST
LEVELOF
EVIDENCE

National Evidence Based Guidelines PDF

Încărcat de

Informații document

Descriere originală:

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

National Evidence Based Guidelines PDF

Încărcat de

Drepturi de autor:

Formate disponibile

National Evidence Based Guidelines

APPROVED BY THE NHMRC 16 SEPTEMBER 2004

Lipids Expert Working Group ................................................................................3

2.0 Guideline for Lipid Control in Type 2 Diabetes ....................................................5

1.0 Lipid Control Guideline Expert Working Group

Professor James Best

Content and Methods Adviser

Professor Stephen Colagiuri

2.0 Guideline for Lipid Control

Aim of the Guideline

The prevention of macrovascular disease is a major goal in the care of

Multifactorial intervention is the key to the prevention of macrovascular

Issues for Lipid Control in Type 2 diabetes

If feasible, lipid levels should be measured after a 10 to 12 hour overnight fast

Triglycerides levels are increased in Type 2 diabetes

HDL cholesterol is decreased in Type 2 diabetes

Total cholesterol is similar in Type 2 diabetes and the general population

Apolipoprotein A1 is reduced, apolipoprotein B is increased, and lipoprotein(a) is not

There is insufficient evidence to draw any conclusion about the importance of

HDL cholesterol and triglycerides predict cardiovascular disease in Type 2 diabetes

The contribution of increased lipoprotein (a) to risk of cardiovascular disease in Type 2

There is limited evidence linking lipid levels and diabetic nephropathy

Background Lipid levels and Type 2 diabetes

Evidence Lipid levels and Type 2 diabetes

Table 1: Lipid levels and Type 2 diabetes

Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001

Table 1: Lipid levels and Type 2 diabetes

Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001. AU: microalbuminuria

Table 1: Lipid levels and Type 2 diabetes

Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001

HDL cholesterol is decreased in Type 2 diabetes

age 60-69 yrs

n=1,846 Type 2 diabetes; 11-yr follow-up

n=1,539 Type 2 diabetes; 2-yr follow-up

Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001

Type 2 West Finland: 328M; 221W, MI+

Control East Finland: 313M; 336W, MI+

Control West Finland: 325M;399W, MI+

n=1,676 diabetes (type not stated)

Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001

Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001

HDL cholesterol and triglycerides predict cardiovascular disease in Type 2 diabetes

Table 3: Lipid levels and diabetic nephropathy

(v normal & control)

n=77 Type 2 diabetes; mean

Between groups comparison p<0.05, p<0.01, p<0.005, p<0.001. AU: microalbuminuria

Table 4: Lipid levels and diabetic retinopathy

n=26 Type 2 diabetes;

p values were not reported for the Dodson study

Summary- Lipid levels and Type 2 diabetes

Measurement of fasting lipids is recommended but it is recognised that only triglycerides

Apolipoprotein B concentrations are higher in people with Type 2 diabetes compared

Lipoprotein(a) levels are not altered in people with Type 2 diabetes

There is limited evidence linking lipid levels and diabetic nephropathy

Evidence Table: Section 1

Evidence Table: Cont

Evidence Table: Cont

High C+, L+, H+, T+

Plant sterol enriched margarines have a modest effect on lipid levels

Anti-oxidant therapy may reduce susceptibility of LDL particles to oxidation

Background Diet and Exercise and Lipids

Evidence - Diet and Exercise on Lipids