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Dyslipidemia and Diabetes: Reducing Macrovascular

Risk
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner,
MD

Copyright © 2005 Joslin Diabetes Center.

This CME activity "Dyslipidemia and Diabetes: Reducing Macrovascular Risk" was originally
offered as a CME-accredited monograph in November 2004.

Faculty affiliations and disclosures are at the end of this activity.

Release Date: January 26, 2005; Valid for credit through January 26, 2006

Target Audience

This accredited activity has been developed for primary care physicians and
other clinicians who manage people with diabetes.

Goal

This activity reviews the pathophysiology of type 2 diabetes and

macrovascular risk factors associated with the metabolic syndrome and
identifies appropriate markers to trigger intervention in patients with the
metabolic syndrome in type 2 diabetes. It presents recent trial data and
recommendations for you to help your patients with diabetes achieve
the new target treatment goals from the National Cholesterol Education
Program.

Learning Objectives

Participants will be provided with evidence-based practical and

clinically relevant information. At the completion of this activity, the
participant should be able to:

1. Recognize people who are at risk for macrovascular disease based

on the presence of components of the metabolic syndrome
2. Utilize an understanding of the interrelationships of the various
components of the metabolic syndrome to design and initiate
comprehensive preventive and treatment strategies aimed at
reducing the risk of macrovascular disease
3. Identify patients with dyslipidemia early in its natural history due
to an improved understanding of the role hyperlipidemia can play
in the development of macrovascular disease, particularly in
people with type 2 diabetes
4. Design, implement, and manage effective treatments for
dyslipidemias in people with diabetes and the metabolic
syndrome

Credits Available
 Physicians - up to 1.25 AMA PRA Category 1 continuing physician
education credits
All other healthcare professionals completing continuing education credit for this
activity will be issued a certificate of participation.

Participants should claim only the number of hours actually spent in completing
the educational activity.

Accreditation Statements

For Physicians

The Joslin Diabetes Center is accredited by the Accreditation Council for

Continuing Medical Education to provide continuing medical education for
physicians.

The Joslin Diabetes Center designates this educational activity for a maximum
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activity.

For questions regarding the content of this activity, contact the

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For technical assistance, contact CME@webmd.net.

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This activity is designed to be completed within the time designated on

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Contents of This CME Activity

1. Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical
Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD
A Growing Epidemic
Diabetes and Cardiovascular Risk
Factors that Contribute to Increased Risk of Cardiovascular Disease
Type 2 Diabetes as a Risk Equivalent
Defining the Metabolic Syndrome
Other Definitions of the Metabolic Syndrome
Prevalence and Impact of the Metabolic Syndrome
Dyslipidemia in Diabetes
The Vascular Injury in Patients With Diabetes
The Impact of Multifactorial Intervention
Current Risk-Reduction Strategies

2. Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD
Characterizing Dyslipidemia in Type 2 Diabetes and the Metabolic Syndrome
How Blood Pressure and Glycemia Relate to Cardiovascular Disease and
Microvascular Complications
Current Control of Risk Factors
Statin Therapy in Patients With Diabetes
Cholesterol-Lowering Goals in Patients With Diabetes
Benefits of Statin Therapy
Use of Other Lipid-Lowering Agents
Combination Therapy for Lipid Lowering
Background on the CARDS Trial
Summary of CARDS Findings
Going Beyond Conventional LDL Goals
Other Continuing Trials in Aggressive Lipid-Lowering Therapy

3. Joslin Diabetes Center Guidelines for Screening and Management of

Dyslipidemia Associated with Diabetes
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

4. References

Dyslipidemia and Diabetes: Reducing Macrovascular Risk

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

A Growing Epidemic
 Table 1. Countries with Highest Number of Estimated Cases of
Diabetes (in millions) for 2000 and 2030

All evidence indicates that we are currently in the middle of a global diabetes epidemic. In
fact, type 2 diabetes is being diagnosed with increasing frequency in children and
adolescents, and in some parts of the world may be more common than type 1 diabetes.[1]
As an illustration of this global increase, according to the World Health Organization (WHO),
in the year 2000 there were 177 million people diagnosed with diabetes around the world,
and by year 2030, that number will grow to 366 million (Table 1). [2] The problem is
particularly serious in countries like India and China, where resources to care for this growing
number of people with diabetes are scarce.

Currently, the US has the third largest number of cases, with an estimated 18 million people
with diabetes. In addition, there are more than 50 million people with metabolic syndrome or
insulin resistance syndrome, which is the pool of people at high risk for developing type 2
diabetes.[2]

One of the major reasons for the increasing prevalence of diabetes and its precursors such
as prediabetes or metabolic syndrome is the increasing rate of obesity. In the United States,
more than 60% of the adult population is currently overweight, defined by body mass index
(BMI) of 25, and about 30% are obese, defined by BMI of about 30. [3] As diabetes develops
so does heart disease. While it is important to prevent diabetes, it has also become essential
to develop strategies for minimizing the risk of cardiovascular complications in people already
diagnosed with diabetes.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Diabetes and Cardiovascular Risk

Macrovascular disease including coronary artery disease and other vascular events such as
stroke and peripheral vascular disease is responsible for nearly 80% of all diabetes mortality,
while 75% of all hospitalizations in diabetes patients is due to cardiovascular events.[4]
Furthermore, because new-onset diabetes often does not cause any symptoms for many
years, 1 out of 3 people with diabetes remains undiagnosed, even in developed countries
such as the United States. [2,4] Therefore, it is not surprising that a third of patients already
have cardiovascular disease (CVD) by the time they are diagnosed with diabetes.

Epidemiologic studies such as the Framingham Heart Study reveal the impact of diabetes on
cardiovascular events. A 30-year follow-up of subjects in that study found an increase in the
prevalence of complications such as coronary heart disease, cardiac failure, intermittent
claudication, and stroke in patients with diabetes, compared with corresponding nondiabetic
men and women in the age range of 35 to 64 years. Women with diabetes showed a
relatively greater increase in the risk of cardiovascular events than women without
diabetes.[5]
 Figure 1. Cardiovascular mortality in type 2 diabetic patients vs
nondiabetic cohort.

A study by Krolewski and colleagues compared the long-term follow-up status of the Joslin
Diabetes Center patient population with the nondiabetic Framingham Heart Study population.
This comparison revealed a 2-fold greater incidence of mortality from cardiovascular disease
in the cohort of men, and a 4- to 5-fold greater mortality from cardiovascular disease in
women with diabetes (Figure 1). [6] This was surprising because the absolute rate of
cardiovascular disease in nondiabetic women is considerably lower than that in nondiabetic
men.

A comparison of the National Health and Nutrition Examination Survey (NHANES) data from
1982 to 1984 vs that of 1971 to 1975 revealed that coronary artery disease mortality actually
decreased by 36% and 27% in the nondiabetic men and women, respectively. However, the
decrease in the cardiovascular mortality among men with diabetes was not nearly as great,
and in women with diabetes, there was actually some increase.[7]

These data raise some questions: What are the factors that increase the risk of coronary
heart disease mortality in people with diabetes? Secondly, what can be done to prevent the
marked increases in cardiovascular events in both men and women with diabetes?

An analysis of the Multiple Risk Factor Intervention Trial (MRFIT), which enrolled more than
350,000 men at its outset, including more than 5000 with diabetes, demonstrated that the
risk in the diabetic population for death from cardiovascular disease was several-fold greater
for those with any 1, 2, or all 3 of these risk factors: Total cholesterol above 200 mg/dL,
smoking, and systolic blood pressure greater than 120 mm Hg. [8] These findings suggest the
need for more intensive risk factor management in people with diabetes, because their
vasculature may be more susceptible to the effects of elevated cholesterol, high blood
pressure, smoking, and other risk factors.

Similarly, mean blood pressure of 144/82 mm Hg compared to 154/87 mm Hg in the United

Kingdom Prospective Diabetes Study (UKPDS) resulted in major benefits in cardiovascular
endpoints.[9]
 Figure 2. Incidence of myocardial infarction in people with type 2
diabetes.
The incidence of myocardial infarction (MI) in people with diabetes was compared with that
of nondiabetics. After 7 years of follow-up, the people without diabetes had an MI rate of
about 3.5%. In those with diabetes, the risk of developing a first MI was the same as that of
nondiabetics who had a previous MI (Figure 2). [ 10]

This study also demonstrated that in people with type 2 diabetes who had a previous MI, the
risk of having a second MI in the next 7 years was as high as 45%.[10] This study has led to
the notion that diabetes is a cardiovascular risk equivalent, which implies that people with
diabetes are considered at the same high risk for a cardiovascular event as people without
diabetes but a prior cardiovascular event.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Factors that Contribute to Increased Risk of Cardiovascular Disease

Table 2. Factors Underlying Accelerated Atherogenesis In Diabetes

What are some of the reasons for this accelerated course of atherosclerosis and marked
atherogenesis in patients with diabetes? (Table 2). Among the many factors involved, an
important one is dyslipidemia. In addition to elevated low-density lipoprotein (LDL) cholesterol
that is prevalent in the general population, patients with type 2 diabetes have specific lipid
abnormalities, including triglyceride-rich lipoproteins, low levels of high-density lipoprotein
(HDL) cholesterol, and a compositional change in the LDL -- smaller, denser LDL particles,
which are more atherogenic. Additional mechanisms include hyperglycemia, resulting in
multiple, intermediary pathways, increased oxidative stress, endothelial dysfunction,
hematological abnormalities leading to a procoagulant state, as well as hypertension and
perhaps insulin resistance itself.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Type 2 Diabetes as a Risk Equivalent

Evidence for increased risk of cardiovascular disease in people with diabetes led the Adult
Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) to label
type 2 diabetes as a coronary heart disease (CHD) risk-equivalent in 2001. The 10-year risk
of CHD in patients with diabetes is considered to be greater than 20%, which defines the
CHD risk-equivalence, according to ATP III. [11]

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Defining the Metabolic Syndrome

Metabolic syndrome is a diagnosis that has been in evolution. In 1988, Dr. Gerald Reaven
coined the term "Syndrome X" to describe a cluster of abnormalities including glucose
intolerance, hyperinsulinemia, elevated triglycerides, low HDL, and hypertension. [12] Each of
these markers is considered a risk factor for coronary artery disease. Since these factors
may work in synergy in people with this syndrome, it is expected that these individuals are at
increased risk of coronary artery disease.

Often concomitant with Syndrome X, which is currently called the metabolic syndrome, is
central obesity. Central obesity is an excessive deposition of fat in the abdominal area. It is
associated with insulin resistance. Some studies have indicated that the greater the
abdominal visceral adiposity, the lower the glucose disposal. [13]

Table 3. ATP III Definition of the Metabolic Syndrome

As mentioned earlier, a large number of people in the United States are considered to have
the metabolic syndrome, which can precede type 2 diabetes. This may also result in coronary
artery disease even in people who never go on to develop type 2 diabetes. The guidelines
released by the NCEP ATP III provide one way to define the metabolic syndrome [11] (Table
3).

These guidelines suggest examining 5 clinical parameters: Abdominal obesity (defined by

waist circumference), triglycerides greater than 150 mg/dL, low HDL cholesterol, blood
pressure of greater than 130/85 mm Hg, and any fasting glucose that is above the normal of
110 mg/dL or less.[11] (Note that the American Diabetes Association recently redefined
normal fasting sugar level as 100 mg/dL or less.[14] ) The presence of any 3 of these 5
factors defines the diagnosis of the metabolic syndrome.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Other Definitions of the Metabolic Syndrome

The WHO has defined the metabolic syndrome slightly differently than the ATP III definition
cited above. WHO stipulates that impaired glucose tolerance, impaired fasting glucose,
diabetes, or any evidence of insulin resistance must be present in order to diagnose this
disorder. In addition, any 2 of these remaining 4 risk factors must also be present: Abdominal
obesity (defined by BMI rather than waist circumference), dyslipidemia, blood pressure of
140/90 mm Hg or greater (different from the ATP III cutoff), and microalbuminuria (not
included in the ATP III guidelines). [15]

The American Association of Clinical Endocrinologists (AACE) uses still another definition.
The AACE criteria are based on whether the patient has any risk factors that suggest insulin
resistance (such as high BMI, sedentary lifestyle, age above 40 years, membership in a
minority population, family history of diabetes, history of gestational diabetes) and any 2
parameters from a list similar to that of the ATP III guidelines, [16] but it includes a 2-hour
post-glucose load level of greater than or equal to 140 mg/dL.

The similarities among these definitions are more important than the differences. The key
point is that the metabolic syndrome increases macrovascular risk, and must be addressed
clinically to reduce the incidence of vascular disease.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Prevalence and Impact of the Metabolic Syndrome

Twenty five percent of adults in the United States aged 20 to 79 years have the metabolic
syndrome as defined by the NCEP, while in people above the age of 50 years, 40% to 45%
or more may have it. There are also ethnic differences in the distribution of the metabolic
syndrome. Type 2 diabetes is more common in all other ethnic populations when compared
to white populations, and the metabolic syndrome follows the same pattern. In fact, the
highest prevalence of the metabolic syndrome is in Mexican American men and Mexican
American women, according to recently published data from the Centers for Disease Control
and Prevention.[17]

Metabolic syndrome frequently precedes the development of diabetes, and it is also a risk
factor for heart disease. An important longitudinal study of the large Mexican American
population of the city of San Antonio compared people over 8 years of age who remained
nondiabetic to those who went on to develop diabetes. The individuals who eventually
developed diabetes were those who had slightly more central abdominal fat, higher
triglycerides, lower HDL cholesterol, and higher systolic blood pressure. They also statistically
had significantly elevated fasting glucose at baseline. Their fasting insulin levels were also
about twice as much, meaning that these individuals had insulin resistance.[18]

Additional data from the San Antonio Heart Study revealed that as insulin sensitivity
decreased, HDL cholesterol decreased progressively, triglycerides increased, and both
systolic and diastolic blood pressure increased.[18,19]
 Figure 3. Elevated risk of CVD prior to clinical diagnosis of type 2
diabetes.

These data are supported by recent 20-year prospective analyses of the Nurses' Health
Study. In this very large population it was shown that the risk of cardiovascular disease
indeed occurred prior to the clinical diagnosis of type 2 diabetes [20] (Figure 3).

In Figure 3, the women who remained nondiabetic throughout the study were assigned a
relative risk of developing heart disease of 1. For those who received a diagnosis of diabetes
after entry into the study, the relative risk for developing heart disease was 3.5 to 4. The risk
for those who had diabetes at baseline was 5. However, even those women who had not yet
been diagnosed with diabetes were having cardiovascular events at a 2.8-fold higher rate
than those who remained nondiabetic throughout the study.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Dyslipidemia in Diabetes

Dyslipidemia in diabetes typically consists of lipid abnormalities that arise years before the
diagnosis of diabetes. Whether a person has diabetes, metabolic syndrome, or insulin
resistance, they tend to have higher triglycerides, increased very low density lipoprotein
(VLDL), and higher levels of small, dense LDL, with or without some increase in the LDL,
while the HDL is usually low.

The prevalence of dyslipidemia is greater among patients with diabetes, particularly women.
An analysis of the second NHANES (NHANES II) revealed that women with diabetes had
twice the prevalence of lipid abnormalities as nondiabetic women. In addition, a fairly
significant proportion of both men and women with diabetes had lower HDL and more
elevated triglycerides than those who did not have diabetes.[21]

Furthermore, in MRFIT, when the age-adjusted cardiovascular disease death rate in patients
with type 2 diabetes was examined according to the levels of total cholesterol, there was a
considerable increase, even among patients with mild elevations (eg, at less than 180 mg/dL
of total cholesterol, equivalent to an LDL of 100 to 110 mg/dL). A similar examination of the
relationship between elevated blood pressure and cardiovascular disease mortality showed
that not only was the risk obviously higher in people with high blood pressure, but people
with diabetes who have systolic blood pressure between 120 and 160 mm Hg have a greater
than 2-fold higher risk of mortality.[8] This reaffirms the increased susceptibility of the
vasculature at each increment of blood pressure.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

The Vascular Injury in Patients With Diabetes

We still are attempting to understand the many factors that contribute to the accentuation of
atherogenesis in diabetes. Receiving a great deal of attention are the early events leading to
the formation of advanced glycosylation end products and the consequences of these end
products, as well as subclinical inflammation. All of these factors result in oxidative stress,
which in turn results in subtle changes in the endothelium at the cellular level, leading to
atherogenesis. In addition, current research shows that nitric oxide synthesis is reduced in
the presence of increased oxidative stress. It is also known that angiotensin II is involved in
perpetuating this process.

Currently, there is considerable debate as to whether C-reactive protein (CRP) should be

measured as a marker of subclinical endothelial inflammation. CRP is almost always
increased in patients with type 2 diabetes, and may even precede the diagnosis. Data from
such trials as the Women's Health Study indicate that subclinical inflammation does correlate
with the increased risk of cardiovascular events. In that study, women with a normal CRP but
documented metabolic syndrome or those with high CRP and no metabolic syndrome both
had a decrease in risk-free survival relative to women who had neither the metabolic
syndrome nor a high CRP level. Moreover, women with both the metabolic syndrome and a
high CRP had the worst prognosis for cardiovascular disease. [22]

There may be some situations--particularly in those patients who are in the intermediate risk
category such as those with 10-year CHD risk at 10%-20% according to ATP III
guidelines [23] --where measurement of CRP may be helpful, particularly in the nondiabetic
population or prediabetic population. Since the level of CRP increases according to a number
of metabolic syndrome risk factors,[24] a high CRP may be a good indicator of metabolic risk
due to endothelial injury. An analysis of data from the Framingham Heart Study confirmed
that CRP can serve a role as a prognostic marker. [25] In addition, recent studies have
reported a decrease in CRP levels with statin treatment, and a greater decrease with higher
doses of certain statins [26-28] although the clinical implications of this finding are unclear.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical

Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

The Impact of Multifactorial Intervention

The Steno-2 trial (from the Steno Diabetes Center in Denmark) was a multifactorial
intervention in people with type 2 diabetes that examined the effects of a comprehensive
approach to managing multiple risk factors in these patients. This study followed 160
subjects with microalbuminuria over 8 years to examine the impact of 2 interventions. All
patients received behavior modification, whereas only one group received, in addition, much
more aggressive intervention for glycemic control, hypertension, dyslipidemia, and
microalbuminuria. [29]

The intensive therapy consisted of better diet, a practical exercise strategy, and smoking
cessation. Glycemic control was attempted with oral agents and/or insulin as needed. For
management of hypertension, a number of agents, including diuretics, angiotensin converting
enzyme inhibitors (ACE-I), calcium channel blockers, and beta blockers were prescribed as
needed. Statins and fibrates were used as needed to achieve good control of both LDL and
triglyceride abnormalities.[29]
 Figure 4. Steno-2: multifactorial intervention and CVD in type 2
diabetes: impact on risk factors.
This long-term study demonstrates how difficult it is to achieve the desirable goals of
glycemic management. Even after comprehensive, intensive therapy and motivation, less
than 20% of the subjects achieved normal hemoglobin HbA 1c (A1C) concentrations less than
6.5% (Figure 4). About 70% of the patients in the intensive therapy group were able to
achieve a significant improvement in total cholesterol level, but triglyceride differences
between the 2 groups were not significant. [29]

The systolic blood pressure goal of less than 130 mm Hg was achieved in about twice as
many people in the intensive therapy group. Diastolic blood pressure, which is somewhat
easier to control, was well controlled in both groups. [29]

Figure 5. Steno-2: multifactorial intervention and CVD in type 2

diabetes: impact on end points.

Although success was less than perfect in the reduction of risk factors, the risk factor
improvement was certainly better in the intensive therapy group. With this comprehensive
approach, a 53% reduction in the combined endpoints of cardiovascular disease was seen,
including mortality from cardiovascular disease, nonfatal MI, coronary artery bypass grafting
(CABG) surgery, revascularization with stents, nonfatal stroke, amputation, and surgery for
peripheral artery disease[29] (Figure 5).

In addition, there were major reductions in nephropathy, retinopathy, and autonomic

neuropathy. This led the authors to conclude that a targeted, long-term, intensified
intervention aimed at reducing multiple risk factors decreases quite significantly the risk of
both cardiovascular and macrovascular endpoints.[29]
Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical
Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Current Risk-Reduction Strategies

The Steno-2 study and other evidence-based strategies support current treatment
recommendations, which are:

The A1C goal for all patients should be less than 7%, and even lower if possible.

The LDL goal for all patients with diabetes is less than 100 mg/dL, and LDL less than
70 mg/dL is a therapeutic option in patients at very high risk (eg, who have type 2
diabetes plus coronary heart disease or other risk factors).

The goal for blood pressure should be less than 130/80 mm Hg.

Aspirin should be administered to all adult patients, unless contraindicated.

ACE-I or angiotensin II receptor blocker (ARB) should be a part of the therapeutic

regimen for people with diabetes who have albuminuria or are above age 55 years,
and have 1 additional risk factor; this is based on the results of the Heart Outcomes
Prevention Evaluation (HOPE) study.[30]

Beta-blockers should be prescribed for patients with concomitant diabetes and

coronary artery disease. For reducing mortality, the benefits outweigh the risks of
these agents.[31]

Unfortunately, despite the availability of these proven strategies, the vast majority of patients
with diabetes all over the world (including the United States) are not reaching recommended
goals. Greater awareness of the need to reach those goals and further dissemination of
proven strategies should lead to better patient outcomes over the long run. It is important to
note that any reduction in A1C, lipids, and blood pressure benefits patients with diabetes
even if they do not reach these goals.[31,32]

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Characterizing Dyslipidemia in Type 2 Diabetes and the Metabolic Syndrome

Figure 6. Vascular effects of risk factors: elevated LDL-C plays key

role in disease progression.

Considerable data have accrued suggesting a key role for low-density lipoprotein (LDL) in
determining vascular risk, and it plays this role at multiple stages of the disease. During the
initiation phase, LDL contributes to the development of the atherogenic plaque. During the
progression phase, the Glagov hypothesis suggests that as the lipid core becomes much
larger, outward remodeling occurs. The crucial stage, in terms of coronary events, is plaque
rupture, and the risk of rupture is believed to be enhanced by a large lipid core [33]
(Figure 6).

In addition, there is evidence that modifications of lipoproteins, particularly LDL, enhance

their uptake in macrophages, in the production of foam cells.[9] So what characterizes
dyslipidemia in type 2 diabetes and the metabolic syndrome? The previous section
underscored that elevated triglycerides and average LDL cholesterol levels occur in most
people with type 2 diabetes and noted that the composition of the lipoproteins changes so
the particles are smaller, denser, and more atherogenic. [35]

A direct measurement of the number of particles, such as of an apolipoprotein B (APO-B),

reveals that this number is increased. Some groups, such as the Canadian advisory group,
now suggest measuring APO-B as well as LDL cholesterol in some patients. [36] In addition,
there are clearly increases in chylomicrons in very low density lipoproteins. When these are
acted upon by lipoprotein lipase, they form remnants, are atherogenic, and have low high-
density lipoprotein (HDL). [37] These changes occur not only with type 2 diabetes, but also in
people with the metabolic syndrome and prediabetes. Non-HDL cholesterol, which has
recently been identified as a secondary target by the National Cholesterol Education
Program, Adult Treatment Panel III (NCEP, ATP III, [11] is also elevated in type 2 diabetes.

Figure 7. Glucose intolerance increases risk for

dyslipidemia/hypertension: Botnia study.
The Botnia study, performed in Finland, looks at dyslipidemia (Figure 7), defined in this case
as high triglycerides and/or low HDL. This study reveals that the lipid abnormalities are
relatively more severe in people with type 2 diabetes when they are present, and at
intermediate levels for people with impaired fasting glucose (IFG) and impaired glucose
tolerance (IGT), relative to subjects with normal glucose tolerance. It also shows that not only
are lipid abnormalities present when there is IFG and IGT, but also increased blood
pressure. [38]

As discussed, the LDL cholesterol goals in both the NCEP and American Diabetes
Association (ADA) are less than 100 mg/dL. This means that LDL is treated to the same
degree of intensity in people with diabetes as in people with cardiovascular disease. This is
based on meeting 3 criteria:

1. The risk of vascular disease in diabetic subjects without pre-existing vascular disease
is similar to that in nondiabetic subjects with pre-existing vascular disease.

2. Intensive glycemic control alone will not completely eliminate the excess risk of
coronary heart disease (CVD). This is important because, in fact, glycemic control has
some effect on CVD risk, but the slope of the line is not sufficiently great that
glycemic control alone can be the goal.

3. The evidence is now overwhelming that lipid and blood pressure interventions to
reduce coronary heart disease are equally effective in subjects with and without
diabetes.

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

How Blood Pressure and Glycemia Relate to Cardiovascular Disease and

Microvascular Complications

Figure 8. MI and microvascular end points: incidence by mean systolic

BP and A1C concentration.
Data from the United Kingdom Prospective Diabetes Study (UKPDS) show some similarities
in the effects of blood pressure and glucose control on microvascular and macrovascular
disease[9,32] (Figure 8). The left side of Figure 8 shows the average systolic blood pressure
over 10 years. The green line is myocardial infarction (MI), and the red line is microvascular
disease. Note that these 2 lines are parallel, meaning the effect of systolic blood pressure on
microvascular and macrovascular disease is similar.

Secondly, MIs are more common than microvascular events in newly diagnosed patients with
diabetes. A third point that is relevant to the establishment of treatment guidelines is that
there is no evidence that at very low blood pressures there might be an increased risk of
complications. In all studies in subjects with diabetes, both microvascular and macrovascular
disease declined with lower blood pressure.

This is an important issue because the Hypertension Optimal Treatment (HOT) trial, a
randomized controlled trial, justifies diastolic blood pressure goals of less than 80 mm Hg
without corresponding evidence for a 130 mm Hg systolic goal. [39] The UKPDS tests in a
randomized design the effects of a systolic blood pressure of 145 mm Hg vs 155 mm Hg. [40]
So the currently recommended systolic goal of less than 130 mm Hg is a compromise,
halfway between the implications of the clinical trial data and those of the epidemiologic data.

The chart on the right side of Figure 8 reflects the effect of A1C levels on event rates and
covers a large range from 5.5% to 11%. It demonstrates that the risk of MI doubles from one
extreme to another, showing that A1C is related to CHD. However, if we calculate the size of
the effect, each 1% change in A1C is equivalent to about a 15% rise in risk of MI. Therefore,
even if you bring someone's A1C level down from 10% to 6%, it is unlikely you will fully
eliminate the 2- to 4-fold excess of cardiovascular disease in people with diabetes. On the
other hand, a 15% change per 1% A1C is not trivial. A 2% change in A1C would reduce risk
30%, an effect similar to that seen in statin trials. [41] Therefore, it makes sense to use both
approaches -- glucose and lipid control -- in at-risk people.

Another reason to further examine the chart on the right side of Figure 8 is to understand
why the slope is relatively gentle, reflecting modest impact of A1C on event risk. A possible
explanation is that there is already increased risk of cardiovascular disease prior to the onset
of type 2 diabetes. The increased triglycerides, decreased HDL, increased systolic blood
pressure, and increased glucose and insulin levels that these patients have are all
components seen in the various definitions of the metabolic syndrome, thus combining their
effects to increase macrovascular risk beyond that which relates to A1C alone.

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD
Current Control of Risk Factors

Figure 9. Risk factor control in adults with diabetes:

NHANES III (1988-1994)/NHANES (1999-2000)
A recent paper in the Journal of the American Medical Association (JAMA) compared what
has been happening over time to control of risk factors in subjects with diabetes (Figure 9).
In this figure, the red bars represent National Health and Nutrition Examination Survey
(NHANES) III (1988-1994). What this shows is that, while blood pressure, total cholesterol,
and total glucose control have all improved, A1C control has actually deteriorated.[42]
Clearly, given these percentages, we are still a very long way from having most of our
people with diabetes under control. This is especially true since less than half of these
people have adequate cholesterol control, even though a LDL cholesterol level of 100 mg/dL
can be achieved by statins alone.

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Statin Therapy in Patients With Diabetes

How effective are statins in the overall population and in people with diabetes? Generally,
the evidence from major coronary heart disease primary prevention trials such as the Air
Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) and secondary
prevention trials such as Cholesterol and Recurrent Events (CARE), the Scandinavian
Simvastatin Survival Study (4S), and Long-Term Intervention with Pravastatin in Ischaemic
Disease (LIPID) show that coronary heart disease reduction in the overall population is
paralleled in people with diabetes,[43-47] although the data for secondary prevention are
more impressive than that for primary prevention. The Heart Protection Study (HPS) included
about 6000 people with type 2 diabetes and examined the effects of simvastatin vs placebo
on 5-year rates of first major vascular event. Patients in this study could enroll either with
arterial disease and diabetes, occlusive arterial disease alone, or diabetes alone. [48]

HPS also showed that the effectiveness of statins at reducing cardiovascular events was the
same in people with diabetes who had either an LDL cholesterol below 116 mg/dL or above
116 mg/dL. HPS was half secondary and half primary prevention, and the data by LDL
cholesterol have not been broken out for the diabetic primary prevention population. There
was also an analysis of people with type 1 diabetes in this study. About 600 people had type
1 diabetes, and, although the results were not statistically significant, they showed the same
benefit as in the people with type 2 diabetes.[48]

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Cholesterol-Lowering Goals in Patients With Diabetes

The 2 major sets of recommendations for managing dyslipidemia that clinicians in the United
States follow are those of the NCEP and the ADA. [11,49] In both of these sets of
recommendations, lowering LDL cholesterol is the primary goal, and the LDL goal is less
than 100 mg/dL. Recently, the ADA goals have been revised to suggest that all patients with
diabetes should be treated to less than 100 mg/dL,[14] and the American College of
Physicians has recommended that all patients with diabetes should be treated with
statins. [50] This is evidence of considerable evolution recently.

Table 4. NCEP ATP III and ADA: Treatment Goals in Patients With
Diabetes

Table 4 compares the ADA and the NCEP recommendations, showing how the primary
targets are the same. For the NCEP, non-HDL cholesterol (total cholesterol minus HDL
cholesterol) is a secondary target; whereas for the ADA it is HDL and then triglycerides.
Thus, there are really more similarities than differences in these guidelines.

Table 5. ADA: Treatment Recommendations

To achieve these goals, the ADA recommends lifestyle interventions plus statins (Table 5).
Other drugs are discussed, including:[49]

Resins, which are not commonly in use both because of their marked side effects and
because they raise triglyceride levels

Cholesterol absorption inhibitors such as ezetimibe are effective but not as potent as
statins in lowering LDL cholesterol

Niacin, an agent that has shown an appreciable ability to lower LDL but can worsen
glucose tolerance

Fenofibrate, a drug that appears to have only a very modest effect in reducing LDL
cholesterol levels (5% to 6%)

There is no question that raising HDL is difficult, and the most effective options for this
clearly are nicotinic acid and fibric acids; they are discussed in more detail later.

When it comes to reducing triglycerides, the ADA strongly recommends lifestyle interventions.
Weight loss and increased physical activity can be a very effective approach. Further, for
patients with poorly controlled diabetes, significant improvement in glycemic control can
sometimes have a considerable effect on triglycerides.

Treatment with fibric acid derivatives such as fenofibrate or gemfibrozil is also very useful.
Note that gemfibrozil increases risk of myositis in people on statins and niacin. Fenofibrate
would be preferable if fibric acid and statins are used together. High-dose statins may also
be effective in lowering triglyceride levels.[49] Not shown in Table 5, because it is not in the
ADA guidelines, but still useful in lowering high triglyceride levels, are fish oils.

Lowering of LDL is the primary goal of the NCEP. This group, too, recommends statins as
the first choice therapy, with bile acid sequestrants or nicotinic acid the second choice (this
predated the use of ezetimibe). The secondary goal is lowering non-HDL cholesterol; it
becomes a target if the triglycerides are 200 mg/dL or higher.

In the past, the NCEP recommended a high-carbohydrate, low-fat diet for people with insulin
resistance, but they have since modified those recommendations to suggest a fat intake of
between 25% and 35% of total calories. They also suggest weight reduction for the obese--
and almost all patients with diabetes are--and increased physical activity. [11]

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Benefits of Statin Therapy

Statin therapy inhibits cholesterol synthesis and increases LDL receptors. These agents are
the most effective available to lower LDL, although the amount of LDL lowering differs
markedly among the statins. [51] The amount of HDL-raising achieved by this class is
generally modest, but they differ in their effect. Meanwhile, the amount of triglyceride
lowering also differs among statins and, importantly, it is much greater in people who start
with higher levels of triglycerides. In clinical trials, statins have been shown to offer up to a
40% reduction in coronary heart disease and stroke. This effect appears to be attributable
mainly to differences in LDL levels.

There has been considerable discussion of the pleiotropic effects of statins, although some
think that the idea that these medications have multiple effects has been overemphasized.
There is some evidence that statins improve endothelial function, have anti-inflammatory
effects, enhance plaque stability, and attenuate vascular smooth muscle cell proliferation. [52]
While there has been much discussion of this over the last 5 years, more data need to be
collected on these issues to confirm such speculation.

There are adverse effects of statins, the most significant of which include:[53]

Myalgia (muscle pains), which is seen in about 2% to 4% of patients

Myopathy including rhabdomyolysis (very rare: Incidence = 0.5-1 in 10,000
patients)
Increased values on liver function tests (LFTs)
Contraindications to statin therapy include liver disease, defined by the US Food and Drug
Administration (FDA) as a repeated finding of 3-fold higher LFT levels than the upper limits
of normal. The potential for hepatotoxicity and the need to monitor LFTs is one of the major
limitations of statin therapy. Usually with placebo the incidence of FDA-defined liver function
abnormalities is 0.2% to 0.3%; it can be seen in up to 1% of individuals on statin therapy,
rising with the highest doses of statins, which, in some cases, can result in significant LFT
elevations in 2% or 2.5% of people on statins. [53]

Myopathy is generally defined as a creatine kinase greater than 10-fold the upper limit of
normal. Creatine kinase should be measured at initiation of statin therapy to determine the
patient's baseline value. It is not useful to follow creatine kinase levels during therapy,
because they do not predict who will ultimately develop myopathy. Myopathy occurs in about
1 in every 1000 subjects at baseline levels of statins (pravastain 40 mg, simvastatin 20 mg,
or atorvastatin 10 mg). Rhabdomyolysis is said to occur in less than 1 of every 10,000
people on statins. [53] The actual risk is lower for people who do not have renal disease, or
for those not using a combination of statins and fibric acids.

The risk of myopathy may increase with dose escalation. It also clearly occurs when statins
are used in combination with fibric acid, so in such instances it is important to weigh
treatment risks against anticipated benefits. Remember that when a statin is used in
combination with a fibric acid, the fibric acid should be fenofibrate, and this combined
treatment should be utilized with caution in people with renal insufficiency. Niacin in
combination with statins appears to have a much lower risk of myopathy. In nearly all cases,
myopathy is reversed after discontinuation of the statin or fibric acid. [53]

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Use of Other Lipid-Lowering Agents

Ezetimibe is a newer agent that blocks cholesterol absorption. Studies show that, when used
as monotherapy, this agent lowers LDL by about 18%. It is mainly used in combination with
statins, and it has been suggested that it is equivalent to a 3-dose titration of statins (statin
10 mg to 80 mg). Particularly with higher doses, the effect may be somewhat less, maybe a
2-fold dose elevation. This agent causes some decrease in triglycerides (unlike resins, which
raise triglycerides), and a very small increase in HDL is seen.[54] This agent has very few
side effects; however, there currently are no long-term safety data on mono- or combination
therapy with ezetimibe although a large-scale clinical trial in renal failure (n = 9000) is
currently underway.

Fibric acids (including gemfibrozil and fenofibrate) are mainly indicated for treatment of
elevated triglycerides. Fibric acids are known to increase peripheral lipolysis and decrease
hepatic triglyceride production. They also have a peroxisome proliferator-activated receptor
(PPAR)-alpha mechanism. These agents are very effective in lowering triglycerides by 25%
to 50%. They are actually more effective in lowering triglycerides than is nicotinic acid,
although they are less effective at raising HDL.[55]

Use of fenofibrate generally does not increase LDL. It may remain stable or drop by 5% to
10%. Adverse effects include gastrointestinal upset (8%), cholelithiasis, myositis, and
abnormal LFTs. Gemfibrozil is not used as often, even though most of the available clinical
trial data are actually with gemfibrozil. In the Veterans Affairs High-Density Lipoprotein
Cholesterol Intervention Trial (VA-HIT), there was a 24% reduction in the primary endpoint of
fatal and nonfatal coronary heart disease in patients taking gemfibrozil. [56] Note that,
although this study was in people with very low LDLs and HDLs, these results were not
necessarily better than those of other studies, eg High-Risk Patients with Statins (HPS), or
Collaborative Atorvastatin Diabetes Study (CARDS), discussed later in this document.

Nicotinic acid is probably the most controversial cholesterol-lowering drug. It is available both
in immediate release and extended release. The dose range has been truncated for
extended release (maximum 2 g/day), but is often not difficult to tolerate at this dose. In
terms of potency it is the best agent for raising HDL-C. However, it is widely recognized to
have many side effects, such as increases in LFT values, particularly the sustained release
formulation. This is why it is contraindicated in patients with active liver disease or
unexplained LFT elevations. Note that nicotinic acid worsens insulin resistance and increases
hyperglycemia. However, it can be used in patients with diabetes if they are relatively well
controlled and monitor their glucose carefully. In some patients, the benefit of this therapy
may outweigh the risks.

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Combination Therapy for Lipid Lowering

Combination therapy can dramatically improve the lipid profile, and its usage has therefore
increased. This approach may result in a greater lowering of LDL than monotherapy
(particularly when a statin is combined with nicotinic acid). Niacin can effectively lower
lipoprotein(a) (Lp(a)); however, it is important to remember that patients with diabetes do not
have particularly high LP(a) levels unless they have renal failure. In fact, patients with type 2
diabetes may even have somewhat lower Lp(a) levels than nondiabetic subjects. Using
niacin in combination with a statin can significantly improve (increase) particle size, an effect
not usually seen with statin therapy alone. Niacin in conjunction with statins can also
decrease fibrinogen levels. The benefit of treatment with fibric acid derivatives in combination
with statins, as opposed to monotherapy, is also demonstrated by angiography studies and
other data.

The downside of combination therapy includes cost and complexity. While many physicians
worry about the risk of myositis, the risk is overestimated. Even in relatively low-risk patients,
however, drug interactions are a possibility.

There are no outcome data on use of combination therapy. The ongoing Action to Control
Cardiovascular Risk in Diabetes (ACCORD) trial is enrolling 10,000 participants at 70 clinical
centers in the United States and Canada to compare the effects of intensive glycemic control
and intensive blood pressure control on major cardiovascular-related events. This study
includes an arm that will assess intensive lipid control (including combination therapy) in
5800 of the participants. [57] This may help to resolve some of these issues, although the data
are unavailable at the time of the present writing. This study is discussed later in this
document.

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Background on the CARDS Trial

The CARDS trial, which was presented at the 64th Annual ADA meeting in June 2004 has
now been published in The Lancet.[58]

This study was performed only in people with type 2 diabetes, making it the first study
exclusively performed in people with this condition. This was a primary prevention
population, with subjects having at study entry no history of previous MI or coronary heart
disease, and LDLs less than 160 mg/dL. The median LDL was in fact 120 mg/dL, which is
lower than in the general population.[58] Subjects also had to have at least 1 other
cardiovascular risk factor. It is likely that about 80% of subjects had the metabolic syndrome.

Subjects numbering 2830 were to be followed until either 304 primary cardiovascular events
occurred or 4 years of double-blind treatment was completed, whichever came first. The
study was stopped about 2 years early because of highly significant findings, but the median
follow-up was still 3.9 years. [58}

At baseline, about a third of the people were women, and the average age was 61 years.
The average body mass index (BMI) was 28.8. The study was performed in the United
Kingdom.[58] This BMI would have been considered obese for that population, but less obese
than in a typical American population. (The average BMI among non-Asian US diabetic
subjects is about 31).

The baseline LDL averaged 118 and 119 mg/dL for placebo and atorvastatin groups,
respectively. In both groups, 25% of the people had LDLs below 100, and 25% had LDLs
above 137 mg/dL. The triglycerides averaged 150 mg/dL in each group, not remarkably
high. [58] The ADA technical review by this author, published in Diabetes Care in January of
1998, showed an average triglyceride level of about 160 mg/dL in the United States for a
similar population.[59] So the CARDS population's triglyceride levels were not far from that of
the US population.

Figure 10. CARDS: lipid levels by treatment.

In CARDS, the average treatment difference in LDL cholesterol was 40% (Figure 10). There
was also only a 1% change in HDL (unlike in other clinical trials, where atorvastatin 10 mg
caused a 4% to 5% increase relative to placebo), and a 21% reduction in triglyceride levels
(data not shown). This is a little better than what is usually seen with atorvastatin 10 mg at a
triglyceride level of 150 mg/dL. In sum, CARDS results demonstrated a 40% LDL differential,
no major change in HDL, and a 21% mg/dL triglyceride reduction between the atorvastatin
10-mg group and the placebo group.[58]
 Figure 11. CARDS: cumulative hazard for primary endpoint
As this Kaplan-Meier graph shows, the atorvastatin arm had a 37% relative risk reduction
(Figure 11). The primary endpoint of this study was reduction of fatal and nonfatal coronary
events, strokes, and coronary revascularization procedures. By about a year into the study
there was a fairly clear separation of LDL cholesterol levels, leading to the 37% reduction in
cardiovascular events (significant at a .001 level). There were a total of 210 cardiovascular
events; 127 in the placebo group and 83 in the atorvastatin group.[58]

After 3.9 years of follow-up, the overall event rate was 2.2%. In the Steno-2 study discussed
previously, there was a 5% event rate, [29] but those patients had type 2 diabetes with
microalbuminuria, which can have a dramatic effect on cardiovascular events.[60] In CARDS,
there was a 36% reduction in acute coronary events, including fatal and nonfatal MI, as well
as a 31% reduction in revascularization procedures, and a 48% reduction in stroke in the
atorvastatin group compared to the placebo group. And all of these were significant except
for the coronary revascularization. [58] (Note that in US trials, we might expect to see as
many coronary revascularizations as acute coronary events. The figure for coronary events is
twice as high in the United Kingdom, most likely because they do many fewer bypasses.)

As in the HPS, there was the same benefit in people whose baseline LDLs were below 120
mg/dL, half of whom were below 100 mg/dL.[58] This strongly reinforces the idea that patients
with diabetes, even those without preexisting vascular disease, may benefit from statin
therapy regardless of their LDL levels.

It is important to note that statin therapy also had appreciable benefits for people who had
lower HDL levels, and the effect seemed to be similar for people with both higher and lower
triglyceride levels. This seems to show that, even in instances when fibric-acid treatment
might be thought of as optimal, statins appear to work at least as well. In the CARDS data,
there is an average 37% reduction in cardiovascular events as opposed to the 24% seen in
VA-HIT. [56,58]

One of the more impressive results from CARDS was the 27% reduction in all-cause
mortality (data not shown). While the results from CARDS are not statistically significant, at P
= .059 they were very close to significance. [58} To put this into perspective, the 4S study
showed only a 30% reduction (P < .01). [45] However, the CARDS study did not include
people with prevalent coronary heart disease with very high LDLs. To show an effect similar
to what was seen in 4S for patients with diabetes but without CHD at baseline and who had
LDLs averaging 120 mg/dL, as CARDS has done, is particularly impressive in favor of
atorvastatin. Had the trial gone to completion, there would likely have been a significant
difference in all-cause mortality.

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Summary of CARDS Findings

The CARDS data strongly demonstrate the safety and benefits of lipid-lowering drugs.
People often talk about safety in terms of myopathy and liver function abnormalities, but what
safety really consists of are hard events--whether you live or die. In this regard, the CARDS
data are impressive.

The CARDS investigators saw a significant reduction in cardiovascular events in people who
had type 2 diabetes but no preexisting vascular disease. They saw a reduction almost by
half in stroke. The reductions achieved were independent of baseline LDLs. Interestingly, the
investigators also found a slight decrease in noncardiovascular deaths, such as cancer and
accidents (data not shown), factors that traditionally are a source of concern among statin
users. Also, there were no cases of rhabdomyolysis, and LFTs were comparable in the 2
treatment groups. [58]

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Going Beyond Conventional LDL Goals

There is growing interest in the impact of lowering the LDL beyond conventional goals. The
New England Journal of Medicine in April 2004 reported on the Pravastatin or Atorvastatin
Evaluation and Infection Therapy (PROVE-IT) trial. This is a large study of 4162 patients who
had the acute coronary syndrome (ACS) at study entry and were randomized to take
pravastatin 40 mg or atorvastatin 80 mg, in a 2 by 2 factorial design with a 2-year mean
follow-up. The primary endpoint of this trial is death from MI, unstable angina,
revascularizations, or stroke, which is actually very similar to the primary endpoint in the
CARDS trial. [61]

This trial demonstrated a 49% reduction in LDL-C with atorvastatin 80 mg, and a 21%
reduction with pravastatin 40 mg (data not shown). The LDLs achieved were 95 mg/dL in
the pravastatin group (meeting NCEP criteria) and 62 mg/dL in the atorvastatin group
(considerably better than NCEP). More importantly, the trial demonstrated a 16% reduction
in clinical events that appeared to occur early after the initiation of high doses of atorvastatin.
While this is not as large as was seen in CARDS, there was an active comparator
(pravastatin 40 mg) in this trial. [61] In addition, this was a 2-year study, not a 4-year study,
and so the implications of comparing primary prevention to ACS at baseline are not clear.
Nevertheless, these results are impressive.

Also worthy of note in the PROVE-IT trial is the subgroup analysis. In the placebo group,
even among those subjects who had ACS, people with diabetes had a 60% higher event
rate than people without diabetes. This demonstrates that, even among patients with
documented coronary heart disease, diabetes further increases risk. The treatment effect was
similar in the diabetic and nondiabetic groups although they were not quite statistically
significant for the people with diabetes.[61]

The LFT changes in PROVE-IT, as reflected by 3-fold LFT elevations, were significantly
different among the treatment groups comprising PROVE-IT, although this is not really a
surprise. As with CARDS, there were no cases of hepatitis and no cases of rhabdomyolysis,
and the differences were not statistically significant for myalgias or creatine kinase
elevations, so both therapies were well tolerated. [61]

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Other Continuing Trials in Aggressive Lipid-Lowering Therapy

 Table 6. Major Ongoing Lipid Trials
There are many other current trials that are attempting to examine the effect of more
aggressive lipid lowering on outcomes (Table 6). PROVE-IT is an example of a study
suggesting some high-risk subjects may benefit from LDLs much lower than 100 mg/dL. The
NCEP has recently suggested that clinicians consider a lower LDL-C target (< 70 mg/dL) in
very high-risk patients (NCEP White Paper). The 4 groups identified by the NCEP as high
risk include people with cardiovascular disease with at least one of the following: diabetes,
multiple risk factors (especially current cigarette smoking), metabolic syndrome, and ACS. [11]
The new white paper also suggested that cardiovascular disease patients with an LDL
cholesterol less than 100 mg/dL might benefit from lipid lowering. The recommendations
suggested that LDL lowering be at least 30% to 40%.[62]

More definitive data on this topic will come out of 2 big clinical trials, which are expected
soon. These are Treatment to New Targets (TNT) (expected report at the 2005 meeting of
the American College of Cardiology [ACC]) and the Study of Effectiveness of Additional
Reductions in Cholesterol and Homocysteine (SEARCH) (expected report at 2006 ACC).
Each of these trials has about 10,000 subjects and both start with people with documented
coronary heart disease. They also have similar primary endpoints of coronary artery disease
death and nonfatal MI or stroke. TNT compares atorvastatin 10 mg to atorvastatin 80 mg;
SEARCH compares simvastatin 20 mg to 80 mg, plus or minus vitamin B12 and folate.
While SEARCH also sets out to test the homocysteine hypothesis, that topic is beyond the
scope of this monograph. [63]

In addition, there is the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)
study, which has about 6000 subjects, including a subgroup consisting of about 20%
diabetes patients. Since this study is examining the use of fenofibrate, it may not change
clinical practice because the data on statins are so persuasive. [63]

Another study, called IDEAL (Increment Decrease in Endpoints through Aggressive Lipid
Lowering), is being conducted in Scandinavia with 8888 subjects. IDEAL is examining the
effect of simvastatin 20 mg to 40 mg vs atorvastatin 80 mg, on major cardiovascular
endpoints.[64]

Finally, there is the ongoing ACCORD trial mentioned earlier, one arm of which includes
5800 subjects and compares simvastatin 20 mg, plus or minus fenofibrate. This trial
examines the effects of combination therapy, and has a narrow endpoint: Coronary artery
disease death or nonfatal MI. The ACCORD trial is also studying 2 other very important new
perspectives: First, 10,000 subjects will be treated to an A1C goal of less than 6%, vs the
standard 7.5% target. As you can imagine, achieving an A1C of 6% is a very difficult task,
but the investigators have actually gotten some of their subjects pretty close to that so far.
Also, there is a systolic blood pressure intervention in a subgroup of 4200 subjects that
compares a systolic blood pressure of less than 140 mm Hg to one of less than 120 mm
Hg. [57]

In conclusion, as the Steno 2 study shows, multiple interventions are likely to have dramatic
effects on coronary heart disease. From 2002 to 2004, major new lipids trials (HPS, CARDS,
and PROVE-IT) have shown that statins have dramatic effects in subjects with
diabetes.[48,58,61] NCEP recommendations now suggest that all diabetic subjects, regardless
of baseline LDL cholesterol, may benefit from statin therapy.[11] The LDL cholesterol goal is
less than 100 mg/dL.[11,49] Additionally, it has suggested even more aggressive therapy may
be indicated in diabetic subjects with cardiovascular disease, perhaps to as low as below 70
mg/dL.[62]
Joslin Diabetes Center Guidelines for Screening and Management
of Dyslipidemia Associated with Diabetes
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.
Haffner, MD

Screening

Adults should be screened annually for lipid disorders with measurements of serum
cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) and high-density
lipoprotein (HDL-C), preferably fasting.

Lipid Goals

LDL-C: Less than 100 mg/dL

Triglycerides: Less than 150 mg/dL (fasting)

HDL-C: Greater than 40 mg/dL for men; greater than 50 mg/dL for women

Treatment

All patients should receive information about a meal plan designed to lower blood glucose
(BG) and alter lipids, physical activity recommendations, and risk reduction strategies.
(Consult with appropriate education discipline is preferred.) Institute therapy after abnormal
values are confirmed.

If LDL-C greater than 100 mg/dL

Optimize glycemic control

Refer to registered dietician (RD) for intensive dietary modification

Consider referral to exercise specialist or diabetes educator (DE) for exercise

prescription

Recheck lipids within 6 weeks

If LDL remains greater than 100, initiate medication with goal of lowering LDL by at
least 30% or to less than 100, whichever is lower, preferably with a statin

In patients with cardiovascular disease, the goal of LDL cholesterol should be lower
(approximately 70 mg/dL), regardless of baseline level

If LDL-C less than 100 mg/dL

Consider statin therapy if age greater than 40 years, and 1 more cardiovascular disease
(CVD) risk factor is present (hypertension, smoking, albuminuria, or family history of
premature CVD).

Patients with LDL-C less than 100 mg/dL and triglycerides greater than or
equal to 150 mg/dL or HDL-C less than 40 mg/dL

Optimize glycemic control

Refer to RD for dietary modification

Consider referral to exercise specialist for exercise prescription

Recheck lipids within 6 weeks

Consider medication if triglycerides greater than 200 and/or HDL less than 40 mg/dL
(fibrate preferred if triglycerides greater than 500 mg/dL)

In patients with triglyceride levels 200-499 mg/dL, calculate non-HDL-C (total minus
HDL-C) and consider starting or titrating statin if non-HDL-C greater than 130

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2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes:
estimates for the year 2000 and projections for 2030. Diabetes Care.
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3. Mokdad AH, Ford ES, Bowman BA, Nelson DE, et al. Diabetes trends in the
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Authors and Disclosures

It is the policy of Joslin Diabetes Center to ensure fair balance, independence, objectivity,
and scientific rigor in all programming. All faculty participating in CME activities sponsored by
Joslin Diabetes Center are expected to present evidence-based data, identify and reference
off-label product use, and disclose all relevant financial relationships existing within the past
12 months with those entities supporting the activity or any others whose products or
services are discussed, including:

Any commercial product(s) or devices(s)

The manufacturer(s) of any commercial products or devices
The provider(s) of any commercial services

If a faculty member has no information to disclose or refuses to do so, this

information will also be provided.

Author

Richard S. Beaser, MD (Moderator)

Assistant Clinical Professor of Medicine, Harvard Medical

School; Medical Executive Director, Professional Education,
Joslin Diabetes Center, Boston, MA

Disclosure: Consultant: Amgen Inc., Amylin Pharmaceuticals,

Inc., Wyeth Pharmaceuticals; Speakers Bureau: Aventis
Pharmaceuticals, Wyeth Pharmaceuticals.

Om P. Ganda, MD

Associate Clinical Professor of Medicine, Harvard Medical

School; Director, Joslin Diabetes Center Lipid Clinic, Boston,
MA

Disclosure: Grant/Research Support: KOS Pharmaceuticals,

Inc.; Consultant: Merck & Co., Inc., Pfizer Inc, and Takeda
Pharmaceuticals North America, Inc.; Speakers Bureau:
GlaxoSmithKline, KOS Pharmaceuticals, Inc., Merck & Co.,
Inc., Pfizer Inc, Takeda Pharmaceuticals North America, Inc.

Steven M. Haffner, MD

Professor of Internal Medicine, Department of Medicine,

Division of Clinical Epidemiology, University of Texas Health
Science Center, San Antonio, Texas

Disclosure: Consultant: GlaxoSmithKline, Merck & Co., Inc.,

and Pfizer Inc; Speaker's Bureau: GlaxoSmithKline, Merck &
Co., Inc., and Pfizer Inc.

Registration for CME credit, the post test and the evaluation must be
completed online.
To access the activity Post Test and Evaluation link, please go to:
http://www.medscape.com/viewprogram/3743_index