How to Prevent the Progressivity of Type 2 Diabetes,

Insulin Resistance and Prediabetes :

Clinical Consequences and Therapy
Slamet Suyono
Diabetes and Lipid Center
University of Indonesia
Jakarta
UNS Solo 8 Sept 2007
SlametS 2
Scope of the talk
1. Prevention of the Progressivity of Type 2 Diabetes
2. Prevention of the Progression of Insulin Resistance
3. Prevention of the Progression of Prediabetes to Type 2
Diabetes

SlametS 3
1. Prevention of the Progressivity
0f Type 2 Diabetes
100


75


50


25


0
UKPDS :
Natural Progressive Deterioration of b-Cell Function
Years from Diagnosis
Lebovitz H. Diabetes Review 1999;7:139-53
B
e
t
a

C
e
l
l

F
u
n
c
t
i
o
n

(
%
)

-12 10 -6 -2 0 2 6 10 14
Th/Expectation
Facts
Current Treatment is Unsatisfactory
Current Treatments
do not address the pathophysiologic defect of Type 2 DM :
Insulin resistance and
Insulin secretion
Adapted from Type 2 Diabetes BASICS. International Diabetes Center; 2000.
Pancreatic Islet Function Deteriorates over
Time, Causing Disease Progression
Diagnosis
Insulin
Glucose
Prediabetes
(IFG/IGT)
NGT Diabetes
Macrovascular changes
Microvascular changes
Inadequate
-cell function
Postprandial glucose
Fasting glucose
Insulin resistance
Insulin secretion
Why ?
b-Cell Volume Is Significantly Decreased in Obese
IFG and T2DM Patients
IFG = impaired fasting glucose; NGT = normal glucose tolerance;; T2DM = type 2 diabetes
mellitus
*P <.05 vs NGT;

P <.001 vs NGT
0.0
0.5
1.0
1.5
2.0
2.5
3.0
NGT
(n = 31)
IFG
(n = 19)
T2DM
(n = 41)

-
C
e
l
l

V
o
l
u
m
e

(
%
)

*

Adapted from Butler AE, et al. Diabetes. 2003;52:102110.
SlametS 7
The Metabolic Memory
Evidence for a long-term persistence of
hyperglycemia-induced damage
DCC/EDIC Research Group
N Engl J Med 2005
SlametS 8
The Metabolic Memory
The unifying hypothesis suggesting

hyperglycemia-induced free radicals
overgeneration

as the key event in the development of diabetic
complications seem to explain the persistence of the
Metabolic Memory

SlametS 9
The Metabolic Memory
The take-home message is that

good glucose control
should be started as early as possible

to delay or prevent serious diabetes-related
complications
Alan D Cherrington PhD
Presdent
ADA
San Diego 2005
Early and Aggressive Glycemic Control
SlametS 10
7
6
9
8
H
b
A
1
c

(
%
)

10
OAD
monotherapy
Diet and
exercise
OAD
combination
OAD +
basal insulin
OAD
monotherapy
up-titration
Duration of diabetes
OAD +
multiple daily
insulin injections
HbA
1c
= 7%
OAD = oral
antidiabetic
Del Prato S, et al. Int J Clin Pract 2005; 59:13451355.
HbA
1c
= 6.5%
Conservative Management of Glycemia:
Traditional Stepwise Approach
SlametS 11
OAD
+ basal insulin
OAD + multiple daily
insulin injections
OAD
monotherapy
Intensive Management of Glycemia:
Early Combination Approach
OADs
uptitration
7
6
9
8
10
Diet
and exercise
Duration of diabetes
HbA
1c
= 7%
Campbell IW. Br J Cardiol 2000; 7:625631.
OAD = oral antidiabetic
H
b
A
1
c

(
%
)

HbA
1c
= 6.5%
Conservative
management
OAD
combination
OAD
combination
SlametS
12
New Guidelines Help to
Facilitate Best Practice

Despite several sets of regional guidelines for
diabetes management there is a need to standardize
treatment approaches

Therefore, in 2006 the first international consensus
guidelines were developed by the ADA and EASD

ADA, American Diabetes Association
EASD, European Association for the Study of Diabetes
STEP 2:
No strong consensus on the choice of second agent after metformin;
choose from basal insulin (new option), SUs or TZDs (traditional approach)
HbA
1c
levels should influence the choice of agent; basal insulin should
be considered for levels > 8.5%
After 23 months, if HbA
1c
levels are still 7%, proceed to STEP 3
SlametS 13
Adapted from Nathan DM, et al. Diabetologia 2006;49:171121
STEP 1:
Initiate metformin with lifestyle intervention to shorten
the period during which patients experience poor
glycemic control
After 23 months, if HbA
1c
levels are still 7%, proceed
to STEP 2
DIAGNOSIS
LIFESTYLE INTERVENTION AND
METFORMIN
HbA
1c
7%
NO YES

STEP 1
ADD
GLITAZONE

INTENSIFY INSULIN

ADD BASAL
INSULIN

ADD SULFONYLUREA

HbA
1c
7% HbA
1c
7%
NO YES

NO YES

INTENSIVE INSULIN + METFORMIN +
GLITAZONE

ADD BASAL or INTENSIFY INSULIN

STEP 3
Check HbA
1c
every 3 months until HbA
1c
is <7%,
and then at least once every 6 months
Lifestyle Intervention + Metformin
is the First Treatment Step
Combination Therapy is the Most
Effective Treatment After 1 Oral Agent
Insulin Therapy is Usually Required
ADD BASAL INSULIN-
MOST EFFECTIVE
ADD SUFONYLUREA-
LEAST EXPENSIVE
ADD GLITAZONE NO
HYPOGLYCEMIA
STEP 2
OR
OR
HbA
1c
7%
HbA
1c
7% HbA
1c
7% NO
YES

NO YES

NO YES

SlametS 14
The Most Acceptable Choice
Adapted from Nathan DM, et al. Diabetologia 2006;49:171121
DIAGNOSIS
LIFESTYLE INTERVENTION AND
METFORMIN
HbA
1c
7%
YES

STEP 1
ADD
GLITAZONE

ADD BASAL
INSULIN

HbA
1c
7%
NO YES

INTENSIVE INSULIN + METFORMIN +
GLITAZONE

ADD BASAL or INTENSIFY INSULIN

STEP 3
Check HbA
1c
every 3 months until HbA
1c
is <7%,
and then at least once every 6 months
ADD SUFONYLUREA-
LEAST EXPENSIVE
STEP 2
HbA
1c
7% NO YES

SlametS 15
Combination Therapy in T2DM
As a Better Choice to Achieve Goals
I. Insulin plus oral hypoglycemic agents
II. Oral plus other oral hypoglycemic agents
Glucovance (glibenclamide + metformin)
Metaglip (Metformin + glipizide)
Avandamet (Avandia + metformin)
Avandaryl (Avandia + glimepiride)
Amaryl M (glimepiride + metformin)
SlametS 16
Characteristics of Fixed-dose Oral
Combination of Glibenclamide and Metformin
(Glucovance)
Engineered for optimal simplification of drug delivery
Each tablet contains glibenclamide particles in a freely
soluble metformin matrix
Glibenclamide within glucovance is absorbed more
rapidly than standard glibenclamide
SlametS 17
Garber et al ADA 2003
-2.5
-2.0
-1.5
-1.0
-0.5
0
Met-glib
tablets
Mean difference -1.0%
-2.4
-1.4
Rosi + met
co-administered
Metformin-Glibenclamide Tablets vs.
Metformin-Rosiglitazone: Baseline HbA
1C
> 9%
M
e
a
n

D

H
b
A
1
C

(
%
)

Mean daily
dosages 1612 / 8.0 mg 1881 + 7.1 mg
Improved Compliance Following
Switch to Combination Tablets
Data from a retrospective analysis
Melikian et al, Clin Ther 2002;24:460-7
A
d
h
e
r
e
n
c
e

r
a
t
e

(
%
)

Met + glib
co-admin
71
87
40
60
80
100
p<0.001
Met-glib
tablets
Switched from met + glib
co-administered (n=59)
Met + glib
co-admin
54
77
40
60
80
100
p<0.001
Met-glib
tablets
New to combination
therapy (n=1815)
A
d
h
e
r
e
n
c
e

r
a
t
e

(
%
)

SlametS 19
500/2.5 500/2.5
Matrix: Metformin
Glibenclamide
Recently Dx (< 2 yrs) T2DM
No previous OHA or ins Rx
Screen FPG range
126-240 mg/dL

Screen
Randomization/
Baseline
Diet/Exercise
Reinforcement
Run-In
4 weeks
Pre-Screen

FPG
126-240
mg/dL

Monotherapy
Failure
Long-term
Observational
F/U
Study
End
Treatment Period*
4-6 years
Metformin
Glyburide
Rosiglitazone
*All study medication titrated to optimal effect using protocol defined titration steps
ADOPT: Study Design
Viberti GV, et al. Diabetes Care 2002; 25:17371743.
ADOPT: summary of key findings
Larger effects on glycaemia with rosiglitazone in ADOPT
Modest additional benefit vs. metformin and marked additional
benefit vs. glibenclamide
Adverse overall effect of rosiglitazone on cardiometabolic risk
LDL-C, little effect on HDL-C versus metformin
Marked increase in body weight with rosiglitazone versus metformin
or glibenclamide
Fewer serious cardiovascular adverse events with glibenclamide vs.
rosiglitazone
AE profile was generally as expected
Oedema and weight increase with rosiglitazone
GI AE with metformin, hypoglycaemia with glibenclamide
Kahn SE et al. N Engl J Med 2006;355:2427-43
Expert View on the Results of ADOPT
Smaller treatment difference for HbA
1C
vs. FPG
HbA
1C
correlates best with risk of complications
High withdrawal rate weakened conclusions
Extraglycaemic effects of medications highlighted
Weight (rosiglitazone, SU), hypos (SU), GI side-effects (metformin)
Only weak support for b-cell protection and no sign of
cardioprotection with rosiglitazone


Editorial accompanying the publication of ADOPT
Overall: "Given the modest glycemic benefit of rosiglitazone
(with the risk of fluid retention and weight gain) and
higher cost (including the need for more statins and
diuretics), metformin remains the logical choice when
initiating pharmacotherapy for type 2 diabetes."
Nathan DM. N Engl J Med 2006;355:2477-80
2. Prevention of the Progression of
Insulin Resistance
Global Cardiometabolic Risk (CMR)*
Gelfand EV et al, 2006; Vasudevan AR et al, 2005
* working definition
Metabolic
Syndrome
Obesity
Insulin
Resistance
Metabolic
Syndrome
Atherosclerosis
ADOPT Study
Rimonabant
STENO 2 Study
SlametS
A PROBE design ( Prospective, Randomized, Open, Blinded Endpoint
study)
160 patients with type 2 diabetes and microalbuminuria were randomized
to conventional therapy at their GP or intensive care at Steno Diabetes
Center
Conventional group assigned to GPs
Intensive group assigned to Steno Diabetes Center
Endpoint examinations
Microvascular Macrovascular
4 years 8 years
80
80
n=160
Multifactorial Intervention and Cardiovascular Disease in
Patients with Type 2 Diabetes
Steno-2 study, Gaede P et al N Engl J Med 2003; 348: 383-393
STENO 2 STUDY
SlametS 32
Stepwise Treatment of Hyperglycaemia
Diet
Diet
Diamicron
Metformin
Diamicron
+
NPH insulin
Metformin
+
NPH insulin
Time
BMI
<27
BMI
27
Diamicron
+
Metformin
Steno-2 study Gaede P et al N Engl J Med 2003; 348: 383-393
SlametS 33
10
20
30
40
50
60
70
80
0
P
a
t
i
e
n
t
s

(

%

)

P < 0.001 P = 0.21
Glycosylated
Hemoglobin
< 6.5 %
Cholesterol <
175 mg/dl
Triglycerides
< 135 mg/dl
Systolic BP
< 130 mm Hg
Diastolic BP <
80 mm Hg
Intensive therapy
Conventional therapy
Gaede P, Larsen N,et al. N Engl J Med 2003; 348: 383-393
P = 0.06
P = 0.19
P < 0.001
Steno-2: Effect of Intensive Multifactorial Treatment
on CV Outcomes in Type 2 Diabetes
Gaede P, et al. N Engl J Med 2003; 348:383393.
Months of follow-up
P
r
i
m
a
r
y

c
o
m
p
o
s
i
t
e


e
n
d
p
o
i
n
t
*

(
%
)

60
50
40
30
20
10
0
0 12 24 36 48 60 72 84 96
No. at risk
Conventional therapy 80 72 70 63 59 50 44 41 13
Intensive therapy 80 78 74 71 66 63 61 59 19
*Primary composite endpoint: death from CV causes, nonfatal MI, CABG, percutaneous coronary
intervention, nonfatal stroke, amputation or surgery for peripheral atherosclerotic artery disease
P = 0.007
P = 0.007
Conventional treatment






Intensive treatment
SlametS
0 4
H
O
M
A


b
-
c
e
l
l

f
u
n
c
t
i
o
n

0 4
Intensive
Conventional
800
700
600
500
400
300
200
100
0
p=0.016 p=0.016
8 years
-cell function =
fasting plasma C-peptide X 3.33 / (fasting plasma glucose 3.5)
Years of follow-up
Submitted to Diabetes, 2004
b-Cell Function in the Steno-2 Study
Parameter
Overall
treatment effect
b
1
Effect independent
of weight loss b
% of overall effect
not explained by
weight b/b
1
HDL-C (%)
8.0 (0.6)
p<0.001
3.6 (0.6)
p<0.001
45%
Triglycerides (%)
-14.0 (1.4)
p<0.001
-6.5 (1.4)
p<0.001
46%
HbA
1c
(%)
-0.67 (0.007)
p<0.001
-0.37 (0.007)
p<0.001
55%
Fasting insulin
(U/mL)
-2.74 (0.48)
p<0.001
-1.34 (0.51)
p=0.018
49%
Adiponectin (g/mL)
1.5 (0.2)
p<0.001
0.85 (.21)
p<0.001
57%
HDL-C and TG = RIO North America, RIO Europe, RIO Lipids and RIO Diabetes
HbA
1c
= RIO Diabetes; Fasting insulin = RIO North America, RIO Europe, RIO Lipids Adiponectin = RIO Lipids
Summary of results for primary analysis of metabolic parameters with and without
adjustment for body weight loss, mean (SEM)
Pi Sunyer X, 2006
Half of the Effect of Rimonabant is due to
Direct CB
1
Blockade on Peripheral Tissues
3. Prevention of the Progression
of Prediabetes to Type 2
Diabetes
Progression from IGT to Type 2 Diabetes
Da Qing IGT and Diabetes Study
3
1
DPP Research Group. N Engl J Med 2002: 346:393403;
2
Lindstrm J, et al.
J Am Soc Nephrol 2003; 14:S108S113;
3
Pan XR, et al. Diabetes Care 1997; 20:537544..
68% patients
IGT T2DM
43% patients
IGT T2DM
Finnish Diabetes Prevention Study
2
Diabetes Prevention Program (DPP)
1
29% patients
IGT T2DM

At 3 years
At 6 years At 6 years
Control populations
Harris MI et al. Consultant 1997;37 Suppl:S9
IGT
Undiagnosed
type 2 diabetes
Diagnosed
type 2 diabetes
50

40

30

20

10

0
20-44 45-54 55-64
65
Age (years)
%

o
f

p
o
p
u
l
a
t
i
o
n

IGT is Driving the Worldwide Diabetes
Pandemic

Pan XR, et al. Diabetes Care 1997; Tuomilehto J, et al. N Engl J Med 2001; Knowler WC, et al. N Engl J Med 2002, 2004; Buchanan TA, et al.
Diabetes 2002;51:27962803; Ramachandran A. 4th World Congress on Prevention of Diabetes and its Complications, Chennai Feb 2005;
Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
Intervention Studies for Diabetes
Prevention
38.2
28.2
60.4
Lifestyle intervention
Metformin
Metformin and lifestyle
Indian Diabetes Prevention Program
(N = 531)

37 Orlistat XENDOS (N = 3305)
25 Acarbose STOP-NIDDM (N = 1418)
58
31
75
Lifestyle intervention
Metformin
Troglitazone*
Diabetes Prevention Program Study
(N = 3234)

55 Troglitazone* TRIPOD (N = 266)
RR (%) Intervention Study
58 Diet and physical exercise Finnish Diabetes Prevention Study
(N = 522)
31
46
42
Diet
Physical exercise
Diet and physical exercise
Da Qing IGT and Diabetes Study
(N = 577)
* Troglitazone is no longer available
Lifestyle Modification
Studies of Lifestyle Modification in
the Prevention of Type 2 Diabetes

Malm Study 1991, 181 subjects with IGT
79 untreated

The Da Qing Study 1997. 577 subjects with IGT
133 control

Tuomilehto J 2001 ; 522 subjects with IGT
265 intervention
257 control

20
18
16
14
12
10
8
6
4
2
0
Total
Lean
Overweight
Control Diet Exercise Diet +
Exercise
I
n
c
i
d
e
n
c
e

/
1
0
0

p
e
r
s
o
n
-
y
r

Da Qing Study: Incidence of Diabetes during
6 Year Evaluation
Pan XR et al Da Qing Study Diabetes Care 1997; 20: 537-544
0 1 2 3 4 5 6
1.0
0.9
0.8
0.7
0.6
0.5
0.4
C
u
m
u
l
a
t
i
v
e

P
r
o
b
a
b
i
l
i
t
y

o
f

R
e
m
a
i
n
i
n
g

F
r
e
e

o
f

D
i
a
b
e
t
e
s

Year
Tuomilheto J et al N Engl J Med 2001; 344; 1343-50
Finnish Diabetes Prevention Study: Proportion of
Subjects without Diabetes during the Trial
Control group
Lifestyle
Sustained Benefit from Lifestyle Intervention after
the Finnish Diabetes Prevention Study
Lindstrom J et al. Lancet 2006;368:1673-9
-58
-43
-36
-60
-40
-20
0
Randomised
intervention
(4 years)
Randomised intervention
+ 3 years post-study
follow-up
D
i
a
b
e
t
e
s

r
i
s
k

r
e
d
u
c
t
i
o
n

(
%
)

3 years
post-study
follow-up only
HR: hazard ratio (95% CI) for diabetes.
HR 0.61
(0.38 to 0.98)
HR 0.57
(0.43 to 0.76)
HR 0.4
(0.3 to 0.7)
Oral Anti Diabetic Drugs that Can Be
Used to Prevent Diabetes
The Diabetes Prevention Program (USA)
3234 subjects with IGT
Metformin

+ standard lifestyle
counselling
Placebo
+ standard lifestyle
counselling

Intensive
lifestyle
counselling
Double-blind
R
Open
Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403
-31
-58
-60
-40
-20
0
Metformin Intensive lifestyle

R
i
s
k

v
s
.

s
t
a
n
d
a
r
d

l
i
f
e
s
t
y
l
e

(
%
)

p<0.001 vs. *baseline,

metformin
*
*

Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403
Diabetes Prevention Program: Metformin
vs. Intensive Lifestyle Intervention
0 1.5 1 1.5 2 2.5 3 3.5 4
40


30


20


10


0
C
u
m
u
l
a
t
i
v
e

I
n
c
i
d
e
n
c
e


o
f

D
i
a
b
e
t
e
s

(
%
)

Year
Placebo
Metformin
Lifestyle
Diabetes Prevention Program Research Group N Engl J Med 2002; 346 :393-403
Cumulative Incidence of Diabetes
According to Study Group
DPP
Development of the Metabolic Syndrome*
Orchard. Ann Intern Med 2005; 142: 611-9
a
p=0.03
b
p<0.001
Placebo
Metformin
Lifestyle
*
17%
a
41%
b
N=490
N=503
N=530
* NCEP ATP III
Time since randomization, years
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e

o
f

t
h
e


m
e
t
a
b
o
l
i
c

s
y
n
d
r
o
m
e

12
10
8
6
4
2
0
P
r
e
v
a
l
e
n
c
e

o
f

D
M

%

Incidence of Diabetes per Year
during 3 Year Time
11.6
8.2
2.0
4.1
Control
Diet+
exercise
Acarbose Metformin
Wenying Y et al Chin J Endocrinol Metab 2001; 17:131-6
Diabetes and Cardiovascular Outcomes in the
STOP-NIDDM Trial
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Diabetes (p=0.0015)
MI (p=0.02)
6.11
18.30
3.07
Revascularisation (p=0.18)
CVE (p=0.51)
Any CV event (p=0.51)
CV death (p=0.63)
PVD (p=0.93)
Hazard ratio (95% CI)
CVE: cerebrovascular event or stroke; PVD: peripheral vascular disease.
Chiasson JL et al. Lancet 2002;359:2072-7; Chiasson JL et al. JAMA 2003;290:486-94
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
p=0.0022
Acarbose
Placebo
Chiason JL et al The Lancet 2002; 359 ; 2072-2077
Stop-NIDDM Trial
Effect of acarbose and placebo on cumulative probability
of remaining free of diabetes over time
DREAM: study design
Age 30 years
IGT defined as 2-h glucose
811 mmol/l (140199 mg/dl) after
a 75 g OGTT or isolated IFG
No history of type 2 diabetes;
history of gestational diabetes OK
Screening
Run-in
173 days
Placebo
Treatment Period
3 years from time of last
patient randomized
Randomization/Baseline
Study End
RSG + Ramipril Placebo
Ramipril + RSG Placebo
RSG + Ramipril
RSG Placebo +
Ramipril Placebo
Washout
23 months
Gerstein HC, et al. Diabetologia 2004;
47:15191527.
DREAM: Effect of Rosiglitazone on
the Progression to Diabetes
DREAM Trial Investigators. Lancet 2006; 368:10961105.
http://www.ccc.mcmaster.ca/dream.htm. Accessed October 2006.
Year
Placebo (n) 2,634 2,470 2,150 1,148 177
Rosiglitazone (n) 2,635 2,538 2,414 1,310 217
60% reduction in risk of diabetes or death
HR 0.40 (0.350.46), P < 0.0001
Rosiglitazone
Placebo
C
u
m
u
l
a
t
i
v
e

h
a
z
a
r
d

0.0
0.1
0.2
0.3
0.4
0.5
0.6
0 1 2 3 4
Intervention Studies for Diabetes Prevention
38.2
28.2
60.4
Lifestyle intervention
Metformin
Metformin and lifestyle
Indian Diabetes Prevention Program
(N = 531)

37 Orlistat XENDOS (N = 3305)
25 Acarbose STOP-NIDDM (N = 1418)
58
31
75
Lifestyle intervention
Metformin
Troglitazone*
Diabetes Prevention Program Study
(N = 3234)

55 Troglitazone* TRIPOD (N = 266)
RR (%) Intervention Study
58 Diet and physical exercise Finnish Diabetes Prevention Study
(N = 522)
31
46
42
Diet
Physical exercise
Diet and physical exercise
Da Qing IGT and Diabetes Study
(N = 577)

Pan XR, et al. Diabetes Care 1997; Tuomilehto J, et al. N Engl J Med 2001; Knowler WC, et al. N Engl J Med 2002, 2004; Buchanan TA, et al.
Diabetes 2002;51:27962803; Ramachandran A. 4th World Congress on Prevention of Diabetes and its Complications, Chennai Feb 2005;
Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004.
* Troglitazone is no longer available
DREAM

Rosiglitazone vs Placebo
Ramipril vs placebo
62%
No significant
effect ( 9%)
Outcome Studies in
IGT/IFG and Type 2 Diabetes Populations
Diabetes duration (years)
20
10
0
10 20 30
Obesity IGT Diabetes (Uncontrolled)
UKPDS
Type 2 diabetes
Microvascular complications
Macrovascular complications
DREAM
ADOPT
STENO-2
Prediabetes
Da Qing
FinDP
DPP
TRIPOD
IDPP
Stop
NIDDM
Xendos
Summary : Impact of Outcome Studies on
Current Management of Type 2 Diabetes
Approach to treatment in diabetes should be
directed toward disease prevention rather than
be reactive
1,2

Outcome studies suggest early and intensive
intervention in type 2 diabetes can reduce disease
progression and complications
1
Del Prato S, et al. Int J Clin Pract 2005; 59:13451355;
2
Bailey CJ, et al. Int J Clin Pract 2005;
59:13091316.
Conclusion
Type 2 diabetes results from the interaction of two defects :
insulin resistance and b-cell dysfuntion which occur early
during the development of diabetes
Prevention should be started at an early stage and should
target both insulin resistance and insulin secretory
dysfunction to preserve b-cell function

Combination therapy
ADA/EASD Consensus
Progressive Decrease
of -cell function
Conclusion

Outcomes Studies showed that
The progressivity of Type 2 diabetes can be prevented by
early and aggressive combination therapy (glucovance)
The progression of prediabetes can be prevented by
lifestyle modification or metformin/rosiglitazone