PREDIABETES, PHARMACOLOGIC

INTERVENTION FOR TYPE 2

DIABETES

John MF Adam

Diabetes and Lipid Centre, Dr. Wahidin Sudirohusodo Hosiptal,

Division of Endocrinology and Metabolism,
Department of Internal Medicine, Faculty of Medicine,
Hasanuddin University,
Makassar
Sudden death is more common in those
who are naturally fat than in the slender
Hippocrates 410 B.C.

Messerli et al Arch Intern Med 1987; 147: 1725 - 1728

“I saw few die of hunger, of eating – 100.000”

Benyamin Franklin
OBESITY - DEFINITION

Obesity is defined as a
condition in which there is an
excess of body fat. The
operational definitions of
obesity and overweight
however are based on BMI
which is closely correlated
with body fatness
 OBESITY - EPIDEMIOLOGY
The prevalence rate of obesity are increasing in
almost all parts of the world, among male as well
as female.
Although varied between countries, several natio
nal health surveys in Asian countries showed a
rapid increase of overweight and obesity,

In the past two decades, the rates of

obesity have tripled in developing
countries
(Hossain P, NEJM 2007)
 OBESITY - EPIDEMIOLOGY
The National Survey
Country Overweight Obesity
Malaysia 20.7% 5.8%
Philippines 16.9% 3.3%
China
Urban area 9.7% 14.9%
Rural area 6.2% 8.4%
Japan 42.3% 5.7%
Singapore 24.4% 6.0%
Indonesia ??? ???
WHAT IS PREDIABETES
TYPE 2 DIABETES: A CHRONIC PROGRESSION DISEASE

Obesity IGT IPH Overt DM

Postprandial
Plasma
Glucose
(mg/dl)
126
Fasting

Insulin Resistance
ß-cell
function
(%)
100
Insulin Level

-20 -10 0 10 20 30
Diabetes duration (years)
Adapted from IDC, Minneapolis
 WHAT IS PREDIABETES
In 1997,The Expert Committee on the Diagnosis
and Classification of Diabetes Mellitus introduced
the term Prediabetes :
“intermediate group of individuals whose
glucose levels, although not meeting criteria
for diabetes, are nevertheless too high to be
considered normal “
Prediabetes IFG FPG levels 100 – 125 mg/dl
IGT 2-H OGGT values 140 – 199 mg/dl
 NEW DIAGNOSTIC CRITERIA
FOR DIABETES IN ADULTS (ADA 2010)

1 A1C > 6,5%. The test should be performed in a laboratory

using a method is NGSP certified and standardized to the DCCT
assay.*
OR
2 FPG > 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric
intake for at least 8h.
OR
3 Two-hour plasma glucose > 200 mg/dl (11.1 mol/l) during an
OGTT. Using a glucose load containing the equivalent of 75 gr
anhydrous glucose dissolved in water.
OR
4 In a patient with classic symptoms of hyperglycemia
orhyperglycemic crisis, a random plasma glucose > 200
mg/dl (11.1 mmol/l).
Diabetes Care 2010; 13 (Suppl 1): S11-
S11-S49
 PREDIABETES, THE NEW CRITERIA
In 2010 American Diabetes Assocation introduced
the new term of prediabetes as
“ categories of increased risk for diabetes”

The new criteria:

IFG FPG 100 - 125 mg/dl
IGT 2-h OGTT 140 - 199 mg/dl
A1C 5,7 - 6,4%
 WHY IS IFG AND IGT
IMPORTANT ?
Prediabetes is not only for the risk of type
2 diabetes mellitus but also as a risk factor
for CVD
The Honolulu Heart program
The Hisayama study
Funagata diabetes study
 THE HISAYAMA STUDY
DIABETES AND CARDIOVASCULAR DISEASE IN A
PROSPECTIVE POPULATION SURVEY IN JAPAN
Diabetes 45 (Suppl.3):S14-S16,1996

2427 subjects 40 – 49 years, free from previous stroke

or myocardial infarction

OGTT 75 g glucose, WHO 1985 criteria 1693

(69.8%) NGT, 474 (19.5%) IGT, and 260
(10.7%) type 2 diabetes

They were follow-up for 5 years

Endpoints : Cardiovascular diseases (CHD, stroke)
THE HISAYAMA STUDY
DIABETES AND CARDIOVASCULAR DISEASES

3 **
Adjusted for age and sex
** p<0.01 vs normal
Relat ive Risk

* p<0.05
2 *
CVD

(n) (1,693) (474) (260)

Normal Impaired Diabetes
Glucose Tolerance

Relative risks of CVD for IGT and diabetes compared with

NGT after adjustment for age, sex
The Hisayama Study. Diabetes 45 (Suppl.3):S14-
(Suppl.3):S14-S16,1996
 THE HISAYAMA STUDY
DIABETES AND CARDIOVASCULAR DISEASE IN A
PROSPECTIVE POPULATION SURVEY IN JAPAN
Diabetes 45 (Suppl.3):S14-S16,1996

Conclusions :

Type 2 diabetes as well as IGT is a

risk factors for cardiovascular disease in
Japanese population
PREDIABETES, PHARMACOLOGIC
INTERVENTION FOR TYPE 2
DIABETES, QUO VADIS ?
 Therapies proven effective in diabetes prevention trials (ADA 2010)
Relative risk
Mean age Duration Intervention
Study n Population reduction (%)
(years) (years) (daily dose)
(95% CI)
Lifestyle
Finnish DPS 522 IGT, BMI > 25 kg/m2 55 3.2 I-D&E 58 (30-70)
DPP 2.161 IGT, BMI > 24 kg/m2 51 3 I-D&E 58 (48-66)
FPG > 5.3 mmol/L
Da Qing 259 IGT (randomised 45 6 G-D&E 38 (14-56)
group)
Toranomon 458 IGT (men), BMI=24 ~55 4 I-D&E 67 (p<0.043)‡
study kg/m2
Indian DPP 269 IGT 46 2.5 I-D&E 29 (21-37)
Medications
DPP 2.155 IGT, BMI > 24 kg/m2 51 2.8 Metformin 31 (17- 43)
FPG> 5.3 mmol/L (1.700 mg)
Indian DPP 269 IGT 46 2.5 Metformin (500mg) 26 (19- 35)
STOP NIDDM 1.419 IGT, FPG > 5.6 mmol/L 54 3.2 Acarbose (300 mg) 25 (10- 37)
XENDOS 3.277 BMI > 30 kg/m2 43 4 Orlistat (360 mg) 37 (14-54)
DREAM 5.269 IGT or IFG 55 3.0 Rosiglitazone 60 (54-65
(8 mg)
Voglibose Ph-3 1.780 IGT 56 3.0 (1-year Voglibose 40 (18-57)
Rx) (0.2 mg)
ACT- NOW 602 IGT or IFG 52 2.6 Pioglitazone 81 (61-91)
(45 mg)
Diabetes Care 2010; 13 (Suppl 1): S11-
S11-S49
 Therapies proven effective in diabetes prevention trials
(ADA 2010)
Relative risk
Mean age Duration Intervention
Study n Population reduction (%)
(years) (years) (daily dose)
(95% CI)

DPP 2.155 IGT, BMI > 24 kg/m2 51 2.8 Metformin 31 (17- 43)
FPG> 5.3 mmol/L (1.700 mg)

Indian DPP 269 IGT 46 2.5 Metformin 26 (19- 35)

(500mg)

STOP NIDDM 1.419 IGT, FPG > 5.6 54 3.2 Acarbose 25 (10- 37)
Mmol/L (300 mg)
DREAM 5.269 IGT or IFG 55 3.0 Rosiglitazone 60 (54- 65)
(8 mg)
ACT- NOW 602 IGT or IFG 52 2.6 Pioglitazone 81 (61-91)
(45 mg)

Diabetes Care 2010; 13 (Suppl 1): S11-

S11-S49
Diabetes Prevention Program Research Group.
Reduction in the incidence of type 2 diabetes
with lifestyle intervention or metformin
Knowler WC, et al. N Engl J Med 2002; 346: 393 – 403

3234 IGT patients, randomized to three group, lifestyle

modification, metformin 850 mg twice daily and
placebo, follow up 3 years
Results
Cumulative prevalence of diabetes among placebo
28,9%, metformin 21,7%, and lifestyle modification
14,4%

The prevalence of diabetes reduce by 58% with lifestyle

change, 31% in the metformin
 The Diabetes Prevention Program (DPP) - 2002
40
Placebo

Cumulative incidence of
diabetes (%) 30
Metformin 31%

20 Life style 58%

10

0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Year
Cumulative incidence of diabetes according to study group in the DPP. The incidence of
diabetes differed significantly among the three groups (P < .001 for each comparison).
Knowler WC, et al. N Engl J Med 2002; 346: 393 - 403
 Diabetes Prevention Program Research Group.
Reduction in the incidence of type 2 diabetes
with lifestyle intervention or metformin
Knowler WC, et al. N Engl J Med 2002; 346: 393 – 403

Conclusion
Lifestyle change and treatment with metformin both
reduced the incidence of diabetes in persons at high risk.
The lifestyle intervention was more effective than
metformin
STOP-NIDDM Trial Research Group. Acarbose
for prevention of type 2 diabetes mellitus:
the STOP-NIDDM randomized trail
Chiasson JL, et al. Lancet 2002; 359: 2072 – 2077

714 IGT was given acarbose or placebo

32% of the acarbose group and 42% of placebo
developed diabetes mellitus (p=0.00015)
 Acarbose and Placebo
1.00
0.95 Acarbose
0.90 Placebo
Cumulative probability

0.85
0.80 P = 0,0022
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0 00 00 00 00 00 00 00 00 00 00 00 00
0

1 0 2 3 4 5 6 7 8 9 10 11 12 13
Days after randomization
Effect of acrbose and placebo on the cumulative probability of remaining free of
diabetes during the STOP-NIDDM trial
Chiasson JL, et al. The Lancet 2002; 359: 2072
 STOP-NIDDM Trial Research Group. Acarbose
for prevention of type 2 diabetes mellitus:
the STOP-NIDDM randomized trail
Chiasson JL, et al. Lancet 2002; 359: 2072 – 2077

Conclusion
Acarbose could be used, either as an alternative or in
addition to changes in lifestyle, to delay development of
type 2 diabetes in patients with impaired glucose
tolerance
 Protection from type 2 diabetes persists
in the TRIPOD cohort eight months after
stopping troglitazone
Buchanan TA, et al. Diabetes 2001; 50 (suppl 2): A81

Women with previous GDM were randomized to

pacebo (n=133) and troglitazone 400 mg/day (an
insulin sensitizing drug) (n=133)
During follow-up for 30 months, annual diabetes
incidence rate was 12,1% assigned to placebo
and only 5,4% among the troglitazone group ( p <
0,01)
 Troglitazone in Prevention of Diabetes (TRIPOD)
60
Cumulative incidence of

40
diabetes (%)

Placebo

20 55%

Troglitazone
0
0 12 24 36 48 60
Month trial
Cumulative incidence rates of type 2 diabetes in women who were enrolled in TRIPOD study.
The rate in the troglitazone groups significantly less than the rates in the placebo group (p=
,009)
Buchanan TA, et al. Diabetes 2002; 51: 2798 - 2803
 Protection from type 2 diabetes persists
in the TRIPOD cohort eight months after
stopping troglitazone
Buchanan TA, et al. Diabetes 2001; 50 (suppl 2): A81

Conclusion
Treatment with troglitazone delayed or prevented
the onset oft type 2 diabetes in high risk hispanic
women (GDM)
Effect of rosiglitazone on the frequency of diabetes
in patients with impaired glucose tolerance or
impaired fasting glucose: a randomized controlled
trial. The Diabetes Reduction Assessment with
Ramipril and Rosiglitazone Medication
(DREAM Study)
Gerstein HC, et al. Lancet 2006; 368: 1096-1105

5269 adults > 30 yrs IFG and IGT were randomly

assigned to receive rosiglitazone 8 mg (n=2365)
or placebo (n=2634), follow up for 3 years
At the end of the study:
306 (11,6%) in the rosiglitazone and 686 (26,0%)
in the placebo group developed DM or death
1330 (50,5%) in rosiglitazone and 798 (30,3%) in
the placebo became normoglycemia
 60
A Rosiglitazone Placebo

Proportional %
50.5
50
43.7
40 P<0.0001 37.9
30.3
30 26.0
20
11.6
10
0
Diabetes IGT, IFG, or Normal +
both FPG < 6.1 mmol/L
60
B 53.5
50 49.8
Proportional

P<0.0001
40 38.6
%

30 26.0
20.5
20
11.6
10
0
Diabetes IGT, IFG, or both Normal +
FPG < 6.1 mmol/L

Proportional of participants who either developed diabetes, regressed to normal, or had

impaired fasting glucose or impaired glucose tolerance, or both, at the last assessment. (A) FPG
defined as concentration < 6.1 mmol/L or (B) < 5.6 mmol/L. The value for the likelihood that the
distribution across categories would have occurred by chance using both FPG cutoff was
<0.0001. Lancet 2006; 368: 1096-1105
 A B
6.8 9.4
FPG 2hour PG
(mmol/L) (mmol/L)
6.6 9

6.4 8.6

6.2 8.2
Placebo
6 7.8

5.8 7.4
Placebo
5.6 7

5.4 6.6 Rosiglitazone

Rosiglitazone

5.2

0 0
Base 1 2 3 4 Final Base 2 3 4 Final

Effect of rosiglitazone on the point estimates of (A) fating plasma glucose (FPG) and (B)
2-h plasma glucose (PG) concentrations. Lancet 2006; 368: 1096-1105
 0.6
Placebo
Rosiglitazone
0.5

0.4
Cumulative
hazard

0.3

0.2

0.1

0.0
0 1 2 3 4
Years

Time to occurrence of primary outcome. Lancet 2006; 368: 1096-1105

 Effect of rosiglitazone on the frequency of diabetes
in patients with impaired glucose tolerance or
impaired fasting glucose: a randomized controlled
trial. The Diabetes Reduction Assessment with
Ramipril and Rosiglitazone Medication
(DREAM Study)
Gerstein HC, et al. Lancet 2006; 368: 1096-1105

Conclusion
Rosiglitazone at 8 mg daily for 3 years substantially
reduces incident type 2 diabetes and increases the
likelihood of regression to normoglycaemic in adults
with impaired fasting glucose or impaired glucose
tolerance, or both
 ACTos NOW Study for the Prevention
of Diabetes (ACT NOW study)
602 IGT were randomized to receive pioglitazone 45
mg/day or placebo
The primary end point is the conversion of IGT to
type DM based on FPG > 126 mg/dl or 2-OGTT >
200 mg/day
Results (late breaking abstract June 2008):
risk reduction of 81%
TYPE 2 DIABETES: A CHRONIC PROGRESSION DISEASE

Obesity IGT IPH Overt DM

Postprandial
Plasma
Glucose
(mg/dl)
126
Fasting

Insulin Resistance
ß-cell
function
(%)
100
Insulin Level

-20 -10 0 10 20 30
Diabetes duration (years)
Adapted from IDC, Minneapolis
 THIAZOLIDINDIONE
AND THE PREVENTION OF DIABATES
Tripod study risk reduction 55.0%
DREAM study 60.0%
ACT NOW study 80.0%

These result were better than metfromin

and acarbose
ARE ALL TZDs TE SAME?
 Pioglitazone + Metformin vs
Rosiglitazone + Metformin:
Effects on Lipids
Pioglitazone + metformin
25
Rosiglitazone + metformin
20
% change from baseline to 1 year

15
*
10
5
0
-5
-10 *
-15 *
-20
-25
LDL-C HDL-C
*
Triglycerides Total cholesterol

*p<0.05 vs rosiglitazone + metformin

Derosa G et al J Clin Pharm Ther 2006;31:375 383
Pioglitazone + SU vs Rosiglitazone + SU:
Effects on Lipids

Pioglitazone + glimepiride
25
Rosiglitazone + glimepiride
20
% change from baseline to 1 year

15 *
10
5
0
-5
-10
-15 *
-20
-25 *
LDL-C HDL-C Triglycerides

*p<0.05 vs rosiglitazone + glimepiride

Derosa G et al Clin Ther 2004;26:744 754
Pioglitazone & Rosiglitazone: Risk of CV Events in
Large-Scale, RCTs & Meta-Analyses

GSK meta-analysis (MI)

FDA meta-analysis (Serious IHD)
Nissen and Wolski meta-analysis (MI)
Rosiglitazone Singh et al meta-analysis (MI)
FDA meta-analysis (IHD)
Pioglitazone
Diamond et al meta-analysis (MI, highest estimate)
GSK meta-analysis (IHD)
Diamond et al meta-analysis (MI, lowest estimate)
FDA meta-analysis (CV death/MI/stroke)
RECORD interim (Fatal/nonfatal MI)
RECORD interim (Primary composite endpoint)
RECORD interim (CV death/MI/stroke)
Lincoff et al (Death/MI)
Lincoff et al (Death/MI/stroke)
Lincoff et al (MI)
PROactive (Primary composite endpoint)
PROactive (Death/MI/stroke)
PROactive (Fatal/nonfatal MI)
PROactive (Recurrent MI)
PROactive (Recurrent stroke)
0 0.5 1.0 1.5 2.0 2.5 3.0 Erdmann E. Rev Endocrinol 2008;May;16–20
HR or OR or RR
 Key Factors when Determining Net Clinical
Benefit Between Pioglitazone & Rosiglitazone
Beneficial /Potentially beneficial factors Pioglitazone Rosiglitazone
• ↓ risk of all-cause mortality, MI and stroke √ —
• ↓ recurrent MI √ —
• ↓ risk of recurrent stroke √ —
• ↓ in restenosis/ repeat target vessel revascularization √ √
(relevant only in patients undergoing PCI)
• effects on traditional metabolic risk factors
- ↓ glucose √ √
- ↓ triglycerides √ —
- ↑ HDL-C, √ √
- ↓ blood pressure √ √
- ↑ LDL particle size √ √
- ↓ LDL particle concentration √ —
• effects of surrogate endpoints
- CIMT √ √
- IVUS √ -
• effects on non-traditional risk markers eg. CRP, PAI-1 √ √

Detrimental/Potentially detrimental factors Pioglitazone Rosiglitazone

• ↑ in edema and weight gain √ √
• ↑ in signs of heart failure √ √
- which is associated with adverse CV outcome — √
• ↑ in peripheral revascularization in PAD patients ? N/A
• possible ↑ in distal fractures (postmenopausal women) √ √
CIMT= carotid intima-media thickness; PCI= percutaneous coronary intervention; IVUS=intravascular sonography)
E Erdmann et al. Curr Cardio Review 2009;5:155-165; Goldberg RB et al. Diabetes Care 2005;28:1547–1554
 ADA 2010, STATEMENT FOR TREATING
PREDIABETES WITH DRUG THERAPY
Metformin (Glucophage) should be the only drug
considered for use in diabetes prevention (=
treatment of IGT)
For other drugs - side effects, cost, lack of experience -
the panel not recommend to use
Indication for metformin only for high risk individual,
such as:
- combined IFG - IGT and obese
- combined IFG - IGT with at least one risk factor
for diabetes (such as CVD)
- age < 60 years
 CONCLUSION
Obesity is an insulin resistance state
Most IGT are obese, so they are also
insulin resistance
Treatment of insulin resistance (IGT)
should be the drug that can increase
insulin sensitivity
The thiazolidinediones
QUA VADIS ????
 SUMMARY
Prediabetes especially IGT are not only a risk
for diabetes mellitus but also CAD
Screening method should be OGTT
Screening for prediabetes (and DM) among
CAD patients should be performed since
prediabetes is high risk for recurrent CAD
Treatment of prediabetes should be focus on
lifestyle modification and to some metformin
(special subjects)