Prevention of

Diabetes Mellitus

Prof. Adel El-EtribyProfessor of Cardiology

Ain Shams Faculty of Medicine

Rationale for Prevention

The incidence of type 2 of diabetes is increasing in epidemic proportions throughout the world.

Once type 2 diabetes develops, it is difficult to treat.

Prevention of type 2 diabetes would result in a significant reduction in social and economic costs.

Data from World Health Organization. Available at http://www.who.int/ncd/dia/databases3.htm. Accessed April 26, 2003.

Prevalence of IGT in Different Ethnic Populations

African & Asian

% o

f P

op

ula

tio

n

0

2

4

6

8

10

12

14

European Pacific American

MenWomen

30 to 64 Years of Age

Current and Projected Prevalence Rates for Diabetes

80

0

10

20

30

40

50

Africa Americas EasternMediterranean

Europe SoutheastAsia

Est

imat

ed P

reva

l en

ce (

mi l

lio

ns) 1995 2000 2025

60

70

WesternPacific

World Health Organization. World Health Report 1997: Message from the Director-General. Available at www.who.int/whr/1997/message.pdf. Accessed November 8, 2002.

Risk Factors for Type 2 Diabetes

Type 2 Type 2 DiabetesDiabetesType 2 Type 2

DiabetesDiabetes

Gestational diabetes, polycystic ovarian

syndrome, and parity

Increasing age

Genetic factors• Ethnicity• Family history

Central obesity

Physical inactivity

Diet

Risk of type 2 diabetes associated with level of physical activity

0

0.2

0.4

0.6

0.8

1

Q1 Q2 Q3 Q4 Q5

Hu et al., JAMA 282:1433, 1999

Adjusted for age, smoking. hypertension,family history, menopause, high cholesterol

Quartile of physical activity vs Q1

Rel

ativ

e R

isk

-23% -25% -38% -46%

8 year follow-up

U.S. Nurses Health Study

Genetic predisposition

Preclinical state

Normal IGT

DisabilityDeath

Clinical disease

NIDDM DisabilityDeath

Complications

Complications

Primary Secondary Tertiaryprevention prevention prevention

Stages in the natural history of Type 2 diabetes

Recent Prospective Diabetes Prevention Trials Finnish Diabetes Prevention Study (DPS)

Chinese Prevention Trial

US Diabetes Prevention Program (DPP)

Study to Prevent Non–Insulin-Dependent Diabetes Mellitus (STOP-NIDDM trial), Europe

Troglitazone in Prevention of Diabetes Study (TRIPOD), United States

Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study, Sweden

Finnish DPS: Intensive Lifestyle Intervention Reduces Diabetes Risk

Adapted from Tuomilehto J et al. N Engl J Med. 2001;344:1343-1349.

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6

Years

Cu

mu

lati

ve P

rob

abil

ity

of

No

Dia

bet

es

Intervention

Control

58% reduction in relative risk

Data from Yang W et al. Chin J Endocrinol Metab. 2001;17:131-136.

Chinese Prevention Trial: Lifestyle Intervention, Acarbose, and Metformin Reduce Risk of Diabetes

0

20

40

60

80

100

120

Control Diet + Exercise Acarbose Metformin

RR

of

Dev

elo

pin

gD

iab

etes

Ove

r 3

y

P = .09

P = .0001

P = .0002

• 43% reduction in relative risk (RR) with diet + exercise• 88% reduction in RR with acarbose• 77% reduction in RR with metformin

DPP: Metformin/Lifestyle Advice Reduces Diabetes Risk

Lifestyle advice: 58% decrease in diabetes incidence

Metformin: 31% decrease in diabetes incidence

Data from DPP Research Group. N Engl J Med. 2002;346:393-403.

0

10

20

30

40

Placebo Metformin Lifestyle

Cu

mu

lati

ve I

nci

den

ce

of

Dia

bet

es a

t 3

y (%

)

P <.001

P <.001

STOP-NIDDM: Acarbose Reduces Diabetes Risk

Adapted from Chiasson J-L et al. Lancet. 2002;359:2072-2077.

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300

Days After Randomization

Cu

mu

lati

ve P

rob

abil

ity

of

No

Dia

bet

es

Acarbose

Placebo

P = .0022

• 25% reduction in RR

TRIPOD: Troglitazone Reduces Diabetes Risk

Data from Buchanan TA et al. Diabetes. 2002;51:2796-2803.

0

5

10

15

20

25

Placebo Troglitazone

An

nu

al I

nci

den

ce o

f D

iab

etes

(%

)

P <.01

• 55% reduction in RR (30 mo on drug)

XENDOS: Orlistat Reduces Diabetes Risk

Sjöström L et al. Poster presented at: Ninth International Congress on Obesity. São Paulo, Brazil. August 24-29, 2002.

0

2

4

6

8

10

Placebo Orlistat

Cu

mu

lati

ve I

nci

den

ce o

f T

ype

2 D

iab

etes

(%

)

P = .0032

• 37% reduction in RR

New-Onset Diabetes in Trials Using Inhibitors of the RAAS

HOPE: Heart Outcomes Prevention Evaluation Study

CAPPP: Captopril Prevention Project

SOLVD: Studies of Left Ventricular Dysfunction

LIFE: Losartan Intervention for Endpoint Reduction Study

HOPE Study: ACE Inhibitor Ramipril Reduces Risk of Cardiovascular Disease and Diabetes in High-Risk Patients

Data from HOPE Study Investigators. N Engl J Med. 2000;342:145-153.

33% risk reduction33% risk reduction

0

5

10

15

20

Primary End Point: Composite of MI,Stroke, Death from CV Causes

Pa

tie

nts

(%

)

P <.001

0

5

10

New Diagnosis of Diabetes

P <.001

Placebo Ramipril

CAPPP Study: Results

Data from Hansson L et al. Lancet. 1999;353:611-616.

13% risk reduction13% risk reduction

0

5

10

15

20

Primary End Point: Composite ofFatal and Nonfatal MI, Stroke, Death

from CV Causes

Pa

tien

ts (

%)

P = NS

0

5

10

Incidence of Diabetes

P <.04

Conventional Captopril

SOLVD: Enalapril Reduces New-Onset Diabetes Risk in CHF Patients

0

6

12

18

24

30

36

Placebo Enalapril

P <.0001

• 16.5% absolute risk reduction in development of diabetes

No

. of

New

Dia

bet

es C

ases

N = 291

Vermes E et al. Circulation. 2003;107:1291-1296.

LIFE Study: Results

Dahlöf B et al. Lancet. 2002;359:995-1003.

0

5

10

15

20

25

30

Primary Endpoint: CV Death, MI,and Stroke

New-Onset Diabetes

Eve

nts

/100

0 P

atie

nt-

Yea

rs Atenolol

Losartan

P <.001

P <.05

• 25% reduction in RR

ALLHAT: Incidence of New-Onset Diabetes at 4 Years*

*43.2% lower onset of new diabetes with lisinopril compared to chlorthalidone (P .001 at 4 y).ALLHAT Officers and Coordinators. JAMA. 2002;288:2981-2997.

0

5

10

15

Chlorthalidone Amlodipine Lisinopril

P .001

P = .04

11.6%

9.8%8.1%

%

Summary

Type 2 diabetes and CVD are common chronic diseases that cause suffering to millions and are a major drain on healthcare resources

Disease prevention is possible and desirable

Patients with IGT at high risk of diabetes and CVD are ideal population for type 2 diabetes prevention trials

Intensive lifestyle interventions may not be broadly applicable or sustained; effective pharmacological therapies must also be identified

Several drug classes have been shown to reduce incidence of type 2 diabetes

Summary

It seems that the combination of an

insulin sensitizer and a RAAS is the

best tool for prevention and future

studies will clarify this fact.