1. Prevention of Diabetes Mellitus Prof. Adel El-Etriby Professor of Cardiology Ain Shams Faculty of Medicine

2. 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.

3. 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 % of Population 0 2 4 6 8 10 12 14 EuropeanPacificAmerican Men Women 30 to 64 Years of Age

4. Current and Projected Prevalence Rates for Diabetes 80 0 10 20 30 40 50 AfricaAmericasEastern Mediterranean EuropeSoutheast Asia Estimated Prevalence (millions) 199520002025 60 70 Western Pacific 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.

5. Risk Factors for Type 2 Diabetes Type 2 Diabetes Diabetes Gestational diabetes, polycystic ovarian syndrome, and parity Increasing age Genetic factors Ethnicity Family history Central obesity Physical inactivity Diet

6. Risk of type 2 diabetes associated with level of physical activity Hu et al., JAMA 282:1433, 1999 Adjusted for age, smoking. hypertension, family history, menopause, high cholesterol Quartile of physical activity vs Q1 Relative Risk -23% -25% -38% -46% 8 year follow-up U.S. Nurses Health Study

7. Genetic predisposition Preclinical state NormalIGT Disability Death Clinical disease NIDDM Disability Death Complications Primary Secondary Tertiary prevention prevention prevention Stages in the natural history of Type 2 diabetes

8. 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

9. 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 0123456 Years Cumulative Probability of No Diabetes Intervention Control 58% reduction in relative risk

10. 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 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

11. 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 PlaceboMetforminLifestyle Cumulative Incidence of Diabetes at 3 y (%) P <.001

12. STOP-NIDDM: Acarbose Reduces Diabetes Risk Adapted from Chiasson J-L et al. Lancet. 2002;359:2072-2077.

13. TRIPOD: Troglitazone Reduces Diabetes Risk Data from Buchanan TA et al. Diabetes. 2002;51:2796-2803. 0 5 10 15 20 25 PlaceboTroglitazone Annual Incidence of Diabetes (%) P <.01 55% reduction in RR (30 mo on drug)

14. 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 PlaceboOrlistat Cumulative Incidence of Type 2 Diabetes (%) P =.0032 37% reduction in RR

15. 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

16. 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 reduction P <.001 0 5 10 New Diagnosis of Diabetes P <.001 PlaceboRamipril

17. CAPPP Study: Results Data from Hansson L et al. Lancet. 1999;353:611-616. 13% risk reduction 0 5 10 15 20 Primary End Point: Composite of Fatal and Nonfatal MI, Stroke, Death from CV Causes Patients (%) P = NS 0 5 10 Incidence of Diabetes P <.04 ConventionalCaptopril

18. SOLVD: Enalapril Reduces New- Onset Diabetes Risk in CHF Patients P <.0001 16.5% absolute risk reduction in development of diabetes No. of New Diabetes Cases N = 291 Vermes E et al. Circulation. 2003;107:1291-1296.

19. 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 Events/1000 Patient-Years Atenolol Losartan P <.001 P <.05 25% reduction in RR

20. 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.

21. 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

22. 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.