1. The Obesity/Diabetes Epidemic: Perspectives, Consequences, Prevention, Treatment Stan Schwartz MD, FACP, FACE Private Practice, Ardmore Obesity Program Cardiometabolic Diabetes Center and Affiliate, Main Line Health System Emeritus, Clinical Associate Professor University of Pennsylvania Part 6

2. Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars PPG increases –Variability –Microvasular disease and adverse pregnancy outcomes – ASVD risk factors – adverse CV outcomes Treating elevated PPG leads to –Reduce Pregnancy Outcomes –Reduce CV Markers and Outcomes –Prevent Diabetes

5. Incidence 4-10%/year

6. Purest proof of benefit in treating PPG elevations is that, without treating pathophysiology, just treating ppg, with acarbose, decreases CV risk

7. Prevention DM IR Phenotype Atherosclerosis Obesity Hypertension  HDL,  TG, HYPERINSULINEMIA Endothelial Dysfunction PCO,ED Envir.+ Other Disease Obesity(visceral) Poor Diet Inactivity Insulin Resistance Risk of Complications ETOH BP Smoking Eye Nerve Kidney   -Cell Secretion Genes Blindness Amputation CRF Disability Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT Type 2 DM Microvascular Complications DEATH pp>7.8

8. Outline Epidemiology and Economics of obesity/diabetes Perspectives on Obesity Consequences of Obesity, Prediabetes, Obesity Obesity/ Diabetes Risk Factors, Obesity/ Diabetes Onset can be Prevented or Delayed – Early Risk Identification and Intervention. Medical Benefits to Weight Loss Treatment-CDC’s diabetes prevention program and other Evidence-Based Interventions- –Basics, –Next Lecture in Series

9. Genetic Clues to PREVENTION of TYPE 2 DIABETES STRONGLY GENETIC- twin studies BUT Diabetes skips generations –EVEN IF HAVE GENES, eg: NO INCREASED RESISTANCE, IMPROVE FIRST PHASE INSULIN RELEASE; b-CELLS DON’T WEAR OUT: So if a generation or individual patient stays Ideal Body Weigh PREVENT DIABETES

10. Trials to Prevent / Delay Progression From IGT to Type 2 Diabetes Lifestyle Changes Malmo Study Da Qing Study Finnish Diabetes Prevention Study Diabetes Prevention Program Medications Diabetes Prevention Program: metformin, (troglitazone) TRIPOD: troglitazone STOP-NIDDM: acarbose NAVIGATOR: nateglinide and valsartan DREAM: rosiglitazone and ramipril XENDOS: orlistat ORIGIN: glargine insulin ACT NOW: pioglitazone TRIPOD = Troglitazone in Prevention of Diabetes Study; STOP-NIDDM = Study to Prevent Non–Insulin- Dependent Diabetes Mellitus; NAVIGATOR = Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; DREAM = Diabetes Reduction Approaches with Ramipril and Rosiglitazone; XENDOS = Xenical in the Prevention of Diabetes in Obese Subjects; ORIGIN = Outcomes Reduction with Initial Glargine Introduction.

11. Is it Possible to Delay the Onset of Type 2 DM? FINNISH=Tuomilehto J, et al. N Engl J Med 2001; 344: 1343-50 DA QING=Pan XR, et al. Diabetes Care. 1997; 20: 537-44 DPP=Diabetes Prevention Program. Nathan DM, et al. N Engl J Med 2002; 346:393-403 STOP-NIDDM=Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus. Chiasson JL, et al. Lancet 2002; 359:2072–77 TRIPOD=Troglitazone in the Prevention of Diabetes. Buchanan T, et al. Diabetes 2002; 51(9): 2796-2803 XENDOS=XEnical in the Prevention of Diabetes in Obese Subjects. Torgerson JS, et al. Diabetes Care 2004; 27 (1): 155-61 DREAM=Diabetes Reduction Assessment with Ramipril & Rosiglitazone Medication. Gerstein H, et al. Lancet 2006; 368:1096-1105 0 10 20 30 40 50 60 70 Diabetes Prevention Clinical Trials Finnish-Diet+ Exercise Da Qing – Diet + Exercise DPP-Lifestyle DPP-Metformin STOP-NIDDM TRIPOD XENDOS Diabetes Mellitus Reduction (%) DREAM 41% 25% 42% 58% 31% 55% 62% PIOPOD 55% 80 ActNOW 80% 74% >5% loss

12. Modest Weight Loss and Lifestyle Changes Can Have a Positive Health Impact Diabetes Prevention Program An example of effectiveness DPP Research Group. N Engl J Med 2002;346:393-403 Lifestyle Metformin Placebo 58% 5% /year instead of 10% / year by lifestyle intervention

13. And if Achieve Normal Glucose Tolerance --Markedly Delay Future Overt Diabetes ~50% reduction in risk; Only ~18% risk 6 years after study ie: only 3%/yr incidence