1. The Obesity/Diabetes Epidemic: Adiposopathy & Obesity- The New Disease! Dx & (Rx) of Insulin Resistance & Early DM Part 5 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

2. Prediabetes

4. Clinical Consequences of Abnormal First-phase Secretion and Elevated Post-Prandial Sugars PPG increases –Variability –Microvascular 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. 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

8. 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 Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT – OMINOUS OCTET Type II DM 8 mechanisms of hyperglycemia Microvascular Complications DEATH pp>7.8

9. Genetic Clues to PREVENTION of TYPE 2 DIABETES STRONGLY GENETIC- twin studies BUT, one might say, diabetes skips generations –So, conclude: EVEN IF HAVE GENES, and thus NO INCREASED RESISTANCE, IMPROVE FIRST PHASE INSULIN RELEASE; b-CELLS DON’T WEAR OUT: So if a generation or individual patient stays at Ideal Body Weight you PREVENT DIABETES!

10. 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

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

12. ACT NOW Study Results: Time to Occurrence of Diabetes (Kaplan-Meier analysis) 0 0.05 0.15 0.20 0.30 Cumulative Hazard 102040030 Months 50 0.10 0.25 Placebo Pioglitazone 1.5% per year 6.8% per year HR = 0.19 (95%, CI) = 0.09, 0.39 P<0.00001 DeFronzo RA. ADA Scientific Sessions, Late-Breaking Clinical Studies, June 9, 2008. NNT = 3.5 patients with IGT for 1 year to prevent the development of 1 case of T2DM 80% reduction in progression to DM

13. Prevention Increased with Use of Incretin 9 m, 105 pts