1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. 6105472000 An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye Part 5

2. Treatment of Type 2 Diabetes: Pathophysiology

3. Natural History of Type 2 Diabetes 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 Type II DM Microvascular Complications DEATH pp>7.8

4. Prevention 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

5. 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 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%

6. Diabetes Prevention Program Main Study - Results And if Achieve Normal Glucose Tolerance, Reduce Risk Future DM to only 3%/year Metf.-30% reduction 50% reduction DeFronzo pilot- 3 drugs get 60% of pre-diabetes to normal

7. 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

8. Alter the Natural History of Diabetes 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

10. ADOPT: Treatment effect on primary outcome Kahn SE et al. N Engl J Med. 2006;355:2427-43. 40 30 20 10 0 Glyburide Metformin Rosiglitazone 012345 Years Cumulative incidence of mono- therapy failure* (%) Hazard ratio (95% CI) Rosiglitazone vs metformin, 0.68 (0.55–0.85), P < 0.001 Rosiglitazone vs glyburide, 0.37 (0.30–0.45), P < 0.001 N = 4351 *Time to FPG >180mg/dL

11. Exenatide: Sustained Reductions Exenatide: Sustained A 1c Reductions Time (wk) Mean  A 1c (%) 0102030405060708090 -2.0 -1.5 -0.5 0.0 0.5 Open-Label Extension Placebo BID (N = 128) Exenatide 5 mcg BID (N = 128) Exenatide 10 mcg BID (N = 137) Baseline A 1C 8.3% Placebo-Controlled Trials Kendall D, et al. American Diabetes Association Scientific Sessions. June 2005

12. Natural History of Type 2 Diabetes- Insulin Resistance IR phenotype Atherosclerosis obesity hypertension  HDL,  TG Endothelial dysfunction PCO Envir.+ Other Disease Obesity 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 Type II DM Microvascular Complications DEATH d.ec 1st phase Inc 2nd phase

14. Peripheral Insulin Resistance- Induced Hyperinsulinemia has Adverse Downstream Effects Insulin Metabolic pathway (PI3K) Mitogenic pathway (MAPK) Proliferation, ENDOTHELIAL DYSFUCTION, INFLAMMATION Glucose transport Glykogen synthese Hyperglycemia Hyperinsulinemia Insulin- Resistance

15. Greater the Insulin Level, > CV Risk

16. Multiple Causes of Insulin Resistance- Multiple Therapies OBESITY Peripheral IR OBESITY Peripheral IR Central IR Central IR Inflam- mation IR Inflam- mation IR Biome IR Biome IR Pioglitazone Metformin Bromocriptine-QR Anti- Inflam. Incretins Pro- Biotics, Pre-Biotics’ Antibiotics Weight Reduction DM MEDS- SGLT-2 inh. GLP-1 RAs Appetite suppressants

17. Implications for Therapy  Understand and Treat Central Mechanisms IR  Understand and Treat Peripheral IR- fat, liver, muscle  Understand and Treat Inflammation  Understand and Treat Biome