1. Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Stanley Schwartz MD, FACE, FACP Emeritus, Clinical Associate Professor of Medicine University of Pennsylvania Affiliate, Main Line Health System Wynnewood, Pa. Part 3

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. 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

8. 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

9. 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

10. 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

11. Metformin  Advantages  Improves insulin resistance in liver  High initial response rate  Effective, 2%  HbA 1c (1% with extended-release metformin)  No initial weight gain or modest weight loss (UKPDS)  Advantageous lipid profile  No hypoglycemia when used alone or with TZD, incretins  Potential to delay or prevent DM and progression, but secondary failure is = SU  Decreases MIs (39% UKPDS obese subgroup,retrospective analysis)  Decreases AGEs, improved endothelial dysfunction  Cheap

12. Metformin  Disadvantages  GI side effects on initiation  Hold after radiologic studies using intravascular iodinated contrast media until Cr stable  Risk of lactic acidosis: Don’t use if… Cr >1.4 female, >1.5 male Cr Clearance 70), blood levels increase Cr Clearance <40, lactic acidosis cases seen Impaired hepatic function (CHF not a contr-indication any more) Don’t order metformin as admit to hospital

13. The Adipocytokine Syndrome: A New Model for Insulin Resistance and ß- Cell Dysfunction Muscle Pancreas Liver Brain Visceral fat cells FFA, TNF  Leptin Leptin Sns FFA, TNF  IL-6 Angiotensinogen, PAI-1 Adiponectin CRP, PAI-1 Atherothrombosis FFA, TNF  Adiponectin Artery FFA Resistin, TNF  ObesityIRDiabetesASVD

14. Pleotrophic Effects of PIOGLITAZONE : Modifying The Adipocytokine Syndrome: A Model Relating Obesity, Insulin Resistance and ß-Cell Dysfunction and ASCVD Muscle PANCREAS:Improve beta cell function Liver: ↓ ↓ Insulin resistance Brain: Improve Satiety ↓ ↓ FFA, TNF  Leptin ↓ ↓ FFA, TNF  IL-6 Angiotensinogen, PAI-1 et al ↑ ↑ Adiponectin ↓ ↓ CRP, PAI-1 ↓ ↓ Atherothrombosis ↓ ↓ FFA, TNF  ↑ ↑ Adiponectin Reduce Atherosclerotic Risk Factors ↓ ↓ FFA resistin, TNF  ↓ ↓ Size, Insulin Resistance in Visceral Fat cells PIOGLITAZONE Improves peripheral Insulin Resistance in

15. Intra-muscular fat Intra-hepatic fat Intra-abdominal fat Subcutaneous fat TZD MECHANISM OF ACTION Effect of Meds on Fat Topography Direct PPAR effect on vascular cells to decrease endothelial dysfunction and inflammation IR, TG, FFA Insulin, BP Inflam. En Dys. TZD IR, TG, FFA Insulin, BP, Inflam. En Dys.

16. Weight Gain: Subcutaneous Adipose Tissue: Reduced Visceral Fat DeterioratedLipid ProfileImproved  Triglycerides   HDL cholesterol   Cholesterol/HDL cholesterol  ? LDL cholesterol ? ? LDL Particle Concentration and Size // ObeseViscerally Obese Subcutaneous adipose tissue Visceral Adipose Tissue PPAR-  Agonists -Pio- DeterioratedInsulin SensitivityImproved  Insulinemia   Glycemia   HbA 1C  Coronary Heart Disease Risk HIGHLOW HDL = high-density lipoprotein; LDL = low-density lipoprotein.