Therapy of Type 2 Diabetes Mellitus: UPDATE Glycemic Goals in the Care of Patients with Type 2 Diabetes- 2013 ADA and AACE Guidelines: Room For Improvement (Be HAPPY/ Avoid Burnout, While Caring for Patients with DM) Stan Schwartz MD, FACP, FACE Affiliate, Main Line Health System Clinical Associate Professor of Medicine, Emeritus, U of Pa. Part 3 1

Treatment of Type 2 Diabetes: Pathophysiologic Approaches

Natural History of Type 2 Diabetes Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity (visceral) Poor Diet Inactivity IR phenotype Atherosclerosis obesity hypertensionHDL,TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Disability Insulin Resistance MI CVA Amp pp>7.8 IGT – OMINOUS OCTET Type II DM 8 mechanisms of hyperglycemia DEATH  Beta Cell Secretion Eye Nerve Kidney Blindness Amputation CRF Disability Risk of Dev. Complications ETOH BP Smoking Microvascular Complications 3 3

Prevention Age 0-15 15-40+ 15-50+ 25-70+ Genes DEATH Envir.+ Other Disease Genes Macrovascular Complications Obesity (visceral) Poor Diet Inactivity IR phenotype Atherosclerosis obesity hypertensionHDL,TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Disability Insulin Resistance MI CVA Amp pp>7.8 IGT – OMINOUS OCTET Type II DM 8 mechanisms of hyperglycemia DEATH  Beta Cell Secretion Eye Nerve Kidney Blindness Amputation CRF Disability Risk of Dev. Complications ETOH BP Smoking Microvascular Complications 4 4

Treat Pre-Diabetes to Prevent DM: Delay/ Prevent/ Reverse Beta-Cell Dysfunction 72% 80 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% 55% See “Pre-Diabetes: The Challenge of Prevention” Slide kit from your Eli Lilly medical education department with respect to details of the above studies. Earlier therapeutic intervention may result in delay of onset of type 2 diabetes. IFG = impaired fasting glucose PIOPOD ActNOW 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

Prevention Increased with Use of Incretin 9 m, 105 pts

IN DPP TRIAL- if Achieve Normal Glucose Tolerance--Markedly Delay Future Overt Diabetes 10 % / YEAR PROGRESS TO DM IF NO TREATMENT ~50% reduction in risk = 5%/ YEAR IF DON’T REACH NGT BUT Only ~18% risk 6 years after study ie: only 3%/yr incidence IF GET TO NORMAL GLUCOSE TOLERANCE

Treating elevated PPG leads to Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars, ie: treat PPG PPG increases Variability Microvasular disease and adverse pregnancy outcomes ASVD risk factors adverse CV outcomes Treating elevated PPG leads to Reduce Pregnancy Outcomes Reduce micro/macrovascular risk// CV Outcomes Prevent Diabetes

Alter the Natural History of Diabetes Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity(visceral) Poor Diet Inactivity IR Phenotype Atherosclerosis Obesity HypertensionHDL,TG, HYPERINSULINEMIA Endothelial Dysfunction PCO,ED Disability Insulin Resistance MI CVA Amp pp>7.8 IGT Type 2 DM DEATH  -Cell Secretion Blindness Amputation CRF Eye Nerve Kidney Risk of Complications ETOH BP Smoking Disability Microvascular Complications 9

ADOPT: Treatment effect on primary outcome 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 40 Glyburide 30 Cumulative incidence of mono-therapy failure* (%) Metformin 20 Rosiglitazone 10 1 2 3 4 5 Years *Time to FPG >180mg/dL Kahn SE et al. N Engl J Med. 2006;355:2427-43. 11

Natural History of Type 2 Diabetes Insulin Resistance Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity (visceral) Poor Diet Inactivity IR phenotype Atherosclerosis obesity hypertensionHDL,TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Disability Insulin Resistance MI CVA Amp pp>7.8 IGT – OMINOUS OCTET Type II DM 8 mechanisms of hyperglycemia DEATH  Beta Cell Secretion Eye Nerve Kidney Blindness Amputation CRF Disability Risk of Dev. Complications ETOH BP Smoking Microvascular Complications 12 12