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. Cost of Prevention Total cost $174.3 million Diet and exercise prevented diabetes in 162 people Metformin prevented diabetes in 77 people (237 people did not develop diabetes over 3 yrs) NNT = 7 for life style intervention NNT= 14 for Metformin Costs per person over 3 yr excluding research cost Metformin $2542 Life style intervention $2780

3. 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

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

5. 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

7. Insulin Sensitivity Improves With Weight Loss in Patients With Type 2 Diabetes *P<0.01 vs before. Wing et al. Arch Intern Med 1987;147:1749. Insulin (pmol/L) Weight Loss at 1 Year (%) 0 50 100 150 * * * Before 0–2.4 2.5–6.9  15 7.0–14.0

8. Relationship Between Weight Change and CHD Risk Factor Sum: Framingham Offspring Study *P<0.002 vs baseline. Wilson et al. Arch Intern Med 1999;159:1104. Weight Change During 16-y Follow-up Men Women 0 20 40 60 -20 -40 -60 Change in Risk Factor Sum (%) * * * * Loss  2.25 kg Gain  2.25 kg +37% –40% –48% +20%

9. Plasma Lipids Improve With Weight Loss Meta-analysis of 70 Clinical Trials Dattilo et al. Am J Clin Nutr 1992;56:320. -0.06 -0.04 -0.02 0.00 0.02 Total Cholesterol LDL-CTG HDL-C (weight stable) HDL-C (actively losing)  mmol/L per kg of Weight Loss -2.5 -2.0 -1.5 -0.5 0.0 0.5  mg/dL per kg of Weight Loss * * * * * *P  0.05. LDL-C=low density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; TG=triglycerides.

10. Relationship Between Change in Weight and Blood Pressure: Trials of Hypertension Prevention II Stevens et al. Ann Intern Med 2001;134:1. Change in Weight (kg) Change in Blood Pressure (mm Hg) 1234 5 -10 -5 0 5 10 6 4 2 0 -2 -4 -6 -8 Quintile of Weight Change Diastolic Systolic

11. Effect of Weight Change on Apnea-Hypopnea Index (AHI) Peppard et al. JAMA 2000;284:3015. Change in Body Weight (%) -20 to <-10 (n=22) -10 to <-5 (n=39) -5 to <+5 (n=371) +5 to <+10 (n=179) +10 to +20 (n=79) 6 4 2 0 -2 -4 Mean Change in AHI (Events/h)

12. 2 0 -2-4 -6 -8 -10 -12-14 20 10 0 -10 Reduction in Body Weight (%) Reduction in Body Weight (%) Change in FMD of Brachial Artery (%) R 2 = 0.468 p = 0.001 7% Relation Between %Weight Loss and Endothelial Function Hamdy et al Diabetes Care 2003;26:2119-25

13. p<0.05 NS NS p<0.001 p<0.01 NS IL-6 TNF-  hCRP PAI-1 Leptin % Change From Baseline Monzillo LU Obes Res. 2003;11(9):1048-54 Hamdy O et al. Diabetes Care. 2003;26:2119-2125 Adiponectin Benefits of weight reduction on cytokines in type 2 DM and in pre-diabetes

14. Weight Loss Can Increase Life Expectancy in Obese Patients With Type 2 Diabetes Weight Loss in First 12 Months (kg) Life Expectancy (y) 18 16 14 12 10 8 0 02468 121416 Lean et al. Diabet Med 1990;7:228.

15. Impact of Intensive Therapy in Type 2 Diabetes Summary of Major Clinical Trials : BUT Subset Evaluations Show Reduced CV Outcomes if shorter duration of DM, without significant pre-existing complications StudyMicrovascularMacrovascularMortality UGDP ↔↔↔ UKPDS ↓↓↔↓↔↓ DCCT/EDIC* ↓↓↔↓↔ ↔ ACCORD ↓↔ ↑ (unadj.), ↔ (adj.) ADVANCE ↓↔↔ VADT ↔↔↔ Initial Trial Long Term Follow-up Meinert CL. Diabetes. 1970;19(suppl):789-830. Goldner MG. JAMA. 1971;218(9):1400-1410. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008;359(15):1577-1589. DCCT Research Group. N Engl J Med. 1993;329;977-986. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. Patel A, et al. N Engl J Med. 2008;358:2560-2572. Duckworth W, et al. N Engl J Med. 2009;360. *T1DM study. ↑- likely due to hypoglycemia hypoglycemia and weight gain