1. ACCORD - Action to Control Cardiovascular Risk in Diabetes ADVANCE - Action in Diabetes to Prevent Vascular Disease VADT - Veterans Administration Diabetes Trail Summary of ACCORD, ADVANCE, and VADT Trials ACCORD Study Group, NEJM 2008, 358:2545-2559. ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572. VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008 Stephen Rith-Najarian, Diabetes Consultant Bemidji Area IHS

2. ACCORD, ADVANCE, and VADT Background Study Design and Results Lessons Learned

3. ACCORD, ADVANCE, and VADT Trials Background Cardiovascular Disease (CVD) is the leading cause of morality and much is attributed to Type 2 diabetes Intensive glucose control can reduce microvascular disease, but the impact on macrovascular disease is not know

4. American Indian Mortality Rates Trends in Indian Health; Age-adjusted data

5. Contribution of Diabetes to CHD Strong Heart Study Hazard Ratio6.33.1 Prevalence60%50% Attributable risk 76%51% WomenMen Diabetes is the engine driving the increase in CVD

6. UKPDS Myocardial Infarction (cumulative) fatal or non fatal myocardial infarction, sudden death573 of 3867 patients (15%) 0% 10% 20% 30% 03691215 % of patients with an event Years from randomization Intensive Conventional p=0.052 Risk reduction 16% (95% CI: 0% to 29%) UKPDS 35: Lancet. 1998, 352:837-53.

7. UKPDS HbA 1c trend cross-sectional, median values UKPDS 35: Lancet. 1998, 352:837-53.

8. Selvin, Ann Intern Med. 2004:141:421-431 Estimated Cardiovascular Disease Risk Reduction from a 0.9% reduction in HbA1c: UKPDS and Meta-Analysis of Prospective Cohort Studies OutcomeUKPDSMeta-Analysis CHD and MI (fatal and nonfatal)  16%  11%* Fatal CHD and MI  6%  13%* Stroke (fatal and nonfatal)  11%  16%* Peripheral Vascular Disease  35%  20%* * P <0.05

9. Risk* of Cardiovascular Events according to baseline (white bars) and treatment (tan bars) HbA1c deciles: HOPE Trial *age- and sex-adjusted hazard ratio HbA1c deciles Gerstein, Diabetologia 2005;48:1749-55.

10. ACCORD, ADVANCE, and VADT Trials Research Question ACCORD Study Group, NEJM 2008, 358:2545-2559. ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572. VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008 Does Intensive Glucose Control Reduce Risk for Cardiovascular Disease in Type 2 Diabetes?

11. ACCORD, ADVANCE, and VADT Background Study Design and Results Lessons Learned

12. ACCORD, ADVANCE and VADT Study Design ACCORDADVANCEVADT Major EndpointsCV death, Non-fatal MI/Stroke CV death, Non-fatal MI/Stroke, macrovacs event CV death, Non-fatal MI/Stroke, CHF macrovacs event StudyRCT designGlucose Intensive vs Standard Arm 2x2 BP control +/-fenofibrate v placebo Glucose Intensive vs Standard Arm 2x2 Perindopril +indamide v placebo Glucose Intensive vs Standard Arm 2x1 All received BP and Lipid Rx ACCORD Study Group, NEJM 2008, 358:2545-2559. ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572. VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008

13. ACCORD, ADVANCE and VADT Demographics ACCORDADVANCEVADT # Participants10,25111,1401,791 populationNorth AmericaEurope /AsiaUS Male62%58%97% Age group mean age 40-79 62.2 >55 yrs 66 >40yrs 60.5 Non-Hispanic White Ethnic Representation 27% Hispanic, African Am 37% Asian38% Hispanic, African Am, Native Am ACCORD Study Group, NEJM 2008, 358:2545-2559. ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572. VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008

14. ACCORD, ADVANCE and VADT Baseline Clinical Characteristics ACCORDADVANCEVADT Weight93.578 kg97.2 BMI32.22831 Duration DM10811.5 Baseline A1c8.37.59.4 Prior CVD35%32%40% ACCORD Study Group, NEJM 2008, 358:2545-2559. ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572. VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008

15. Therapeutic Approach: ACCORD, ADVANCE and VADT ACCORDADVANCEVADT ProtocolProvider Directed Formulary-based Poly-pharmacy Stepped Approach: SU, Met, TZD, Insulin Stepped Approach: Met BMI ≥27; SU BMI <27, TZD, Insulin Meds (Inten v Std) Metformin TZD (Rosi) Oral Hypoglycemic Insulin Exenatide 95 v 87 % 91 v 58 % 87 v 74 % 73 v 58 % 12 v 4 % 74 v 67 % 17 v 11% 94 v 84 % 41 v 24 % - - - 75 v 71% 85 v 78% 55 v 45% 90 v 74% - - - Follow-up intensive group Q mo x 4, then q 2 mo Q mo x 4, then Q 3 mo - ACCORD Study Group, NEJM 2008, 358:2545-2559. ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572. VADT Study Results ADA Scientific Session San Francisco, 2008

16. Outcomes: Summary of ACCORD, ADVANCE and VADT *ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial halted intensive glucose group (2/6/08) † significant difference between intensive and standard group ACCORD*ADVANCEVADT A1C (%) (Intensive vs. Std) 6.4 vs.7.5 †6.4 vs. 7.0 †6.9 vs. 8.4 † Nonfatal MI (%) (Intensive vs. Std) 3.6 vs 4.6% †2.7 vs.2.86.3 vs. 6.1 CV Death (%) (Intensive vs. Std) 2.6 vs. 1.8 † (1.35 Hazard Ratio) 4.5 vs. 5.22.1 vs.1.7 Microvascular-nephropathy ↓ 21% retinopathy ↓ 5% NS - Take home↓ risk MIs, but ↑ risk death in intensive arm Glucose control has no impact on CV events, but ↓ Microvascular risk Glucose control has no impact on CV events ACCORD Study Group, NEJM 2008, 358:2545-2559. ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572. VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008

17. Adverse Outcomes: ACCORD, ADVANCE and VADT Intensive vs StdACCORD*ADVANCEVADT Severe Hypoglycemia (% per yr) 3.0 vs 1.00.7 vs 0.4- Hypoglycemia requiring assistance (% per year) 4.6 vs 1.51.8 vs 0.62.3 vs 1.1 Weight Gain > 10Kg 27.8 % vs 14.1%0.0 vs -1.0- Wt gain (Kg) Intensive group 3.50.76.8 Increased Mortality Rosigliatzone? No ACCORD Study Group, NEJM 2008, 358:2545-2559. ADVANCE Collaborative Group, NEJM 2008, 358:2560-2572. VADT Study Results ADA Scientific Session San Francisco, 2008 In Press, Diabetes Obesity and Metabolism, 2008

18. Hazard Ratios for the Primary Outcome and Death from Any Cause in Pre-specified Subgroups: ACCORD Study N Engl J Med 358;24, 2008 Prior CVD A1c >8.1 Age <65

19. ACCORD, ADVANCE, and VADT Background Study Design and Results Lessons Learned

20. ACCORD, ADVANCE, and VADT Lessons Learned Intensive glucose control does not reduce CVD mortality in T2DM, and may increase risk, especially in patients with pre-existing CHD Aggressive A1c targets (<6.5%) were associated with a 3-fold increased risk hypoglycemia No excess CVD Mortality was seen with Rosigliatazone

21. ACCORD, ADVANCE, and VADT Lessons Learned- Continued Intensive control associated with reduced risk for nephropathy in ADVANCE. To reach and maintain A1c targets of <6.5 required frequent adjustments of multiple anti- diabetic medications Aggressive Targets (<6.5) are probably reasonable for healthy patients to reduce risk micro-vascular complications

22. ADA Consensus Statement on Medical Management of Hyperglycemia in Type 2 Diabetes Achieve and Maintain near normoglycemia, A1c <7.0 Initiate Therapy with Lifestyle and Metformin Rapid addition of medications, and transition to new regimens when targets are not achieved Early addition of insulin therapy in patients who do not met target goals Nathan, Diabetes Care 2008;31:1-11

23. ACCORD, ADVANCE, and VADT Background Study Design and Results Lessons Learned