1. Part 3

2. Diabetes Report Card: HbA 1c Levels in the United States Hoerger TJ, et al. Diabetes Care. 2008;31:81-86. Patients (%) HbA 1c (%) <6.0 6.0-6.9 7.0-7.9 8.0-8.9 9.0-9.9 >10.0 0 20 40 60 80 100 22% 35% 20% 11% 6%

3. NHANES1988-1994 Advances in Therapy, but Falling Short of Goals 5 6 7 8 9 10  1980s 1990s 2000s  HbA 1c (%) SU / Insulin Metformin (1995) TZDs (1998) Incretins (2004) Pre-DCCT9.0% 7.7NHANES 1999- 2000 7.8 NHANES2001-2002 7.5 NHANES2003-2004 7.2 Future 6.0% ? 1997: ADA lowered T2DM diagnosis from FPG ≥7.8 mmol/L to ≥7.0 mmol/L 2003: ADA eliminated HbA 1c “action point” of <8% from guidelines SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes. Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86. 2005: ADA added HbA 1c goal of <6% for “individual patients” to guidelines General ADA Target: <7% 1998: UKPDS results published 2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published 2009: ADA added “less stringent” HbA 1c goal for patients with significant comorbidities or risk of hypoglycemia, or short life expectancy

4. CVD=cardiovascular disease. Adapted from © 2005 International Diabetes Center, Minneapolis, MN. All rights reserved. Weight Management Type 2 Diabetes Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Hyperglycemia Unmet Needs in Diabetes Care CVD Risk (Lipid and Hypertension Control)

5. Relationship Between Hyperglycemia and Microvascular and Macrovascular Complications

6. IGT (HbA 1c =5.9%) IGT………..…7.9% IGT (HbA 1c =6.1%) T2DM………12.6% Neuropathy (%) IGT………..…13%* *Prevalence. Diabetes Prevention Program Research Group. Diabet Med. 2007;24:137-144; Singleton JR, et al. Diabetes Care. 2001;24:1448-1453; Ziegler D, et al. Diabetes Care. 2008;31:464-469. Diabetic Retinopathy (%) Incidence of Microvascular Complications in IGT

7. Diabetes Is a Cardiovascular Disease Risk Equivalent DM=diabetes mellitus; MI=myocardial infarction. Haffner SM, et al. N Engl J Med. 1998;339:229-234. 0 10 20 30 40 50 7-Year Incidence Rate of MI (%) Diabeticn=1059 P<0.001 3.5 18.8 20.2 45.0 DM MI DM No MI No DM MI No DM No MI Nondiabeticn=1373

8. Microvascular Disease 0 10 20 30 40 50 60 70 80 567891011 Mean HbA 1c (%) Stratton IM, et al. BMJ. 2000;321:405-412. Estimated 37% decrease in microvascular risk for each 1% decrement in HbA 1c (P<0.0001) Historic Rationale for Improving Glycemia: Microvascular Risk Reduction Incidence per 1000 Person- Years (%)

9. Microvascular Disease Stratton IM, et al. BMJ. 2000;321:405-412. Macrovascular Disease Estimated 14% decrease in myocardial infarction risk for each 1% decrement in HbA 1c (P<0.0001) Less Strong Association Between Hyperglycemia and Macrovascular Risk in Type 2 Diabetes Estimated 37% decrease in microvascular risk for each 1% decrement in HbA 1c (P<0.0001) 0 10 20 30 40 50 60 70 80 567891011 Mean HbA 1c (%) Incidence per 1000 Person- Years (%)

10. Optimizing Glycemia in Advanced Type 2 Diabetes Exerts Unclear Macrovascular Benefit ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572; Duckworth W, et al. N Engl J Med. 2009;360:129-139. Endpoint HbA 1c (%) 6 7 8 9 Primary Endpoint Macro ↓6% P=0.37 Macro ↓10% P=0.16 Intensive therapy Conventional therapy ADVANCEN=11,140 ACCOR D N=10,251VADTN=1791 Macro ↓13% P=0.12

11. Lasting Benefits of Early, Intensive Intervention: UKPDS “Legacy” Effect P=0.029 P=0.040 P=0.0099 P=0.001 P=0.052 P=0.014 P=0.44 P=0.007 Any Diabetes Endpoint Microvascular Disease Myocardial Infarction All-cause Mortality Relative Risk Reduction (%) Intervention Post-trial Monitoring Holman RR, et al. N Engl J Med. 2008;359:1577-1589; UKPDS Study Group. Lancet. 1998;352:837-853.

12. ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572; Duckworth W, et al. N Engl J Med. 2009;360:129-139; Holman RR, et al. N Engl J Med. 2008;359:1577-1589. Early vs Late Intervention in Type 2 DiabetesTrial Intensive Arm HbA 1c Reduction No Patients / Trial Duration Disease Severity Macrovascular Benefit ACCORD Goal: <6.0% Endpoint: 6.4% ↓1.4% from BL in 4 months N=10,251 3.4 yr CVD or 2 risk factors 10 yr from T2DM diagnosis No ADVANCE Goal: <6.5% Endpoint: 6.5% ↓0.6% from BL in 12 months N=11,140 5.0 yr Vascular disease or 1 risk factor 8 yr from T2DM diagnosis VADT Goal: ↓1.5% vs standard Endpoint: 6.9% ↓2.5% from BL in 3 months N=1791 5.6 yr 12 yr from T2DM diagnosis UKPDS 80 Goal: FPG <6.0 mmol/L (108 mg/dL) Intervention endpoint: 7.0% Follow-up: 7.7% N=4209 17 yr Newly diagnosed with T2DM Yes

13. Steno-2: Time to Cardiovascular Events Gaede P, et al. N Engl J Med. 2008;358:580-591. 20 40 60 80 0 024681012 Cumulative Incidence of Any CV Event (%) Years No. at Risk Conventional8070604638292514 Intensive8072656156504731 P<0.001 Conventional Treatment Intensive Treatment InterventionFollow-up

14. Steno-2: Goal Attainment BP=blood pressure. Gaede P, et al. N Engl J Med. 2008;358:580-591. HbA 1c <6.5% Cholesterol <175 mg/dL Triglycerides <150 mg/dL Systolic BP <130 mm Hg Diastolic BP <80 mm Hg P=0.31 P=0.35 P=0.005 P=0.27 P=0.14 Patients (%) Intensive therapyConventional therapy P=0.06 P<0.001 P=0.005 P=0.001 P=0.21 0 20 40 60 80 100 Intervention Follow-up 0 20 40 60 80 100