1. 1 NHLBI/NEI National Institutes of Health NHLBI/NEI National Institutes of Health

2. 2 Diabetes & CVD Patients with type 2 diabetes 2 to 4 X increased risk of CVD Question: What is value of intensive control of CVD risk factors in reducing CVD rates? Glycemia Lipids (HDL-C/TG) Systolic Blood Pressure

3. 3 Overall Goal for ACCORD To test three complementary medical treatment strategies for type 2 diabetes to enhance options for reducing the very high rate of major CVD morbidity and mortality

4. 4 The Three Medical Strategies (Three Trials in One) Intensive glycemic control A1C < 6% versus 7.0%-7.9% Treatment to increase HDL-C and lower TG (in context of good LDL-C and glycemia control) Fenofibrate + Simvastatin versus Simvastatin Intensive blood pressure control (in context of good glycemia control) SBP < 120 mmHg versus SBP < 140 mmHg

5. 5 Double 2 x 2 Intensive Glycemic Control 5000 Standard Glycemic Control 5000 LipidBP FibratePlaceboIntensiveStd 2100 2900 1450 1050 10,000 42005800

6. 6 Primary Outcome Measure First occurrence of a major cardiovascular disease event: Nonfatal MI Nonfatal Stroke Cardiovascular Death MI’s, Strokes, and Deaths adjudicated by a committee masked to treatment assignment

7. 7 Other ACCORD Outcomes Other cardiovascular outcomes Total mortality Microvascular outcomes Health-related Quality of Life (subset) Cost-effectiveness (subset)

8. 8 ACCORD Eye Study National Eye Institute

9. 9 important primary endpoint common cause of vision loss medical management crucial standard of care: yearly dilated eye exams Diabetic Retinopathy ACCORD Eye Study Rationale

10. 10 important primary endpoint DCCT – Primary outcome UKPDS – Composite primary outcome Diabetic Retinopathy

11. 11 Diabetes Control and Complications Trial (DCCT) Randomized Clinical Trial Intensive Blood Glucose Control vs. Conventional Blood Glucose Control Type 1 Diabetes

12. 12 Primary Intervention - 3 Step Change Years Percent With Event DCCT Results Conventional Intensive

13. 13 Secondary Intervention - 3 Step Change Years Percent With Event DCCT Results Conventional Intensive

14. 14 Secondary Intervention - 3 Step Change Years Percent With Event DCCT Results P < 0.02 Conventional Intensive

15. 15 Results of Intensive Therapy: Clinically Important Retinopathy (34-76%) Photocoagulation (34%) First Appearance of Retinopathy (27%) DCCT Summary Reduction in Retinopathy

16. 16 Further Retinopathy Progression from the Level at DCCT Closeout Adjusted For DCCT Closeout Level Percentage Years of follow-up in EDIC Conventional Rx Tight Control Rx

17. 17 Randomized Clinical Trial Intensive Blood Glucose Control vs. Conventional Blood Glucose Control U K Prospective Diabetes Study Type 2 Diabetes

18. 18 U K Prospective Diabetes Study Microvascular Endpoints 10% 30% 20% 69301512 Years Conventional Intensive 0% Event Rate Photocoagulation/VH Renal Failure/Death Myocardial Infarction p=0.0099

19. 19 U K Prospective Diabetes Study Retinopathy - 2 Step Progression 10% 30% 40% 20% 693012 Years Conventional Intensive 50% 0% Event Rate p=0.78 p=0.02p=0.01

20. 20 Randomized Clinical Trial Intensive Blood Pressure Control vs. Conventional Blood Pressure Control U K Prospective Diabetes Study Type 2 Diabetes

21. 21 U K Prospective Diabetes Study Blood Pressure by Treatment Group mm Hg 100 80 120 140 160 3690 Years 124587 Less Tight - Systolic More Tight - Systolic Less Tight - Diastolic More Tight - Diastolic

22. 22 Retinopathy - 2 Step Progression 10% 30% 40% 20% 693012 Years Less Tight BP Control More Tight BP Control 50% 0% Event Rate UKPDS Blood Pressure Trial P=0.38P=0.02P=0.004

23. 23 Serum Cholesterol Diabetic Retinopathy and

24. 24  Early Treatment Diabetic Retinopathy Study (ETDRS)  Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) Serum cholesterol Observational Data

25. 25  Doubled the risk of retinal hard  50% increased risk of moderate vision  50% increased risk of developing hard exudate at baseline Serum cholesterol-ETDRS Results Elevated levels: exudate during follow-up loss at 5 years

26. 26  to assess the rates of progression of medical treatment on diabetic retinopathy  To evaluate the effects of these 3 diabetic retinopathy ACCORD Eye Study Objectives

27. 27  Baseline (within 4 months of enrollment) Sample size: n=4,065  4 years for all enrolled at baseline ACCORD Eye Study Eye Exam and Fundus Photos

28. 28  Clinical coordinator from the diabetes Coordinating Center (Wake Forest U.) and  Eye exam form, fundus photographs sent to clinic will schedule patient ACCORD Eye Study Study flow Reading Center (U. of Wisconsin)

29. 29 Alexandria meeting Feb 18-20, 2004