1. Diabetes... Common and underdiagnosed Causes macro- and microvascular events Reduces duration and quality of life

2. Estimated Prevalence of Diabetes in the US Adult Men and Women Harris, et al. Diabetes Care. 1998;21:518-24. 0 10 20 30 75+60-7450-5940-4920-39 Age (y) 1.61.7 6.8 6.1 12.9 12.4 20.2 17.8 21.1 17.5 Men Women Percent of Population

3. Diagnosed and Undiagnosed Diabetes in the US Estimated Cases Among Adults, 1997 Harris, et al. Diabetes Care. 1998;21:518-24. 0 2 4 6 8 10 12 UndiagnosedDiagnosed 10.2 5.4 Millions of Cases

4. Retinopathy in Adults not Known to Have Diabetes Rationale for Diagnostic Criteria for Diabetes Glycemic Values in Deciles of Populations Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1999;22(Supp 1):S5-S19. FPG 2hPG HbA 1c Retinopathy (%) 15 10 5 0 US (NHANES III) 42-87-90-93-96-98-101-104-109-120- 34-75-86-94-102-112-120-133-154-195- 3.3-4.9-5.1-5.2-5.4-5.5-5.6-5.7-5.9-6.2- FPG (mg/dL) 2hPG (mg/dL) HbA 1c (%)

5. Retinopathy in Adults not Known to Have Diabetes Rationale for Diagnostic Criteria for Diabetes Glycemic Values in Deciles of Populations Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1999;22(Supp 1):S5-S19. 50 30 10 0 40 20 Retinopathy (%) FPG 2hPG HbA 1c Egypt 57-79-84-89-93-99-108-130-178- 258- 39-80-90-99-110-125-155-218-304- 386- 2.2-4.7-4.9-5.1-5.4-5.6-6.0-6.9- 8.5- 10.3- FPG (mg/dL) 2hPG (mg/dL) HbA 1c (%)

6. Glucose Tolerance Categories Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-97. FPG 126 mg/dL 110 mg/dL 7.0 mmol/L 6.1 mmol/L Impaired Fasting Glucose Normal 2-Hour PG on OGTT 200 mg/dL 140 mg/dL 11.1mmol/L 7.8mmol/L Diabetes Mellitus Impaired Glucose Tolerance Normal Diabetes Mellitus

7. Diagnosis of Diabetes Three Methods 1.Random plasma glucose >200 mg/dL on 2 separate occasions + symptoms (polyuria, polydipsia, unexplained weight loss) 2.FPG >126 mg/dL on 2 separate occasions 3.2-hour plasma glucose >200 mg/dL during OGTT on 2 separate occasions Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-97.

8. THE FUNAGATA DIABETES STUDY Impaired Glucose Tolerance is a CV Risk Factor Tominaga M, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. Diabetes Care 1999;22:920-4. Normal IGT (2 hr PG 140-200) DM (2 hr PG >200) 1.00 Cumulative Cardiovascular Survival 0.99 0.98 0.97 0.96 0.95 0.94 0 1.00 0.98 0.96 0.94 0.92 0 Normal IFG (FPG 110-126) DM (FPG >126) 01234567 01234567 Year

9. FRAMINGHAM STUDY AND JOSLIN PATIENTS Diabetes is a CV Risk Factor Krolewski AS, et al. Evolving natural history of coronary disease in diabetes mellitus. Am J Med 1991;90(Supp 2A):56S-61S. Diabetes No Diabetes 60 Men 0-3 Duration of Follow-up (Years) 50 40 30 20 10 0 Women 4-78-1112-1516-1920-23 60 0-3 Duration of Follow-up (Years) 50 40 30 20 10 0 4-78-1112-1516-1920-23 Mortality Rate Per 1000 2x 4-5x

10. MRFIT Type 2 Diabetes is a CV Risk Factor Additive Effects of Hypertension, Hypercholesterolemia, and Smoking Stamler J, et al. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44. 0 20 40 60 Number of Risk Factors NoneOneTwoAll Three No Diabetes Diabetes Age Adjusted CV Death Rate Per 10,000 Person Years 80 100 120 140

11. Type 2 Diabetes is a CV Risk Factor Diabetes and Prior MI Predict Mortality Equally Haffner SM, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34. 100 Year 3 Survival (%) 80 60 40 20 0 01245678 No Diabetes or MI Diabetes without MI MI without Diabetes Diabetes + MI

12. Reduced Life-expectance with Diabetes US Adults Aged 55 to 64 in 1971 to 1975 Gu K, et al. Mortality in adults with and without diabetes in a national cohort of the US population, 1971-1993. Diabetes Care 1998;21:1138-45. 0 10 20 30 Median Life Expectance WomenMen No Diabetes Diabetes Years 25 17 18 10

13. Lifetime Microvascular Events in Type 2 Diabetes Predictions from a Statistical Model Eastman RC, et al. Model of complications of non-insulin dependent diabetes mellitus. II analysis of the health benefits and cost- effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 1997;20:735-44. Standard CareComprehensive Care Percentage HbA 1c 10%HbA 1c 7.2%Change Blindness19%5%-72 Renal failure17%2%-87 Symptomatic neuropathy31%10%-68 Amputation15%5%-67

14. Treatment Improves Outcomes

15. KUMAMOTO STUDY Effect of Treatment on HbA1 c Ohkubo Y, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non- insulin-dependent diabetes mellitus. A randomized prospective 6-year study. Diab Res Clin Pract 1995;28:103-17. Conventional Intensive Years 9 0 HbA 1c (%) 12 11 10 8 6 5 7 123456 2.3% HbA 1c

16. KUMAMOTO STUDY Risk Reduction of Microvascular Complications Ohkubo Y, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non- insulin-dependent diabetes mellitus. A randomized prospective 6-year study. Diab Res Clin Pract 1995;28:103-17. Cumulative Percent Progressing 50 40 30 20 10 0 50 40 30 20 10 0 40 30 20 10 0 40 30 20 10 0 Years 0123456 0123456 Retinopathy Primary Prevention Nephropathy Primary Prevention Retinopathy Secondary Intervention Nephropathy Secondary Intervention -62% P=0.032 -70% P=0.039 -52% P=0.049 -52% P=0.044 Conventional Intensive

17. UKPDS MAIN STUDY Effect of Treatment on HbA1 c Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53. Conventional (10-y cohort) 9 8 7 6 0 036 6.2% upper limit of normal range ADA goal ADA action 91215 Time From Randomization (y) Intensive (all patients) Conventional (all patients) Intensive (10-y cohort) Median HbA 1c (%)

18. UKPDS MAIN STUDY Risk Reduction of Microvascular Complications UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53. % of Patients With an Event Risk Reduction 25% P=0.0099 Conventional Intensive 036 0 10 20 30 91215 Time From Randomization (y)

19. UKPDS MAIN STUDY Risk Reduction of Various Endpoints UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. Risk Reduction (%) P=0.000054 P=0.015 P=0.052 P=0.0099 P=0.029 05101520253035 Diabetes-related end points Myocardial infarction Albuminuria Retinopathy Microvascular 25% 21% 16% 33% 12%

20. UKPDS METFORMIN SUBSTUDY Effect of Treatment on HbA 1c Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. Median HbA 1c (%) Conventional (200) Insulin (199) Chlorpropamide (129) Glyburide (148) Metformin (181) 024 0 6 7 8 9 6810 Time From Randomization (y) Upper limit of normal range (6.2%) ADA goal ADA action

21. UKPDS METFORMIN SUBSTUDY Gain of Weight During Treatment Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. Mean Change (kg) Conventional (200) Insulin (199) Chlorpropamide (129) Glyburide (148) Metformin (181) 024 -5 0 5 10 68 Time From Randomization (y) Baseline = 85 kg

22. UKPDS METFORMIN SUBSTUDY Risk-Reduction of Microvascular Complications Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. % of Patients With Event Conventional (411) Intensive (951) Metformin (342) 036 0 10 20 30 91215 Time From Randomization (y) P=0.19 M vs. C P=0.39 M vs. I

23. UKPDS METFORMIN SUBSTUDY Diabetes-Related Deaths Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Patients at Risk Conventional Metformin Intensive 404 339 930 378 321 870 304 267 701 132 123 319 23 28 61 Conventional (411) Metformin (342) Intensive (951) Proportion With Event (%) 30 20 10 0 03691216 Time From Randomization (y) M vs. C P=.017 M vs. I P=.11

24. UKPDS HYPERTENSION SUBSTUDY Effect of Atenolol or Captopril on Blood Pressure UK Prospective Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13. Less Tight Control Tight Control with Atenolol or Captopril Years from Randomization 0 Mean Blood Pressure (mm Hg) 160 123456789 140 120 100 80 0 Systolic Diastolic

25. UKPDS HYPERTENSION SUBSTUDY Risk-Reduction of Microvascular Endpoints UK Prospective Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13. Years from Randomization 0 Patients With Events (%) 20 123456789 10 0 Less Tight Control Tight Control Risk-Reduction 37% P=0.0092

26. UKPDS HYPERTENSION SUBSTUDY Risk-Reduction of Stroke UK Prospective Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13. 0 Patients With Events (%) 20 123456789 10 0 Years from Randomization Risk-Reduction 44% P=0.013 Less Tight Control Tight Control

27. UKPDS HYPERTENSION SUBSTUDY Diabetes-Related Deaths UK Prospective Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13. Years from Randomization 0 Mortality (%) 40 123456789 20 0 30 10 Less Tight Control Tight Control Risk-Reduction 32% P=0.019

28. UKPDS HYPERTENSION SUBSTUDY Diabetes-Related Deaths: Atenolol vs. Captopril UK Prospective Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascualr complications in type 2 diabetes.: UKPDS 39. BMJ 1998;317:713-720. Years from Randomization 0 Mortality (%) 20 123456789 10 0 15 5 Less Tight Control Captopril Atenolol P=0.28

29. SYSTOLIC HYPERTENSION IN THE ELDERLY PROGRAM (SHEP) Diabetes Subgroup Analysis Effect of Thiazide-Based Treatment on Blood Pressure Curb JD, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-92. Placebo Treatment Years Blood Pressure (mm Hg) 180 160 140 120 100 80 60 40 20 0 180 160 140 120 100 80 60 40 20 0 012345 012345 Years Blood Pressure (mm Hg) Diastolic Systolic Diastolic No Diabetes Diabetes

30. SYSTOLIC HYPERTENSION IN THE ELDERLY PROGRAM (SHEP) Diabetes Subgroup Analysis Effect of Thiazide-Based Treatment on CV Events Curb JD et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-92. 0 10 20 40 Risk Reduction 34% No Diabetes (n=4736) Diabetes (n=583) Placebo Treatment Percent With Events at 5 Years 18.4 13.3 31.5 21.4 30 Risk Reduction 34%

31. SCANDINAVIAN SIMVASTATIN SURVIVAL STUDY (4S) Diabetes Subgroup Analysis Reduction of LDL-Cholesterol Pyorala K et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 1997;20:614-20. No DiabetesDiabetes n4242202 Baseline mmol/L4.884.80 mg/dL189186 Reduction34%36%

32. SCANDINAVIAN SIMVASTATIN SURVIVAL STUDY (4S) Diabetes Subgroup Analysis Reduction of Major Recurrent CV Events Pyorala K et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 1997;20:614-20. Years Since Randomization Proportion With Major CHD Event 0.60 0 0.50 0.40 0.30 0.20 0.10 0.00 123456 Placebo Simvastatin Diabetes Years Since Randomization Proportion With Major CHD Event 0.60 0 0.50 0.40 0.30 0.20 0.10 0.00 123456 No Diabetes Placebo Simvastatin Risk Reduction 32% P=0.0001 Risk Reduction 55% P=0.002

33. CARE TRIAL Diabetes Subgroup Analysis Reduction of LDL-Cholesterol by Pravastatin Goldberg RB, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analysis in the Cholesterol And Recurrent Events (CARE) Trial. Circulation 1998;98:2513-19. No DiabetesDiabetes n3573586 Baseline mmol/L3.593.52 mg/dL139136 On Pravastatin 40 mg mmol/L2.562.48 mg/dL9996 Reduction29%29%

34. CARE TRIAL Diabetes Subgroup Analysis Reduction of Recurrent CV Events Goldberg RB et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analysis in the Cholesterol And Recurrent Events (CARE) Trial. Circulation 1998;98:2513-19. Years of Follow-up 0 Percent With Event 45 Placebo Pravastatin 12345 40 35 30 25 20 15 10 5 0 0 Percent With Event 45 12345 40 35 30 25 20 15 10 5 0 Placebo Pravastatin No Diabetes Diabetes Risk Reduction 23% P<0.001 Risk Reduction 25% P<0.05

35. CV Risk-Reduction With Antiplatelet Therapy High-Risk Patients Diabetes Subgroup Meta-analysis Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patient. BMJ 1994;308:71-2. No DiabetesDiabetes n21,19721,136 Vascular events Control16.4%22.3% Antiplatelet Rx (usually ASA)12.8%18.5% Risk Reduction28%21%

36. Targets and Tactics for Typical Patients

37. UKPDS Metabolic Profile at Diagnosis of Type 2 Diabetes UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997;20:1683-7. WomenMen N15742139 Age years5352 BMI kg/m 2 30.828.3 FPG mmol/L12.411.6 mg/dL223209 HbA 1c %9.39.0 BP mm/Hg140/84134/82 LDL-cholesterol mmol/L3.903.35 mg/dL151139

38. ADA Glycemic Targets American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41. NormalGoalAction Level HbA 1c (%) 8 Fasting and preprandial blood glucose mmol/L 7.8 mg/dL 140

39. ADA Blood Pressure Targets American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41. Goal mm Hg Usual patient<130/85 Isolated systolic hypertension If ≥180<160 If 160 to 179Reduce by 20

40. ADA LDL-Cholesterol Targets American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41 & S56-S59. Medical Nutrition Therapy Drug Therapy Begin RxGoalBegin RxGoal With CV disease>100≤100>100≤100 No CV disease>100≤100>130≤100

41. Tactics for Reaching Glycemic Targets Medical Management of Type 2 Diabetes, Fourth Edition, Zimmerman BR ed, American Diabetes Association, Alexandria, VA, 1998. Lifestyle intervention Oral monotherapy Oral combination Oral-insulin combinations Multiple insulin injections

42. Tactics for Reaching Blood Pressure Targets Kaplan NM. Hypertension in patients with diabetes. In Current Management of Diabetes Mellitus, ed. De Fronzo RA, Mosby, 1998. American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 1999;22(Suppl):S56-S59. Lifestyle InterventionControl weight Limit sodium and alcohol Optimize activity Initial Drug ChoicesACE-inhibitor or  -blocker or Low-dose diuretic CombinationsTwo or three of the above Other options  -blockers Calcium antagonists Hydralazine

43. Calcium Antagonists vs. Other Antihypertensives Controversy Over Use in Diabetes Pahor M et al. Treatment of hypertensive patients with diabetes. Lancet 1998;351:690-1. TrialComparisonCalciumRisk DrugAntagonist Ratio ABCDEnalaprilNisoldipine1/5.5 FACETFosinoprilAmilodipine1/2.4 MIDASHydrochlorothiazideIsradipine1/2.7

44. Tactics for Reaching Lipid Targets American Diabetes Association. Management of Dyslipidemia in Adults with Diabetes. Diabetes Care 1999;22(Suppl):S56-S59. Lifestyle InterventionControl weight Limit fat Optimize activity Initial Drug ChoicesUsual patient Statin Triglyceride >400 mg/dL Fibric acid derivative CombinationsStatin + fibric acid derivative Other options Bile acid binding resins Nicotinic acid

45. THE CURVES STUDY LDL Reduction With Various Statins Jones P et al. Comparative dose efficacy of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia. Am J Cardiol 1998;81:582-7. Total Daily Dose (mg) Mean % Change in LDL-C -10 10 mg20 mg40 mg80 mg -30 -60 -20 -50 -40 Fluvastatin Pravastatin Lovastatin Simvastatin Atorvastatin

46. Summary Epidemiologic and interventional evidence defines these targets HbA 1c 7% Blood Pressure 130/85 mm Hg LDL-cholesterol 100 mg/dL Basic treatment tactics include For glycemic control –Oral and oral-insulin combinations For blood pressure control –ACE-inhibitor,  -blocker, and diuretic combinations For LDL-cholesterol control –Statins For vascular protection –ASA 81-325 mg daily