1. Clinical Imperatives When Treating Patients with Diabetes

2. Diabetes, IFG, IGT: Diagnostic criteria ≥200 – 140 to 199 (ADA) >140 to <200 (AACE) Casual Fasting2-hr postload* Plasma glucose (mg/dL) *Following equivalent of 75 g anhydrous glucose in water ADA. Diabetes Care. 2006;29(suppl 1):S43-8. AACE. Endocr Pract. 2003;9:240-52. Diabetes Impaired fasting glucose (IFG) Impaired glucose tolerance (IGT) ≥200 – ≥126 100 to 125 (ADA) >110 to <126 (AACE) –

3. TargetRecommendations A1C<7% <6% if possible without inducing hypoglycemia BP (mm Hg)<130/<80 ACEI or ARB in BP-lowering regimen Lipids (mg/dL) LDL-C HDL-C TG <100 (<70 optional) >40 men, >50 women <150 Statin for CV history or age >40 yr (regardless of baseline LDL) to lower LDL 30%–40% AHA/ACC/ADA: Multiple risk reduction in diabetes Pearson T et al. Circulation 2002. Grundy SM et al. Circulation 2004. ADA. Diabetes Care 2006. ASA: Age >40 yr or with other risk factors, all with CV disease history ACE inhibitor: Age >55 yr with another CV risk factor

4. Intensive glycemic control Intensive management of comorbid conditions* A1C ≤6.5% Glucose (mg/dL) –Preprandial ≤110 –Postprandial ≤140 Lipid modifying BP lowering ASA for prevention of vascular events AACE: Managing diabetes Lifestyle intervention Optimal nutrition Physical activity Smoking cessation Weight control AACE. Endocr Pract. 2002;8(suppl 1):40-65. American Association of Clinical Endocrinologists *Dyslipidemia, hypertension, early renal disease

5. AHA/ACC secondary prevention guidelines: Diabetes management Initiate lifestyle and pharmacotherapy to achieve near- normal A1C (IB) Begin vigorous modification of other risk factors (eg, physical activity, weight management, BP control, cholesterol management) (IB) Coordinate diabetic care with patient’s primary care physician or endocrinologist (IC) Smith SC et al. Circulation. 2006;113:2363-72. A1C goal <7%

6. DPP: Benefit of diet/exercise or metformin on diabetes prevention in at-risk patients DPP Research Group. N Engl J Med. 2002;346:393-403. Years N = 3234 with IFG/IGT without diabetes 0 0 10 20 30 40 1.02.03.04.0 Placebo Metformin Lifestyle Cumulative incidence of diabetes (%)  31%  58% P < 0.001

7. DPP: Benefit of diet/exercise or metformin on diabetes by race/ethnicity DPP Research Group. N Engl J Med. 2002;346:393-403. Reduction in new-onset diabetes (%) White n = 1768 African American n = 645 Hispanic n = 508 American Indian n = 171 Asian n = 142 N = 3234 with IFG/IGT and without diabetes Lifestyle vs placeboMetformin vs placebo Lifestyle vs metformin 0 -20 -40 -60 -80

8. 3-Week diet + exercise yield favorable metabolic changes *P < 0.01 † P < 0.05 Roberts CK. et al. J Appl Physiol. 2006;100:1657-65. μU/mL N = 31 overweight/obese men; weight  8.4 lbs Baseline Follow-up

9. 3-Week diet + exercise reduce proatherogenic factors MPO = myeloperoxidase; 8-iso-PGF 2α = 8-isoprostaglandin F 2α sICAM-1 = soluble intracellular adhesion molecule 1 *P < 0.05; † P < 0.01 Roberts CK. et al. J Appl Physiol. 2006;100:1657-65. pg/mLmg/L * N = 31 overweight/obese men; weight  8.4 lbs † † † * Baseline Follow-up 8-iso-PGF 2α

10. Beyond lifestyle: Aggressive medical therapy in diabetes Adapted from Beckman JA et al. JAMA. 2002;287:2570-81. Atherosclerosis Platelet activation and aggregation Dyslipidemia Hyperglycemia Insulin resistance Hypertension Metformin TZDs Sulfonylureas Nonsulfonylureas Secretagogues Insulin Statins Fibric acid derivatives ACE inhibitors ARBs β-blockers CCBs Diuretics ASA Clopidogrel Ticlopidine

11. Steno-2 supports aggressive multifactorial intervention in type 2 diabetes Objective: Target-driven, long-term, intensified intervention aimed at multiple risk factors compared with conventional therapy N = 160 patients with type 2 diabetes and microalbuminuria Intensive treatment targets –BP <130/80 mm Hg –A1C <6.5% –Total-C <175 mg/dL –Triglycerides <150 mg/dL Gæde P et al. N Engl J Med. 2003;348:383-93.

12. Steno-2: Multifactorial intervention on CV outcomes N = 160 with type 2 diabetes and microalbuminuria Gæde P et al. N Engl J Med. 2003;348:383-93. *CV death, MI, stroke, CABG/PCI, amputation, PAD surgery † Adjusted for duration of diabetes, age, sex, smoking, CV disease Primary composite outcome* (%) 60 50 40 30 20 10 0 53% RRR † P = 0.01 Follow-up (months) Conventional Intensive 01224364860728496

13. 8 Steno-2: Better risk factor control with intensive therapy Gæde P et al. N Engl J Med. 2003;348:383-93. Conventional therapy (n = 80)Intensive therapy (n = 80) 0 0 5 6 7 8 9 11 10 AlC (%) Follow-up (years) 0 110 120 130 140 150 160 170 0 SBP (mm Hg) Follow-up (years) 0 50 100 150 200 250 300 350 0 TG (mg/dL) 0 0 50 100 150 200 250 300 350 Total-C (mg/dL) 12345678 P < 0.001 12345678 1234567 P = 0.015 12345678 P < 0.001

14. Steno-2: Effects of multifactorial intervention on microvascular and neuropathic outcomes Gæde P et al. N Engl J Med. 2003;348:383-93. Nephropathy Retinopathy Autonomic neuropathy Peripheral neuropathy VariableRRP 0.39 0.42 0.37 1.09 0.003 0.02 0.002 0.66 Reductions in the risk of microvascular complications were maintained at 8 years 0.00.51.01.52.02.5 Intensive better Conventional better Relative risk

15. Benefits of aggressive LDL-C lowering in diabetes Shepherd J et al. Diabetes Care 2006. Sever PS et al. Diabetes Care 2005. HPS Collaborative Group. Lancet 2003. Colhoun HM et al. Lancet 2004. Difference in LDL-C (mg/dL) Aggressive lipid-lowering better Aggressive lipid-lowering worse 0.026 0.036 0.001 <0.0001 0.0003 Primary event rate (%) 17.9 11.9 9.0 12.6 13.5 Control 13.8 9.2 5.8 9.4 9.3 Treatment 0.63 0.67 0.73 P TNT Diabetes, CHD ASCOT-LLA Diabetes, HTN CARDS Diabetes, no CVD HPS All diabetes Diabetes, no CVD *Atorvastatin 10 vs 80 mg/day † Statin vs placebo Relative risk 0.70.910.5 1.7 0.77 22* 35 † 46 † 39 † 0.75

16. Event rate (%) HPS: Statin beneficial irrespective of baseline lipid level and diabetes status Placebo n = 10,267 0.41.01.40.60.81.2 Simvastatin n = 10,269 Event rate ratio Statin betterPlacebo better LDL-C <116 mg/dL With diabetes No diabetes 15.7 18.8 20.9 22.9 LDL-C ≥116 mg/dL With diabetes No diabetes 23.3 20.0 27.9 26.2 24% reduction P < 0.0001 25.219.8All patients HPS Collaborative Group. Lancet. 2003;361:2005-16. Heart Protection Study

17. ASCOT-LLA: Atorvastatin reduces CV events in patients with diabetes and hypertension N = 2532, baseline LDL-C 128 mg/dL Nonfatal MI, CV mortality, UA, stable angina, arrhythmias, stroke, TIA, PAD, retinal vascular thrombosis, revascularization Sever PS et al. Diabetes Care. 2005;28:1151-7. % Number at risk Placebo 1258 Atorvastatin 1274 14.0 12.0 10.0 8.0 6.0 4.0 2.0 0 0 12311209119111711065699370 12371219120011751058714375 0.51.01.52.02.53.03.5 Years Atorvastatin 10 mg Placebo HR = 0.77 (0.61–0.98) 23% Risk reduction P = 0.036

18. HOPE Study Investigators. Lancet. 2000;355:253-9. Daly CA et al. Eur Heart J. 2005;26:1369-78. PERSUADE (n = 1502) CV death/MI/cardiac arrest MICRO-HOPE (n = 3577) CV death/MI/stroke MICRO-HOPE, PERSUADE: ACEI reduces CV events in diabetes Placebo 25 Ramipri l 10 mg 20 15 10 5 0 Primary outcome (%) Follow-up (years) 012345 25% RRR P = 0.0004 20 15 10 5 0 012345 Follow-up (years) Placebo Perindopril 8 mg 19% RRR P = 0.13 25

19. TZD + statin: Favorable effects on inflammatory markers and adiponectin *P < 0.05 vs baseline; † P < 0.05 vs ROSI monotherapy Chu C-S et al. Am J Cardiol. 2006;97:646-50. N = 30 with DM2 and hyperlipidemia treated with rosiglitazone; add-on atorvastatin after 3 months; follow-up 6 months Adiponectin † Change from baseline (%) † † * * * * * * ROSI 4 mgROSI 4 mg + ATORVA 10 mg

20. Principal mechanisms of action for oral diabetic agents Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411. α-Glucosidase inhibitors Intestine: ↓glucose absorption Biguanides Liver: ↓hepatic glucose output ↑glucose uptake Blood glucose Sulfonylureas and repaglinide Pancreas: ↑insulin secretion Muscle and adipose tissue: ↓insulin resistance ↑glucose uptake Thiazolidinediones

21. Oral antihyperglycemic agents Drug classAgentsMechanism of action Alpha-glucosidase inhibitors Acarbose, miglitolDelay intestinal carbohydrate absorption BiguanidesMetformin↓ Hepatic glucose production ↑ Liver and muscle insulin sensitivity Insulin secretagogues— Sulfonylureas Glimepiride, glipizide, glyburide ↑ Insulin secretion from pancreatic β-cells Insulin secretagogues— Meglitinides Nateglinide, repaglinide↑ Insulin secretion from pancreatic β-cells ThiazolidinedionesPioglitazone, rosiglitazone↑ Adipose and muscle insulin sensitivity Trujillo J. Formulary. 2006;41:130-41. Luna B, Feinglos MN. Am Fam Physician. 2001;63:1747-56.

22. Beyond glucose lowering: Effects of antidiabetic agents TZDMetformin Insulin secretagogues*AGI Insulin resistance  Hypertension  or  or  Altered hemostasis PAI-1 tPA   or   or   NA Dyslipidemia TG HDL-C LDL particle size  or   or    or   or   NA  or   or  NA C-reactive protein  NA *Sulfonylureas and meglitinides AGI = alpha glucosidase inhibitor  = no change Adapted from Granberry MC, Fonseca VA. Am J Cardiovasc Drugs. 2005;5:201-9. NA = data not available

23. TZD vs sulfonylurea: Glycemic control over time St. John Sutton M et al. Diabetes Care. 2002;25:2058-64. N = 203 patients with type 2 diabetes A1CFasting plasma glucose mg/dL 0 8.5 10.0 Treatment week % 9.5 9.0 8.0 7.5 -8-40481216284052 GLYBROSI 8 mg/d GLYB = glyburide BaselineWeek 8Week 52 0 200 250

24. TZD + sulfonylurea efficacy in type 2 diabetes Pfützner A et al. Metabol Clin Exp. 2006;55:20-5. N = 102; changes after 16 weeks Adiponectin ‡ % Change *P < 0.05 vs baseline † P < 0.005 vs baseline ‡ Adjusted for BMI changes GLIM = glimepiride 3 mg; ROSI = rosiglitazone GLIMGLIM + ROSI 4 mgGLIM + ROSI 8 mg HOMA-IR Intact proinsulin CRP * † * † * † -20 0 80 160 *

25. PROactive: Reduced requirement for insulin use Dormandy JA et al. Lancet. 2005;366:1279-89. 5 10 15 25 0 6 20 01218243036 Pioglitazone n = 183 (11%) Placebo n = 362 (21%) Follow-up (months) Patients (%) 53% RRR HR 0.47 (0.39–0.56)* P < 0.0001 *Unadjusted

26. Sulfonylurea + TZD or metformin: Comparison of lipid and renal effects Hanefeld M et al. Diabetes Care. 2004;27:141-7. N = 639 with poorly controlled DM2; change after 52 weeks * † ‡ † † *P = 0.008, † P < 0.001, ‡ P = NS Pioglitazone 15–45 mg + sulfonylurea Metformin 850–2550 mg + sulfonylurea Change (%)

27. TZDs and metformin reduce risk of MI Case-control study of first MI in patients with type 2 diabetes *Adjusted for age, sex, BMI, ACE inhibitor use, history of hypertension or hypercholesterolemia Sauer WH et al. Am J Cardiol. 2006; 97:651-4. Monotherapy Metformin TZD TZD + sulfonylurea Metformin + sulfonylurea Insulin- sensitizing drugs Sulfonylurea monotherapy P 0.01 0.03 0.04 0.19 Odds ratio for MI (95% CI)* Combination therapy PatientsControls 3887 719 718 4062 00.20.40.60.81.01.2 n

28. Improving blood glucose control: Potential role of combination therapy AACE Goal  6.5% ADA Goal <7% Baseline A1C (%) = n = 7.9 277 8.0 296 Adapted from Weissman P et al. Curr Med Res Opin. 2005;21:2029-2035. Metformin 1 g/day Uptitrated to 2 g/day Rosiglitazone 8 mg/day + Metformin 1 g/day Patients reaching A1C goal (%)

29. DPP-IV inhibitors Potentially important in early DM2 to prevent deterioration of glucose metabolism Decrease rate of GLP-1 degradation Partially restore impaired insulin secretion Protect  -cells Oral DPP-IV inhibitors in phase 3 development –Sitagliptin –Vildagliptin Smyth S, Heron A. Nat Med. 2005;12:75-80. DPP-IV = dipeptidyl peptidase-IV GLP-1 = glucagon-like peptide-1

30. DPP-IV inhibitors, GLP-1 analogs: New classes of antidiabetic agents GLP-1 is released after meals  Glucose-dependent insulin secretion from  -cells  Levels in type 2 diabetes (“incretin defect”) Rapidly inactivated by DPP-IV GLP-1: An incretin hormone  GLP-1 degradation  Glucose-dependent insulin secretion DPP-IV inhibitors Mest H-J, Mentlein R. Diabetologia. 2005;48:616-20. Smyth S, Heron A. Nat Med. 2005;12:75-80. GLP-1 analogs  Glucose-dependent insulin secretion Resistant to DPP-IV degradation New antidiabetic agents: Dual actions

31. AMIGO trials: GLP-1 analog in type 2 diabetes Active treatment Change from baseline Exenatide 5 µg bid Exenatide 10 µg bid Placebo Sulfonylurea 1 A1C (%)–0.46–0.86+0.12 (N = 377)Weight (lb)–2.0–3.6–1.3 Metformin 2 A1C (%)–0.40–0.78+0.08 (N = 336)Weight (lb)–3.6–6.2–0.7 Metformin + sulfonylurea 3 A1C (%)–0.55–0.77+0.23 (N = 733)Weight (lb)–3.6 –2.0 AC 2993: Diabetes Management for Improving Glucose Outcomes; 30-week, placebo-controlled trials of exenatide sc added to oral hypoglycemic therapy 1 Buse JB et al. Diabetes Care. 2004;27:2628-35. 2 DeFronzo RA et al. Diabetes Care. 2005;28:1092-100. 3 Kendall DM et al. Diabetes Care. 2005;28:1083-91.

32. Adapted from Cohen JD. Lancet. 2001;357:972-3. B  -blockade Blood pressure control A Aspirin ACE inhibition A1C control C Cholesterol management Managing diabetes as a CHD equivalent: ABCs of coronary prevention Diet Don’t smoke Decrease diabetes risk D Exercise E

33. Insulin resistance Proatherogenic effects of insulin resistance HypertensionObesityInflammationHyperinsulinemiaDiabetesDyslipidemiaThrombosis Atherosclerosis

34. Summary: Expanding risk factor control to enhance CV outcomes Insulin resistance is an independent risk factor for atherosclerosis Aggressive lifestyle modification and pharmacotherapy can decrease CV risk and prevent new-onset diabetes TZDs target insulin resistance and appear to improve CV risk factors