Diabetes and Cardiovascular Diseases in Type 2 Diabetes: From UKPDS to Steno 2

1. Diabetes and Cardiovascular Diseases in Type 2 Diabetes: From UKPDS to Steno 2  Dara P. Schuster, MD

2. Cardiovascular Disease • Early, aggressive interventions for risk reduction • New, more effective therapies for treatment of HTN and hyperlipidemia • Dramatic improvement in cardiovascular interventions • Marked reduction in smoking Yet the increase in prevalence of obesity and diabetes is epidemic, with CVD the leading complication of DM

3. Diabetes Doubles Risk for MI Mortality Despite Advances in Cardiac Care

5. The Metabolic Syndrome: A Network of Atherogenic Factors • Glycemic disorders • Dyslipidemia • - Low HDL • - Small, dense LDL • Hypertriglyceridemia • Postprandial lipemia • Hypertension • Impaired thrombolysis • - PAI-1, fibrinogen • Endothelial dysfunction/ • inflammation • - CRP, MMP-9, adiponectin • Microalbuminuria Insulin Resistance  Free Fatty Acids VisceralObesity Atherosclerosis Brunzell J, Hokanson J. Diabetes Care. 1999;22(Suppl 3):C10-C13. McFarlane S, et al. J Clin Endocrinol Metab. 2001;86(2):713-718. Frohlich M, et al. Diabetes Care. 2000;23(12):1835-1839. Kuusisto J, et al. Circulation. 1995;91:831-837. Parulkar AA, et al. Ann Intern Med. 2001;134:61-71. Hseuh WA, et al. Diabetes Care. 2001;24(2):392-397. Lebovitz H. Clin Chem. 1999;45(8B):1339-1345.

6. Cardiovascular Mortality AssociatedWith Metabolic Syndrome p < 0.001 Diabetes Care 2001;24:683

7. Association of MI* With the Metabolic Syndrome and Individual Components

8. Obesity, Insulin Resistance and Endothelial Dysfunction FFA IL-1 IL-6 PAI-1 TNF- leptin adiponectin Obesity CRP FFA TNF- leptin resistin adiponectin Endothelial Dysfunction Hyper- insulinemia Hyperglycemia Hypertension Dyslipidemia Altered coag/fib Insulin Resistance Caballero AE. Obes Res. 2003; 11: 1278-1289

9. Diabetes and Heart Failure:Current Knowledge

10. Relation of Glucose Tolerance Status to LVM

11. Treatment Standards for Cardiovascular Disease in Diabetes

12. Stenting in Diabetes: Clinical and Angiographic Outcomes BARI – Mortality after CABG vs. PTCA, 2000

13. BARI I: Poorer Outcome with Revascularization in Diabetics 100 Non DM PTCA 86.8% Non DM CABG 86.4% DM CABG 76.4% DM PTCA 55.7% 80 60 Percent Survival 40 Treatment Comparisons Non-diabetics: p=0.72 Diabetics: p=0.0011 20 0 Years 0 1 2 3 4 5 6 7

14. Revascularization in Diabetes: • Co-morbidity (PVD , CRF ) • Peri-procedural complications  • Worse long-term clinical outcomes • death, MI, stroke  • Excessive restenosis • intimal hyperplasia  • negative remodeling  • Accelerated atherosclerosis • progression of disease  • small vessel/diffuse disease  BARI 2-D All-cause mortality CVD mortality & MI Angina, employment Retinopathy Neuropathy Nephropathy PVD HbA1c, BP, cholesterol Cost-effectiveness

15. Blood Glucose Relates to Mortality and Risk for Heart Failure in MI

16. Glycemic Control and Risk of Development of HF in Diabetes

17. Improved Glycemic Control Has Been Shown to Reduce the Risk of Complications According to the United Kingdom Prospective DiabetesStudy (UKPDS) 35, Every 1% Decrease in A1C Resulted in: 14% 12% 21% 37% Decrease in risk of microvascular complications (P<.0001) Decrease in risk of any diabetes-related end point (P<.0001) Decrease in risk of stroke (P=.04) Decreasein risk of MI (P<.0001) Stratton IM et al. BMJ. 2000;321:405-412.

18. ADA Standards of Care • ADA recommends a general A1C target of <7% • The goal of therapy for the individual patient is to achieve an A1C as close to normal (<6%) as possible without hypoglycemia • More stringent glycemic goals may reduce the risk of serious diabetes-related complications • Less stringent treatment goals may be appropriate for certain patient populations and patients with severe or more frequent hypoglycemia American Diabetes Association. Diabetes Care. 2006;29:S4-S42.

19. The Role of Combination Therapy in Improving Glycemic Control: AACE Recommendations • To reduce the risk of serious disease-related complications,1,2 AACE recommends: • Target A1C goal of ≤6.5%2,3 • Intensive treatment of type 2 diabetes (i.e., earlier intervention with appropriate therapies and persistent titration to achieve goal)2,3 • AACE recommends combining medications with different mechanisms of action to target multiple defects2,3 1. Stratton IM, et al. BMJ. 2000;321:405-412. 2. Davidson J, et al. Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement. July 8, 2005. Available at: http://www.aace.com/meetings/consensus/odimplementation/index.php. Accessed May 25, 2006. 3. Davidson J, et al. Road Map for the Prevention and Treatment of Type 2 Diabetes. 2005. Available at: http://www.aace.com/meetings/consensus/odimplementation/index.php. Accessed May 25, 2006.

20. Skeletal Muscle The Rationale for Combination Therapy:Multiple Mechanisms of Action Targeting Multiple Sites Glucose Increase Insulin Secretion in Functioning Pancreatic b-Cells2 Sulfonylureas/Secretagogues PrimarilyDecreases Hepatic Glucose Production*1 Liver Insulin Pancreas Metformin Adipose Tissue Decrease Insulin Resistance and Increase Peripheral Glucose Uptake3 Thiazolidinediones * Also decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization. 1. Glucophage [prescribing information]. Bristol-Myers Squibb. 2. Amaryl [prescribing information]. Aventis Pharmaceuticals. 3. AVANDIA® (rosiglitazone maleate) [prescribing information]. GlaxoSmithKline.

21. Effect of Aspirin Use on Survival in Patients With CAD

22. Syst-Eur: Reduction in Event Rate in Adults (60 Years) With Diabetes

23. HOT: Cardiovascular Events by Target DBP in Diabetes Subgroup

26. MRFIT: Impact of Diabetes on Cardiovascular Disease Mortality

27. Steno-2: Study Design

28. Steno-2: Treatment Goals

29. Steno-2: Multifactorial Intervention and CV Events in Type 2 Diabetes

30. ACE Inhibitor Therapy for Patients With Diabetes

31. HOPE: Outcomes in Patients With Diabetes

32. BIP: b-Blocker Treatment Improves Survival of Patients With Diabetes

33. ACCORD 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

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

35. ACCORD Timeline 1/03 Training 2/03 - 6/05 Recruit >8800 pts (30 months) 7/05 - 2/09 Follow-up (44 months) 3/09 - 6/09 Participant close-out (4 months) 7/09 - 3/10 Analysis & reporting (9 months)

36. Summary

37. Summary, cont

38. DREAM: Diabetes Reduction Approaches with ramipril and rosiglitazone Medications • Funded by King Pharmaceuticals, Aventis, SmithKline Beecham in conjunction with CIHR • F/U to the HOPE trial (heart outcomes prevention evaluation) • 5.5 year study • Rosiglitazone reduced the risk of Diabetes by 60% • Rosiglitazone had no effect on CVD outcome

39. UKPDS Follow-up • UKPDS 66 Patients with fatal MI had higher HbA(1c) than those with nonfatal MI (odds ratio 1.17 per 1% HbA(1c), P = 0.014). Patients with fatal stroke had higher HbA(1c) than those with nonfatal stroke (odds ratio 1.37 per 1% HbA(1c), P = 0.007). Stevens et. al. Diabetes care vol. 27, no. 1 (2004 Jan): 201-7. • High BP is detrimental to each aspect of diabetic retinopathy; a tight BP control policy reduces the risk of clinical complications from diabetic eye disease. Matthews DR, et. al.Archives of ophthalmology. vol. 122, no. 11 (2004 Nov): 1631-40

40. The Need for Early Intervention • Norfolk Cohort (EPIC) – HbA1c predicted CVD • Nurses Health Study – CVD RR 3.17 before dx and 3.97 after dx. • Meta-analysis – progressive relationship between glu and CVD at levels below DM Dx • DECODE – glucose and CVD did not show a threshold effect (hazard ratios, IGT 1.1, 1.6 DM) Khaw,et.al. BMJ 2001, 25. Hu et.al. Diabetes Care 2002:25. Coutinho et.al. Diabetes Care 1999:22. Decode study group Diabetes Care 2003:26.

41. Earlier Addition of Rosiglitazone vs Uptitration of SU Rosiglitazone Added to SU Confers Durable Control Over 2 Years Intent-to-Treat* Completers† Mean A1C(%) Mean A1C(%) 0 0 Months Months * This is a repeated measures analysis accounting for baseline A1C, visit and treatment-visit interaction, and the correlation among visits within a patient. Baseline values reflect the average baseline A1C across all treatments as estimated using this model. All available values are utilized, including early visits from patients who subsequently withdrew from treatment. The A1C values at these early visits are reflected in estimated means for subsequent visits based on trends within each treatment. † Data shown are for those subjects who completed the study without experiencing glycemic failure. Data on file, GlaxoSmithKline.

42. Effect of Pioglitazone Monotherapy on the Atherogenic Index of Plasma (AIP)*

43. Relative floatation (Rf) Rf <0.2632 (small dense) Rf 0.2632 (large, more buoyant) Rosiglitazone Treatment Improves LDL Particle Density Phenotype 100 80 70 55 60 45 Patients (%) 40 30 20 0 Pre-RSG Week 8 Study 108. Data on file. GlaxoSmithKline.

44. Effect of Pioglitazone onAbdominal Fat Distribution

45. Before occlusion 700 700 * After occlusion * 600 600 500 500 * * 400 400 * 300 300 200 200 100 100 0 0 Fasting 30 min 1 h 2 h Fasting 30 min 1 h 2 h Brachial Artery Flow in IGT and PVD Before and 4 Months After Troglitazone Therapy Flow(mL/min) Before therapy After therapy Avena R et al. J Vasc Surg. 1998;28:1024-1031. *P<0.05 Before vs after occlusion (N=10). ©1999 PPS

46. Impact of Treating Insulin Resistance: Effects of TZDs on Carotid Artery IMT

47. Effects of Thiazolidinediones on Potential Determinants of Vasculopathy Parameter Troglitazone Pioglitazone PAI-1  in vivo  in vitro Platelet aggregation  in vitro No effect in vitro Intimal hyperplasia  in vivo  in vivo* Smooth muscle cell proliferation/migration  in vitro  in vitro Endothelial function  in vivo  in vitro* *Experimental animal study Marx N et al. Circ Res. 1998;83:1097-1103. Minamikawa J et al. J Clin Endocrinol Metab. 1998;83:1818-1820. Morikang E et al. Am J Hypertens. 1997;10:440-446. Notoya Y et al. Diabetes. 1998;47:A365-366. Abstract. Yamakawa K et al. Diabetes. 1998;47:A366. Abstract. Avena R et al. J Vasc Surg. 1998;28:1024-1031. Ehrmann DA et al. J Clin Endocrinol Metab. 1997;82:2108-2116. Igarashi M et al. Horm Metab Res. 1997;29:444-449. Ishizuka T et al. Diabetes. 1998;47:1494-1500. Kotchen TA et al. Am J Physiol. 1996;270:R660-R666. ©1999 PPS

48. Effect of Rosiglitazone on Microalbuminuria

49. Earlier Addition of Rosiglitazone vs Uptitration of SU Safety Profile Over a 2-Year Period 32% 27% 23% 10.3% 9% 9% 2.7% 3.4% CardiacIschemia Symptomatic Hypoglycemia CHF Edema Rosenstock J, et al. Diabetes Obes Metab. 2006;8:49-57. Data on file, GlaxoSmithKline.