Craig Williams, Pharm.D ., FNLA Associate Professor; OSU School of Pharmacy and OHSU School of Medicine williacr@ohsu.e

1. Craig Williams, Pharm.D., FNLA Associate Professor; OSU School of Pharmacy and OHSU School of Medicine williacr@ohsu.edu 2011 Annual Diabetes Practice Update Session: Update on Cardiovascular Disease & Diabetes: Prevention of CVD in Patients with Diabetes September 30th, 2011

2. Craig Williams, Pharm.D., FNLA Associate Professor; OSU School of Pharmacy and OHSU School of Medicine williacr@ohsu.edu 2011 Annual Diabetes Practice Update Session: Prevention of CVDAtherothrombosis in Patients with Diabetes September 30th, 2011

3. Presenter Disclosure Information In compliance with the accrediting board policies, theAmerican Diabetes Association requires the following disclosure to the participants: Name of Presenter: Craig Williams, Pharm.D., FNLA Research Support: Merck & Co., Inc. Speakers Bureau: Merck & Co., Inc.

4. VI. Prevention and management of complications A. Cardiovascular disease 1. HTN control 2. Dyslipidemia management 3. Anti-platelet 4. Smoking cessastion 5. Hyperglycemia?

5. There is a clear epidemiologic association between glycemic control and CVD NEW ENGLAND JOURNAL OF MEDICINE March 4, 2010 Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Non-diabetic Adults Elizabeth Selvin, Michael Steffes, Hong Zhu, Kunihiro Matusushita, et al. Data from 11,092 black and white subjects in the ARIC trial (Atherosclerosis Risk in Communities) Median follow approximately 14 years.

6. Despite clear epidemiology, controversy continues regarding the role of glucose lowering to prevent coronary events ADA position on glycemia and macrovascular disease in 2010 Standards of Care guideline ADA Standards of Care. Diabetes Care 2010;33:S11-62

7. Three large trials of glycemic control published in 2008 failed to find CVD benefit Non-fatal MI significantly reduced 24% (p=0.001) So hyperglycemia doesn’t matter to the heart? Sklyer JS, et al. Intentive glycemic control and the prevention of cardiovascular events. A position statement of the ADA/ACC/AHA. Diabetes Care 2009;32:187-92.

8. Hyperglycemia is toxic at several steps in the atherosclerosis process Retnakaran R, Zinman B. Lancet 2008;371:1790-99.

9. Failure to find benefit may have related to the A1C levels tested: 6.4% vs. 7.5% 6.3% vs. 7.0% 6.9% vs. 8.5% So hyperglycemia matters to the heart but intense control (A1C < 7%) provides little additional benefit over moderate control (A1C 7-8%) Sklyer JS, et al. Intentive glycemic control and the prevention of cardiovascular events. A position statement of the ADA/ACC/AHA. Diabetes Care 2009;32:187-92.

10. 2011 ADA guideline appropriately discusses microvascular benefits of A1C < 7% while acknowledging lack of proven macrovascular benefits at the A1C values that were studied.

11. VI. Prevention and management of complications A. Cardiovascular disease 1. HTN control 2. Dyslipidemia management 3. Anti-platelet 4. Smoking cessastion

12. 2. Dyslipidemia/ lipid management ADA Standards of Care; Diabetes Care, January 2011

13. “Alternative goals…..”

14. Three points critical to understanding the evidence base of the ADA guidelines for lipid management: The etiologic role of lipoproteins in atherosclerosis The etiology of dyslipidemia as seen in patients with diabetes The clinical outcomes literature in patients with diabetes

15. 1. Atherosclerosis is a lipoprotein driven process Basic Science for CliniciansSubendothelial Lipoprotein Retention as the Initiating Process in AtherosclerosisUpdate and Therapeutic Implications Ira Tabas, MD, PhD; Kevin Jon Williams, MD; Jan Borén, MD, PhD Circulation, October 16th, 2007

16. Lipoproteins share structural homologyChylomicrons, VLDL, IDL, LDL, HDL all share a basic biochemistry Liver TG Lipase enzymes VLDL Lipase enzymes IDL LDLc LDL

17. Fredrickson Classification of Dyslipidemia We look at this Artery wall sees these

18. The primary atherogenic lipoprotein is LDLlipoproteins of > 70 nm have limited transcytosis past the endothelium Nascent chylomicron Nascet VLDL Vessel Lumen Monocyte Χ LDL Χ AdhesionMolecules Endothelium MCP-1 LDL Artery wall Modified LDL Taken up by Macrophage Intima Macrophage Foam Cell Steinberg D et al. N Engl J Med 1989;320:915-924.

19. 2. Dyslipidemia vs. hyperlipdemia: Prevalence in NHANES 2008 data: High TG or low HDLc more common than high LDLc Am Heart J 2008;156:112-119

20. Prevalence of Dyslipidemia is high in Type 2 Diabetes N = 498 adults (projected to 13.4 million) aged > or = 18 years with diabetes representative of the US population and surveyed within the cross-sectional National Health and Nutrition Examination Survey 1999-2000. Jacobs MJ, et al. Diabetes Res Clin Pract. 2005;70:263-269.

21. ‘Dyslipidemia’ is a state of relative insulin resistance resulting in a conversion of adipose tissue to an exocrine state. Excessive production of free fatty acids (FFA) increases hepatic VLDL production ↑ TG ↑ ApoB ↓ HDLc ↔ LDLc Fat Cells Liver  FFA  FFA CE HDL VLDL Kidney CETP X Insulin resistance Hepatic lipase TG ApoA-I TG CE CETP IDL Liver Small, denseLDL LDL Insulin Lipoprotein lipaseor hepatic lipase While LDLc is similar, particle burden is heavier CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides. Ginsberg HN. J Clin Invest. 2000;106:453–458.

22. LDL particle count vs. cholesterol contentTo carry the same amount of cholesterol, a larger number of particles are needed if they are smaller Small, dense: 25-30 nm Large, buoyant: 30-35 nm LDLc=115 mg/dl LDLc=115 mg/dl apoB is a measure of number of atherogenic lipoproteins (essentially VLDL, IDL, LDL). Non-HDL is measure of cholesterol carried in these same particles LDLc measures cholesterol carried in LDL and IDL

23. Summary: Patients with diabetes have elevated TG and lower HDLc but also a greater number of LDL particles which confers greater risk at any measured LDLc value 3. What are the data for LDLc lowering?

24. ADA guidelines: Major statin trials or sub-studies in diabetic patients *Num. needed to treat (NNT) for moderate-high risk DM to avoid one death or MI: 3-50 Lancet 2004;364:685 Diabetes Care 2006;29:1220Lancet 2003;361:2005Diabetes Care 2006;7:1478Diabetes Care 1997;20:614 ADA Standards of Care; Diabetes Care, January 2011

25. Reduction in 10-year CVD events with statin therapy in patients with diabetes: Event reduction correlates with relative risk – more risk, more benefitEndpoint: 10-year Fatal CHD/Non-fatal MI and LDL lowering Relative Risk reductionARRLDL reduction 4S-DM 85.7 to 43.2% (50%) 42.5% 186 to 119 mg/dL (36%) ASPEN 20 35.1 to 23.2% (34%) 11.9% 112 to 79 mg/dL (29%) HPS-DM 20 43.8 to 36.3% (17%) 7.5% 123 to 84 mg/dL (31%) CARE-DM 40.8 to 35.4% (13%) 5.4% 136 to 99 mg/dL (27%) TNT-DM 26.3 to 21.6% (18%) 4.7% 99 to 77 mg/dL (22%) HPS-DM 10 17.5 to 11.5% (34%) 6.0% 124 to 86 mg/dL (31%) CARDS 11.5 to 7.5% (35%) 4% 118 to 71 mg/dL (40%) ASCOT-DM 11.1 to 10.2% (8%) 0.9% 125 to 82 mg/dL (34%) ASPEN 10 9.8 to 7.9% (19%) 1.9% 114 to 80 mg/dL (30%) 2○ 1○ 10: Primary prevention data 20: Secondary prevention

26. The differential benefit of LDLc lowering in patients with diabetes has been evident from the earliest statin trials and is more evidence that higher risk=greater benefit : 4S study: Major Coronary Events Coronary Death and non-fatal MI 100 90 80 Percent of patients without major CV event Diabetic - simvastatin 70 55% Diabetic – simvastatinDiabetic – placeboNondiabetic – simvastatinNondiabetic - placebo 60 Risk reduction p=0.002 Diabetic - placebo 50 0 1 2 3 4 5 6 0 Years since randomization Pyörälä K, et al. Diabetes Care. 1997;20:614–620

27. Within a given population, lower goals do further reduce CVD events: Risk Curve ConceptHigher risk patients have more to gain from aggressive therapy 80 70 CHD + Diabetes 60 50 CHD + MS or IFG Cardiovascular Event Rate (%) 40 30 CHD - NoMS or IFG 20 Diabetes - No CVD 10 No CVD - No diabetes 0 0 20 40 60 80 180 200 100 120 140 160 LDL (mg/dL) Robinson JG, Stone NJ. Am J Cardiol. 2006;98:1405-1408

28. What aggressive LDL lowering does: reduces atheroma volume in arterial wall providing plaque ‘stabilization’ Treated: LDLc of 84 mg/dL (47% reduction) Untreated: LDLc of 163 mg/dL with statin+resin Brown et al. Arter Thromb Vasc Biol 2001;21:1623

29. LDLc lowering and residual risk – more is needed The majority of CVD events still occur: CVD events occurring in the on-treatment groups in major statin trials J Am Coll Card 2005;46:1225-8 % CHD events on statin N 4,444 9,014 4,159 20,536 6,595 6,605 ∆LDL -36% -25% -28% -29% -26% -27% TxLDL 119 154 98 90 113 112 secondary high risk primary

30. Despite the need beyond LDLc lowering, outcomes data supporting combination therapy still limited ADA Standards of Care; Diabetes Care, January 2011

31. The lipid arm of the ACCORD trial was relatively disappointing for combination therapy (as was FIELD in 2005)– WHY? April 29, 2010 N Engl J Med Conclusion: “The combination of fenofibrate and simvatatin did not reduce the rate of fatal cardiovascular events, non-fatal MI or non-fatal stroke, as compared with simvatatin alone.”

32. ACCORD LIPID: Lipid parameters

33. ADA guidelines changed text related to lipoprotein control in 2008: ADA guidelines, 2007 ADA guidelines, 2008-2011

34. Statins are safe but nothing is without risk: Review of 35 statin therapy trials FDA-approved statin* monotherapy vs placebo (N = 74,102) Statin better Placebo better -30 -15 0 15 30 *Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin CK = creatine kinase AE = adverse events Risk difference per 1000 patients (RD) (95% CI) Kashani A et al. Circulation. 2006;114:2788-97.

35. Subjective myopathy incidence is high but myositis and rhabdomyolysis is low 20,536 patients from HPS (40mg simvastatin vs. placebo): 8 cases of rhabdomyolysis, 3 on placebo Lancet 2002;360:7-23

36. Rhabdomyolysis per 10,000 person-years of therapy with lipid lowering agents* Drug Monotherapy incidence +agent Combo. Incidence rates rates‡ Atorvastatin 0.54 fenofibrate 22.45 Cerivatatin 5.34 gemfibrozil 1035 Simvastatin 0.49 gemfibrozil 18.73 Gemfibrozil 3.70 *Data from 252,460 patients enrolled in 11 different health care plans in U.S. with at least 180 days enrolled in respective health care plan ‡ Data based on 7300 patient-years of combination therapy Data from: [CDER] Graham D. JAMA 2004;292:2585-2590.

37. Use of run-in phases in recent, large trials of statin drugs results in likely under-estimation of myopathy incidence in practice Waters DD et al. Am J Cardiol. 2004;93:154-8. HPS investigators, Lancet 2002;360:7-22 Run-in Control Wash-out Blinded Statin Statin 40-80 mg 4-8 weeks ~ 5 years 1-8 weeks HPS: 63,603 patients 32,145 20,536 TNT: 18,469 patients 15,464 10,003 Run-in: HPS, of 11,609 excluded after drug exposure, 1% for self- identifed ADRs TNT, of 5,461 excluded after drug exposure, 3.7% for self- identified ADRs

38. Lipid summary: • Lipid management for cardiometabolic risk reduction: • Use statin-based LDLc-lowering therapy to: • Achieve LDLc < 100 mg/dL in patients with diabetes 40 years of age and older with another risk factor • Achieve LDLc < 70 mg/dL in patients with diabetes and CVD

39. VI. Prevention and management of complications A. Cardiovascular disease 1. HTN control 2. Dyslipidemia management 3. Anti-platelet 4. Smoking cessastion

40. Historic goal SBP of < 130 mmHg in diabetes is an extrapolation of data regarding benefits in nephropathy AJKD 2004;43(suppl 1):S120

41. July, 2009

42. Haven’t previous trials found a benefit from tighter BP control in diabetes? …ended up comparing mean of 154/87 to 144/82

43. Four trials looked at major CVD outcomes based on randomized BP control; Two trials (ABCD) were exclusively in patients with diabetes Cochrane review 2009

44. April 29th, 2010 N Engl J Med

45. ACCORD BP: Using an average of 3 drugs, the authors achieved a SBP of 119 mmHg vs. 133 mmHg

46. ACCORD BP: Results Conclusions: “In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mmHg, as compared with less than 140 mmHg, did not reduce the rate of fatal and nonfatal major CVD events.”

47. Implications on practice • Summary of the evidence: • Lower BP goals • Lower BP goals: • Do not change overall CV outcomes (all 3 trials). • Do reduce rates of stroke (ABCD (H) and ACCORD, but how clinically sig?). • Do help to reduce the progression of nephropathy in terms of urinary albumin excretion and progression of microalbuminuria to overt albuminuria (ABCD (H) and (N)).

48. VI. Prevention and management of complications A. Cardiovascular disease 1. HTN control 2. Dyslipidemia management 3. Anti-platelet 4. Smoking cessastion

49. We have known for decades that platelets are more “responsive” in patients with diabetes. Reasons are still not fully understood nor the impact on use of anti-platelet agents

50. NEJM 2007;357:2482-94