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Doubletree Hotel Seattle Airport Seattle, Washington June 21, 2008

Doubletree Hotel Seattle Airport Seattle, Washington June 21, 2008. 2008. Symposia Series 2. 1. Dyslipidemia: When Statins Alone Fail. Joyce L. Ross, MSN, ANP, CRNP, CS Certified Clinical Lipid Specialist Diplomat, Accreditation Council for Clinical Lipidology

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Doubletree Hotel Seattle Airport Seattle, Washington June 21, 2008

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  1. Doubletree Hotel Seattle Airport Seattle, Washington June 21, 2008 2008 Symposia Series 2 1

  2. Dyslipidemia:When Statins Alone Fail Joyce L. Ross, MSN, ANP, CRNP, CS Certified Clinical Lipid Specialist Diplomat, Accreditation Council for Clinical Lipidology Cardiovascular Risk Intervention Program University of Pennsylvania Philadelphia, Pennsylvania 2

  3. Faculty Disclosure Ms Ross: consultant: Kaneka America LLC; speakers bureau: Abbott Laboratories, AstraZeneca International, Bristol-Myers Squibb, Pfizer Inc 3

  4. ? 0 KEY QUESTION What percentage of your patients with dyslipidemia who are receiving statin therapy alone achieve their LDL-C goal? • ≤25% • 26%-50% • 51%-75% • 76%-100% Use your keypad to vote now! LDL-C = low-density lipoprotein cholesterol.

  5. ? 0 KEY QUESTION For what percentage of your patients do you use non–HDL-C to guide management of dyslipidemia? • ≤25% • 26%-50% • 51%-75% • 76%-100% Use your keypad to vote now! HDL-C = high-density lipoprotein cholesterol. 5

  6. Learning Objectives • Identify patients who would benefit from combination therapy for dyslipidemia based on results of recent clinical trials • Develop optimal treatment strategies for lowering LDL-C and raising HDL-C levels in patients with mixed dyslipidemia • Educate patients on the benefits and long-term safety data associated with combination drug therapy for dyslipidemia

  7. Case Study 7

  8. History and Physical Findings ABI = ankle-brachial index; BMI = body mass index; BP = blood pressure. • 68-year-old white woman • History • Type 2 diabetes mellitus (10 years) • Hypertension (12 years) • Stage 3 renal insufficiency (3 years) • Physical findings • Height: 5 ft 3 in; weight: 185 lb; waist circumference: 39 in; BMI: 32.8 kg/m2 • BP: 126/72 mm Hg • ABI: 0.84

  9. Current Medications Lisinopril/hydrochlorothiazide (20/12.5 mg once daily) Pravastatin (80 mg once daily) Glimepiride (2 mg once daily) Metformin (850 mg twice daily) Acetylsalicylic acid (aspirin) 81 mg (once daily)

  10. Lipid profile TC: 178 mg/dL LDL-C: 72 mg/dL HDL-C: 44 mg/dL TG: 240 mg/dL Non–HDL-C: 134 mg/dL Glucose metabolism FPG level: 114 mg/dL A1C: 6.9% Renal function Creatinine: 1.3 mg/dL Estimated GFR: 54 mL/min Microalbumin: 34 mg/L Laboratory Results A1C = glycosylated hemoglobin; FPG = fasting plasma glucose; GFR = glomerular filtration rate; TC = total cholesterol; TG = triglyceride.

  11. ? 0 DECISION POINT What is this patient’s CHD risk category? • Very high • High • Moderately high • Moderate • Low Use your keypad to vote now! CHD = coronary heart disease. 11

  12. Type 2 Diabetes and CHD: 7-Year Incidence of Fatal/Nonfatal MI(East West Study) Patients without diabetes Patients with diabetes (n = 1373) (n = 1059) 50 45.0% 45 P <.001 P <.001 40 35 30 7-Year Incidence (%) 20.2% 25 18.8% 20 15 10 3.5% 5 0 No Prior MI* No Prior MI* Prior MI* Prior MI* MI = myocardial infarction. *At baseline. Haffner SM, et al. N Engl J Med. 1998;339:229-234. 12

  13. ? 0 DECISION POINT What would be your next step in treating this patient? • Change pravastatin (80 mg once daily) to atorvastatin (80 mg once daily) • Add pioglitazone (15 mg once daily) to her pravastatin regimen • Add fenofibrate (145 mg/d) to her pravastatin regimen • Add omega-3 fatty acids to her pravastatin regimen • Add niacin to her pravastatin regimen and titrate slowly to effective dose Use your keypad to vote now! 14

  14. Treatment Decision (Option 1) What would be your next step in treating this patient? • Change pravastatin (80 mg once daily) to atorvastatin (80 mg once daily) • Add pioglitazone (15 mg once daily) to her pravastatin regimen • Add fenofibrate (145 mg/d) to her pravastatin regimen • Add omega-3 fatty acids to her pravastatin regimen • Add niacin to her pravastatin regimen and titrate slowly to effective dose

  15. Residual CHD Risk in Major Statin Trials CHD events occur in patients treated with statins Placebo Statin 28.0 Patients Experiencing Major CHD Events (%) 19.4 15.9 13.2 11.8 12.3 10.2 10.9 7.9 8.7 6.8 5.5 4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/ TexCAPS6 N 4444 9014 4159 20,536 6595 6605  LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary 1. 4S Group. Lancet. 1994;344:1383-1389; 2. LIPID Study Group. N Engl J Med. 1998;339:1349-1357; 3. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009; 4. HPS Collaborative Group. Lancet. 2002;360:7-22; 5. Shepherd J, et al. N Engl J Med. 1995;333:1301-1307; 6. Downs JR, et al. JAMA. 1998;279:1615-1622.

  16. Patients With Diabetes Have Particularly High Residual CVD Risk After Statin Treatment *CHD death, nonfatal MI, stroke, revascularizations †CHD death, nonfatal MI, CABG, PTCA ‡CHD death and nonfatal MI §CHD death, nonfatal MI, stroke ║CHD death, nonfatal MI, resuscitated cardiac arrest, stroke (80-mg vs 10-mg atorvastatin) MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty. 1. HPS Collaborative Group. Lancet. 2003;361:2005-2016. 2. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009. 3. LIPID Study Group. N Engl J Med. 1998;339:1349-1357.4. Shepherd J, et al. Lancet. 2002;360:1623-1630. 5. Sever PS, et al. Lancet. 2003;361:1149-1158. 6. Shepherd J, et al. Diabetes Care. 2006;29:1220-1226.

  17. ? 0 KEY QUESTION Independent risk factors for CVD in patients with diabetes and the metabolic syndrome include: • Low TG levels and high LDL-C levels • Low TG levels and high HDL-C levels • High TG levels and low LDL-C levels • High TG levels and low HDL-C levels Use your keypad to vote now! 18

  18. Atherogenic Changes Associated With High TG Levels Low HDL-C Increased VLDL Remnants Small, Dense LDL-P HYPERTRIGLYCERIDEMIA Coagulation Changes Increased PAI-1 Increased fibrinogen Increased Chylomicron Remnants PAI-1 = plasminogen activator inhibitor type 1. Source: Vascular Biology Working Group.

  19. 3.0 Men 2.5 Women 2.0 n = 5127 1.5 Relative Risk 1.0 0.5 0.0 50 100 150 200 250 300 350 400 TG Level (mg/dL) Risk of CHD by TG Level:The Framingham Heart Study Castelli WP. Am J Cardiol. 1992;70:3H-9H.

  20. TG Level Is Significant CVD Risk Factor: Recent Meta-Analysis of 29 Studies GroupsCHD Cases N = 262,525 Duration of follow-up ≥10 years 5902 <10 years 4256 Sex Male 7728 Female 1994 Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 1.72 (1.56-1.90) *Individuals in top vs bottom third of usual log-TG values; adjusted for at least age, sex, smoking status, and lipid concentrations; also adjusted for BP (in most studies). 1 2 CHD Risk Ratio* (95% CI) Sarwar N, et al. Circulation. 2007;115:450-458. 23

  21. NCEP ATP III: TG-Rich Remnant Lipoproteins Are Atherogenic • Elevated TG levels are a marker for elevated levels of atherogenic remnant lipoproteins • VLDL-C is the most readily available measure of atherogenic remnant lipoproteins for clinical practice • When TG levels are elevated, non–HDL-C better represents the concentrations of all atherogenic lipoproteins than LDL-C alone • Non–HDL-C is a secondary target of therapy when TG levels are ≥200 mg/dL as defined by the NCEP VLDL-C = very low-density lipoprotein cholesterol. NCEP ATP III. Circulation. 2002;106:3143-3421.

  22. Calculate non–HDL-C when: TGs are 200 mg/dL Target goal is 30 mg/dL higher than LDL-C goal Example: TG: 240 mg/dL >200 need non–HDL-C TC: 178 mg/dL 178 HDL-C: 44 mg/dL - 44 LDL-C: 72 Non–HDL-C: 134 mg/dL Patient’s LDL-C goal 70; non–HDL-C goal 100 mg/dL Importance of Non–HDL-C

  23. ? 0 KEY QUESTION In patients with diabetes who receive statin therapy to reduce LDL-C levels: • Residual CVD risk remains high • Residual CVD risk is low • Residual CVD risk has no impact on event rates • Residual CVD risk from low HDL-C levels is not clinically significant Use your keypad to vote now! 26

  24. Key Points • Residual CVD risk remains after patients are treated with statins to reduce LDL-C and is particularly high in patients with diabetes who are treated with statins • Atherogenic dyslipidemia contributes to residual risk for atherosclerosis and CVD risk • Increased levels of TG and TG-rich remnant lipoproteins • Increased levels of non–HDL-C • Increased numbers of Apo B–containing particles, including small, dense LDL • Decreased levels of HDL-C • The combination of high TG with low HDL-C and/or high LDL-C synergistically increases CHD risk

  25. Treatment Decision (Option 2) What would be your next step in treating this patient? • Change pravastatin (80 mg once daily) to atorvastatin (80 mg once daily) • Add pioglitazone (15 mg once daily) to her pravastatin regimen • Add fenofibrate (145 mg/d) to her pravastatin regimen • Add omega-3 fatty acids to her pravastatin regimen • Add niacin to her pravastatin regimen and titrate slowly to effective dose

  26. Treatment Decision (Option 3) What would be your next step in treating this patient? • Change pravastatin (80 mg once daily) to atorvastatin (80 mg once daily) • Add pioglitazone (15 mg once daily) to her pravastatin regimen • Add fenofibrate (145 mg/d) to her pravastatin regimen • Add omega-3 fatty acids to her pravastatin regimen • Add niacin to her pravastatin regimen and titrate slowly to effective dose

  27. Treatment Decision (Option 3): 3-Month Follow-up • Visit 1 • TLC (diet, exercise) reinforced • Fenofibrate (145 mg/d) prescribed as add-on to her statin therapy • Visit 2 • Improvements in lipid profile • No musculoskeletal side effects; no hepatic or renal laboratory abnormalities

  28. Treatment Decision (Option 3): 3-Month Follow-up (cont’d) • After 3 months’ therapy with pravastatin plus fenofibrate

  29. Treating Beyond LDL-C: Other Targets of Lipid-Lowering Therapy • Lipoproteins other than LDL are involved in atherogenesis (pro: VLDL, IDL; anti: HDL)1 • NCEP ATP III concluded (on the basis of several types of data) that an elevated non–HDL-C in patients with hypertriglyceridemia will impart increased risk even after the goal of LDL-C has been reached1 • NCEP ATP III 2004 update: “For those high-risk patients who have elevated triglycerides or low HDL-C levels, addition of a fibrate or nicotinic acid to LDL-lowering therapy can be considered.”2 IDL = intermediate-density lipoprotein. 1. Grundy SM. Circulation. 2002;106:2526-2529; 2. Grundy SM, et al. Circulation. 2004;110:227-239.

  30. Outcomes in Fibrate Trials: Patients With Diabetes or Metabolic Syndrome Major CVD Event Rate Trial N Control Drug RRR P Primary Prevention HHS1* 292 13.0% 3.9% 71% <.005 FIELD2† 7664 10.8% 8.9% 19% .004 Secondary Prevention BIP3‡ 1470 18.4% 14.1% 25% .03 VA-HIT4§ 769 29.4% 21.2% 32% .004 *Patients with TG >204 mg/dL and an LDL:HDL >5 (may or may not have had diabetes or metabolic syndrome). †Patients with diabetes and no prior CVD. ‡Patients with metabolic syndrome. §Patients with diabetes. 1. Manninen V, et al. Circulation. 1992;85:37-45; 2. Keech A, et al. Lancet. 2005;366:1849-1861; 3. Tenenbaum A, et al. Arch Intern Med. 2005;165:1154-1160; 4. Rubins HB, et al. Arch Intern Med. 2002;162:2597-2604.

  31. VA-HIT: CVD Risk Reduction in Diabetics Compared With Nondiabetics Combined End Point Nonfatal MI CHD Death Stroke 0 5 3 P = .88 10 10 15 P = .67 Cumulative Event Rate Change (%) 18 20 22 21 P = .07 25 P = .09 P = .17 30 32 35 P = .004 DM 40 No DM 40 41 P = .26 45 P = .046 P = .02 DM = diabetes mellitus. Rubins HB, et al. Arch Intern Med. 2002;162:2597-2604.

  32. ? 0 KEY QUESTION Fibrate/statin combination therapy has the potential to increase the risk of: • Arrhythmia • Myopathy • Osteoporosis • Thrombosis Use your keypad to vote now! 39

  33. Safety of Fibrate/Statin Combination Therapy 1. Grundy SM, et al. Circulation. 2004;109:551-556; 2. Davidson MH. Expert Opin Drug Saf. 2006;5:145-156; 3. Davidson MH. Am J Cardiol. 2002;90:50K-60K. Fibrates improve all components of atherogenic dyslipidemia and appear to reduce the risk for CVD; their use in combination with statins is particularly attractive1 Both statins and fibrates have the potential to produce myopathy, and the risk for myopathy is enhanced when they are used together1 Clinical and preclinical studies indicate that gemfibrozil interferes with catabolism of statins in the liver (ie, inhibits glucuronidation), which can raise statin blood levels, thereby predisposing to myopathy1-3 Fenofibrate does not interact adversely with statin catabolism and thus may be safer to use in combination therapy with statins1-3 40

  34. Number of Cases of Rhabdomyolysis in Combination Therapy With Statins* 10 8.6 9 8 7 6 No. Cases Reported per Million Prescriptions 5 15-Fold Increase 4 3 2 0.58 1 0 Fenofibrate Gemfibrozil *Excludes cases involving cerivastatin. Jones PH, et al. Am J Cardiol. 2005;95:120-122. 41

  35. Treatment Decision (Option 4) What would be your next step in treating this patient? • Change pravastatin (80 mg once daily) to atorvastatin (80 mg once daily) • Add pioglitazone (15 mg once daily) to her pravastatin regimen • Add fenofibrate (145 mg/d) to her pravastatin regimen • Add omega-3 fatty acids to her pravastatin regimen • Add niacin to her pravastatin regimen and titrate slowly to effective dose

  36. Treatment Decision (Option 4) • Data suggest omega-3 fatty acid supplementation is a useful treatment option for patients with hypertriglyceridemia • This patient’s TG level (on statin monotherapy) is 240 mg/dL • Interesting data available for omega-3 fatty acids include: • JELIS trial1 • GISSI-P trial2 1. Yokoyama M, et al. Lancet 2007;369:1090-1098; 2. GISSI-P Investigators. Lancet. 1999;354:447-455.

  37. All patients had TC levels >6.5 mmol/L (>251 mg/dL) Randomized to treatment with a statin or a statin plus 1800 mg/d EPA JELIS: Omega-3 Fatty Acids Plus Statins in Patients With Hypercholesterolemia *P = .011 CABG = coronary artery bypass graft; EPA = eicosapentaenoic acid. Yokoyama M, et al. Lancet 2007;369:1090-1098.

  38. LDL-C HDL-C VLDL-C TG Efficacy of Omega-3 Fatty Acids for Patients With Severe Hypertriglyceridemia* Placebo † Omega-3 fatty acids 4 g † Change From Baseline (%) † † *TG level: 500-2000 mg/dL, N = 42. †P <.02 vs placebo. Harris WS, et al. J Cardiovasc Risk. 1997;4:385-391.

  39. Treatment Decision (Option 5) What would be your next step in treating this patient? Change pravastatin (80 mg once daily) to atorvastatin (80 mg once daily) Add pioglitazone (15 mg once daily) to her pravastatin regimen Add fenofibrate (145 mg/d) to her pravastatin regimen Add omega-3 fatty acids to her pravastatin regimen Add niacin to her pravastatin regimen and titrate slowly to effective dose

  40. Treatment Decision (Option 5):3-Month Follow-up • Visit 1 • TLC (diet, exercise) reinforced • Long-acting niacin prescribed as add-on to statin therapy, at 500 mg/d and increased to 1000 mg/d after 4 weeks • Visit 2 • Lipid profile improved • No worsening of diabetes control noted • Normal liver function studies

  41. Treatment Decision (Option 5):3-Month Follow-up (cont’d) After 3 months’ therapy with pravastatin plus niacin

  42. NCEP ATP III: HDL-C Is an Independent Risk Factor for CHD NCEP ATP III. Circulation. 2002;106:3143-3421. • A low HDL-C level is strongly and inversely associated with CHD risk • Independent relationship holds after correction for other risk variables in multivariate analysis • A low HDL-C level often correlates with elevations of serum TG and remnant lipoproteins • HDL may be antiatherogenic • Promotes reverse cholesterol transport • Antioxidant and anti-inflammatory properties inhibit atherogenesis 51

  43. Other Antiatherogenic Actions of HDL Anti-inflammatory Activity Reverse Cholesterol Transport CellularCholesterolEfflux HDL Antiapoptotic Activity Antithrombotic Activity Antioxidative Activity Anti-infectious Activity VasodilatoryActivity EndothelialRepair Chapman MJ, et al. Curr Med Res Opin. 2004;20:1253-1268. Assmann G, et al. Ann Rev Med. 2003;53:321-341.

  44. Meta-Analysis: Predictive Value of HDL-C 1 mg/dL Increase in HDL-C CPPT MRFIT LRCS LRCS FHS FHS 2%CHDRisk in Men 3%  CHD Risk in Women Gordon DJ, et al. Circulation. 1989;79:8-15. Coronary Primary Prevention Trial (CPPT) Multiple Risk Factor Intervention Trial (MRFIT) Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCS) Framingham Heart Study (FHS) 53

  45. Low HDL-C Increases CVD Risk Even If LDL-C Levels Are Well Controlled:TNT Study Patients with LDL-C <70 mg/dL (n = 2661) Hazard Ratio (95% CI) versus Q1 Q2 0.85 (0.57-1.25) Q3 0.57 (0.36-0.88) Q4 0.55 (0.35 -0.86) Q5 0.61 (0.38-0.97) 10 9 8 7 6 5-Year Risk of Major CV Events (%) 5 4 3 2 1 0 Q1(<37) Q2(37 to <42) Q3(42 to <47) Q4(47 to <55) Q5(55) Quintile of HDL-C* (mg/dL) *On-treatment level (3 months). Barter P, et al. N Engl J Med. 2007;357:1301-1310. 54

  46. Lipid Effects of Adding Niacin ER to Baseline Statin Therapy Statin + niacin ER 1 g (n = 66) Statin + niacin ER 2 g (n = 29) Change From Baseline Statin Therapy (%) TC LDL-C HDL-C TG niacin ER = niacin extended-release. Wolfe ML, et al. Am J Cardiol. 2001;87:476-479.

  47. COMPELL: Lipid Effects of Niacin ER/Statin Combination Therapy Atorvastatin 40 mg + niacin ER 2 g Simvastatin 40 mg + ezetimibe 10 mg Rosuvastatin 40 mg Rosuvastatin 20 mg + niacin ER 1 g * * * * Change From Baseline (%) * * Lp(a) LDL-C HDL-C TG N = 292; 12 weeks. *P <.05 vs atorvastatin + niacin ER. Lp(a) = lipoprotein (a). McKenney JM, et al. Atherosclerosis. 2007;192:432-437.

  48. ADA Standards of Medical Care in Diabetes:Dyslipidemia Management *An LDL-C goal <70 mg/dL is an option in patients with overt CVD. † An HDL-C goal >50 mg/dL should be considered for women. ‡ At high doses,niacin may increase blood glucose levels. American Diabetes Association. Diabetes Care. 2004;27:S68-S71. American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4-S41. 58

  49. Lipid Management in Patients With Diabetes* or Metabolic Syndrome Adapted from American Diabetes Association. Diabetes Care. 2004;27:S68-S71. Adapted from American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4-S41. Adapted from Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson PDR; 2007:2725-2727. Therapeutic lifestyle changes (TLC) Glycemic control Statin therapy to achieve LDL-C <100 mg/dL (<70 mg/dL with CHD) TG ≥500 mg/dL Fibrate Omega-3 fatty acids TG ≥150-500 mg/dL Fibrate (with slightly low or normal HDL-C) Niacin (with very low HDL-C) TG <150 mg/dL and Niacin Low HDL-C† *Well-controlled diabetes; A1C <7.0%. †HDL-C <40 mg/dL in men or <50 mg/dL in women. 59

  50. Potential Cautions With Intensive Lipid Therapy CHF = congestive heart failure; LV = left ventricular.

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