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Effective use of combination lipid therapy

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Abstract

Despite the benefits of statin therapy, low-density lipoprotein (LDL) cholesterol management remains suboptimal and many patients do not achieve their recommended target goals. The aim of combination lipid drug therapy in high-risk patients is to achieve LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol goals with a minimum of serious adverse effects. Although statins are the drug of first choice, statin monotherapy may be limited by intolerance of dose escalation or failure to attain non-HDL cholesterol goals in those with mixed hyperlipidemia. Statins plus bile acid resins or ezetimibe can achieve greater than 50% reduction in LDL cholesterol, with little or no increase in adverse effects. Fibrates, niacin, and omega-3 fatty acids, when added to statins, can reduce triglycerides, increase HDL cholesterol, and reduce non-HDL cholesterol to a greater extent than statin monotherapy. The safety profile of combination lipid therapy is acceptable if the global coronary heart disease risk of the patient is high, thus producing a favorable risk to benefit ratio. Careful surveillance of hepatic transaminases, avoidance of gemfibrozil in statin-fibrate combinations, and awareness of statin-concomitant drug interactions is key to safe and efficacious use of combination lipid drug therapy.

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References and Recommended Reading

  1. Castelli WP: Epidemiology of coronary heart disease: the Framingham study. Am J Med 1984, 76:4–12.

    Article  PubMed  CAS  Google Scholar 

  2. Stamler J, Wentworth D, Neaton JD: Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986, 256:2823–2828.

    Article  PubMed  CAS  Google Scholar 

  3. Kuller LH, Ockene JK, Townsend M, et al.: The epidemiology of pulmonary function and COPD mortality in the multiple risk factor intervention trial. Am Rev Respir Dis 1989, 140:S76-S81.

    PubMed  CAS  Google Scholar 

  4. Kannel WB, Neaton JD, Wentworth D, et al.: Overall and coronary heart disease mortality rates in relation to major risk factors in 325,348 men screened for the MRFIT. Multiple Risk Factor Intervention Trial. Am Heart J 1986, 112:825–836.

    Article  PubMed  CAS  Google Scholar 

  5. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344:1383–1389.

  6. Shepherd J, Cobbe SM, Ford I, et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995, 333:1301–1307.

    Article  PubMed  CAS  Google Scholar 

  7. Sacks FM, Pfeffer MA, Moye LA, et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996, 335:1001–1009.

    Article  PubMed  CAS  Google Scholar 

  8. Downs JR, Clearfield M, Weis S, et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998, 279:1615–1622.

    Article  PubMed  CAS  Google Scholar 

  9. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002, 360:7–22.

    Article  Google Scholar 

  10. Shepherd J, Blauw GJ, Murphy MB, et al.: Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002, 360:1623–1630.

    Article  PubMed  CAS  Google Scholar 

  11. Nissen SE, Tuzcu EM, Schoenhagen P, et al.: Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004, 291:1071–1080.

    Article  PubMed  CAS  Google Scholar 

  12. Grundy SM, Cleeman JI, Merz CN, et al.: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004, 110:227–239 [Erratum appears in Circulation 2004, 110:763].

    Article  PubMed  Google Scholar 

  13. Austin MA, Hokanson JE, Edwards KL: Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998, 81:7B-12B.

    Article  PubMed  CAS  Google Scholar 

  14. Hokanson JE, Austin MA: Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996, 3:213–219.

    Article  PubMed  CAS  Google Scholar 

  15. Rubins HB, Robins SJ, Collins D: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999, 341:410–418.

    Article  PubMed  CAS  Google Scholar 

  16. Xydakis AM, Ballantyne CM: Combination therapy for combined dyslipidemia. Am J Cardiol 2002, 90:21K-29K.

    Article  PubMed  CAS  Google Scholar 

  17. Pearson TA, Laurora I, Chu H: The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipidlowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000, 160:459–467.

    Article  PubMed  CAS  Google Scholar 

  18. Brown AS, Bakker-Arkema RG, Yellen L: Treating patients with documented atherosclerosis to National Cholesterol Education Program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin. J Am Coll Cardiol 1998, 32:665–672.

    Article  PubMed  CAS  Google Scholar 

  19. Ballantyne CM, Andrews TC, Hsia JA, et al.: Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol 2001, 88:265–269.

    Article  PubMed  CAS  Google Scholar 

  20. Hunninghake D, Insull W Jr, Toth P, et al.: Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively. Atherosclerosis 2001, 158:407–416.

    Article  PubMed  CAS  Google Scholar 

  21. Davidson MH, Toth P, Weiss S, et al.: Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. Clin Cardiol 2001, 24:467–474.

    PubMed  CAS  Google Scholar 

  22. Knapp HH, Schrott H, Ma P, et al.: Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia. Am J Med 2001, 110:352–360.

    Article  PubMed  CAS  Google Scholar 

  23. Ballantyne CM, Blazing MA, King TR, et al.: Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol 2004, 93:1487–1494.

    Article  PubMed  CAS  Google Scholar 

  24. Ballantyne CM, Houri J, Notarbartolo A, et al.: Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003, 107:2409–2415.

    Article  PubMed  CAS  Google Scholar 

  25. Kerzner B, Corbelli J, Sharp S, et al.: Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003, 91:418–424.

    Article  PubMed  CAS  Google Scholar 

  26. Melani L, Mills R, Hassman D, et al.: Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Eur Heart J 2003, 24:717–728.

    Article  PubMed  CAS  Google Scholar 

  27. Pearson TA, Denke MA, McBride PE, et al.: 1A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clin Proc 2005, 80:587–595.

    Article  PubMed  CAS  Google Scholar 

  28. Ballantyne CM, Abate N, Yuan Z, et al.: Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J 2005, 149:464–473.

    Article  PubMed  CAS  Google Scholar 

  29. Baigent C, Landry M: Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003, 84:S207-S210.

    Article  PubMed  Google Scholar 

  30. Kastelein JJ, Sager PT, de Groot E, Veltri E: Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia. Design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. Am Heart J 2005, 149:234–239.

    Article  PubMed  CAS  Google Scholar 

  31. Leitersdorf E, Muratti EN, Eliav O, et al.: Efficacy and safety of a combination fluvastatin-bezafibrate treatment for familial hypercholesterolemia: comparative analysis with a fluvastatin-cholestyramine combination. Am J Med 1994, 96:401–407.

    Article  PubMed  CAS  Google Scholar 

  32. Pauciullo P, Borgnino C, Paoletti R, et al.: Efficacy and safety of a combination of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia (FACT study). Atherosclerosis 2000, 150:429–436.

    Article  PubMed  CAS  Google Scholar 

  33. Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al.: Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997, 80:608–613.

    Article  PubMed  CAS  Google Scholar 

  34. Athyros VG, Papageorgiou AA, Athyrou VV, et al.: Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 2002, 25:1198–1202.

    Article  PubMed  CAS  Google Scholar 

  35. Koh KK, Quon MJ, Han SH, et al.: Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol 2005, 45:1649–1653.

    Article  PubMed  CAS  Google Scholar 

  36. Derosa G, Cicero AE, Bertone G, et al.: Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial. Clin Ther 2004, 26:1599–1607.

    Article  PubMed  CAS  Google Scholar 

  37. Grundy SM, Vega GL, Yuan Z, et al.: Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol 2005, 95:462–468.

    Article  PubMed  CAS  Google Scholar 

  38. McKenney JM, Proctor JD, Harris S, Chinchili VM: A comparison of the efficacy and toxic effects of sustained-vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994, 271:672–677.

    Article  PubMed  CAS  Google Scholar 

  39. Guyton JR, Goldberg AC, Kreisberg RA, et al.: Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. Am J Cardiol 1998, 82:737–743.

    Article  PubMed  CAS  Google Scholar 

  40. Taylor AJ, Sullenberger LE, Lee HJ, et al.: Arterial Biology for the Investigation of the Treatment Effects of Reducting Cholesterol (ARBITER)2: a double-blind, placebo controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004, 110:3512–3517.

    Article  PubMed  CAS  Google Scholar 

  41. Guyton JR, Capuzzi DM: Treatment of hyperlipidemia with combined niacin-statin regimens. Am J Cardiol 1998, 82:82U-84U; discussion 85U–86U.

    Article  PubMed  CAS  Google Scholar 

  42. Capuzzi DM, Morgan JM, Weiss RJ, et al.: Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels. Am J Cardiol 2003, 91:1304–1310.

    Article  PubMed  CAS  Google Scholar 

  43. Nordoy A, Bonaa KH, Nilsen H, et al.: Effects of simvastatin and omega-3 fatty acids on plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidaemia. J Intern Med 1998, 243:163–170.

    Article  PubMed  CAS  Google Scholar 

  44. Contacos C, Barter PJ, Sullivan DR: Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia. Arterioscler Thromb 1993, 13:1755–1762.

    PubMed  CAS  Google Scholar 

  45. Nordoy A, Hansen JB, Brox J, Svensson B: Effects of atorvastatin and omega-3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis 2001, 11:7–16.

    PubMed  CAS  Google Scholar 

  46. Harris WS, Ginsberg HN, Arunakul N: Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk 1997, 4:385–391.

    Article  PubMed  CAS  Google Scholar 

  47. Simvastatin. In Physician’s Desk Reference. Montvale, NJ: Medical Economics; 2002.

  48. Newman CB, Palmer G, Silbershatz H, Szarek M: Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol 2003, 92:670–676.

    Article  PubMed  CAS  Google Scholar 

  49. Shepherd J, Hunninghake DB, Stein EA: Safety of rosuvastatin. Am J Cardiol 2004, 94:882–888.

    Article  PubMed  CAS  Google Scholar 

  50. Jones PH, Davidson MH: Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol 2005, 95:120–122.

    Article  PubMed  CAS  Google Scholar 

  51. Shanahan RL, Kerzee JA, Sandhoff BG: Low myopathy rates associated with statins as monotherapy or combination therapy with interacting drugs in a group model health maintenance organization. Pharmacotherapy 2005, 25:345–351.

    Article  PubMed  CAS  Google Scholar 

  52. Kashyap ML, Evans R, Simmons PD, et al.: New combination niacin/statin formulation shows pronounced effects on major lipoproteins and is well tolerated [abstract]. J Am Coll Cardiol 2000, 35(Suppl A):326A.

    Google Scholar 

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Correspondence to Peter H. Jones MD.

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Vasudevan, A.R., Jones, P.H. Effective use of combination lipid therapy. Curr Atheroscler Rep 8, 76–84 (2006). https://doi.org/10.1007/s11883-006-0068-y

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