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Opinion statement

Clinical trials have demonstrated the benefit of low-density lipoprotein (LDL) cholesterol reduction and, with less robust evidence, reduction of triglyceride levels and increased high-density lipoprotein (HDL) cholesterol in the prevention of atherosclerotic cardiovascular disease. Although the statins are the cornerstone of lipid-lowering therapy, they may not be adequate to accomplish all of the changes in lipid and lipoprotein levels called for in current guidelines. Combinations of one or more lipid-modifying drugs in addition to lifestyle changes are now part of clinical guidelines and are being used extensively in practice. Clinicians need to be familiar with the individual drugs and how they interact. There is also a need for outcome data with combination therapy, especially for statin-fibrate and statin-niacin combinations. Several clinical trials are underway and should provide further evidence for the benefit of combination therapy of dyslipidemia. New drug classes have the potential to provide additive effects with currently available medications to provide substantial LDL reduction and increased HDL level that may lead to a substantial reduction in the burden of atherosclerotic vascular disease.

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References and Recommended Reading

  1. Baigent C, Keech A, Kearney PM, et al.: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005, 366:1267–1278.

    Article  PubMed  CAS  Google Scholar 

  2. Cannon CP, Braunwald E, McCabe CH, et al.: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004, 350:1495–1504.

    Article  PubMed  CAS  Google Scholar 

  3. LaRosa JC, Grundy SM, Waters DD, et al.: Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005, 352:1425–1435.

    Article  PubMed  CAS  Google Scholar 

  4. Taylor AJ, Sullenberger LE, Lee HJ, et al.: Arterial Biology for the Investigation of the Treatment Effects of Reducing 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 

  5. Whitney EJ, Krasuski RA, Personius BE, et al.: A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Intern Med 2005, 142:95–104.

    PubMed  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. Expert Panel on Detection, Evaluation, and Treatment of High blood Cholesterol in Adults: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001, 285:2486–2497.

    Article  Google Scholar 

  8. Pearson TA, Laurora I, Chu H, Kafonek S: The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000, 160:459–467.

    Article  PubMed  CAS  Google Scholar 

  9. Davidson MH, Toth PP: Combination therapy in the management of complex dyslipidemias. Curr Opin Lipidol 2004, 15:423–431.

    Article  PubMed  CAS  Google Scholar 

  10. Smith SC, Allen J, Blair SN, et al.: AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation 2006, 113:2363–2372.

    Article  PubMed  Google Scholar 

  11. Fodor JG, Frohlich JJ, Genest Jr JJG, et al.: Recommendations for the management and treatment of dyslipidemia. Report of the Working Group on Hypercholesterolemia and Other Dyslipidemias. CMAJ 2000, 162:1441–1447.

    PubMed  CAS  Google Scholar 

  12. Haffner SM: Dyslipidemia management in adults with diabetes. Diabetes Care 2004, 27(suppl 1):S68–S71.

    PubMed  Google Scholar 

  13. American Diabetes Association: Standards of medical care in diabetes—2007. Diabetes Care 2007, 30(suppl):S4–S41.

    Article  CAS  Google Scholar 

  14. Goldberg AC, Ostlund RE, Bateman JH, et al.: Effect of plant stanol tablets on low-density lipoprotein cholesterol lowering in patients on statin drugs. Am J Cardiol 2006, 97:376–379.

    Article  PubMed  CAS  Google Scholar 

  15. Cohen DE, Anania FA, Chalasani N: An assessment of statin safety by hepatologists. Am J Cardiol 2006, 97(suppl):77C–81C.

    Article  PubMed  CAS  Google Scholar 

  16. Neuvonen PJ, Niemi M, Backman JT: Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006, 80:565–581.

    Article  PubMed  CAS  Google Scholar 

  17. Bottorff MB: Statin safety and drug interactions: clinical implications. Am J Cardiol 2006, 97(suppl):27C–31C.

    Article  PubMed  CAS  Google Scholar 

  18. Kashani A, Phillips CO, Foody JM, et al.: Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation 2006, 114:2788–2797.

    Article  PubMed  CAS  Google Scholar 

  19. Bruckert E, Hayem G, Dejager S, et al.: Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemia patients—the PRIMO study. Cardiovasc Drugs Ther 2005, 19:403–414.

    Article  PubMed  CAS  Google Scholar 

  20. Thompson PD, Clarkson PM, Rosenson RS: An assessment of statin safety by muscle experts. Am J Cardiol 2006, 97(suppl):69C–76C.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Law M, Rudnicka AR: Statin safety: a systematic review. Am J Cardiol 2006, 97(suppl):52C–60C.

    Article  PubMed  CAS  Google Scholar 

  23. Pasternak RC, Smith SC, Bairey-Merz CN, et al.: ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Circulation 2002, 106:1024–1028.

    Article  PubMed  Google Scholar 

  24. Davidson MH, Dicklin MR, Maki KC, Kleinpell RM: Colesevelam hydrochloride: a non-absorbed, polymeric cholesterol-lowering agent. Exp Opin Invest Drugs 2000, 9:2663–2671.

    Article  CAS  Google Scholar 

  25. Donovan JM, Stypinski D, Stiles MR, et al.: Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent. Cardiovasc Drugs Ther 2000, 14:681–690.

    Article  PubMed  CAS  Google Scholar 

  26. Goldberg AC, Sapre A, Liu J, et al.: Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2004, 79:620–629.

    Article  PubMed  CAS  Google Scholar 

  27. 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 

  28. Ballantyne CM, Weiss R, Moccetti T, et al.: Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol 2007, 99:673–680.

    Article  PubMed  CAS  Google Scholar 

  29. ClinicalTrials.gov: IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome:Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (Study P04103). Available at http://clinicaltrials.gov/ct/show/NCT00202878?order=3. Accessed February 25, 2007.

  30. 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 

  31. McKenney JM, Jones PH, Bays HE, et al.: Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis 2007, Jan 18; [Epub ahead of print].

  32. Kashyap ML, McGovern ME, Berra K, et al.: Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol 2002, 89:672–678.

    Article  PubMed  CAS  Google Scholar 

  33. Brown BG, Zhao XQ, Chait A, et al.: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001, 345:1583–1592.

    Article  PubMed  CAS  Google Scholar 

  34. Alsheikh-Ali AA, Karas RH: Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system). Am J Cardiol 2007, 99:379–381.

    Article  PubMed  CAS  Google Scholar 

  35. ClinicalTrials.gov: AIM HIGH: Niacin Plus Statin to Prevent Vascular Events. NCT00120289. Available at http://clinicaltrials.gov/ct/show/NCT00120289?order=8. Accessed February 25, 2007.

  36. 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 

  37. Bays H: Statin safety: an overview and assessment of the data—2006. Am J Cardiol 2006, 97(suppl):6C–26C.

    Article  PubMed  CAS  Google Scholar 

  38. ACCORD (Action to Control Cardiovascular Risk in Diabetes). Available at http://www.accordtrial.org/public/index.cfm. Accessed February 25, 2007.

  39. Durrington PN, Bhatnagar D, Mackness MI, et al.: An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart 2001, 85:544–548.

    Article  PubMed  CAS  Google Scholar 

  40. Farnier M, Roth E, Gil-Extremera B, et al.: Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia. Am Heart J 2007, 153:335.e1–335.e8.

    Article  CAS  Google Scholar 

  41. Rosenson RS: Low HDL-C: A secondary target of dyslipidemia therapy. Am J Med 2005, 118:1067–1077.

    Article  PubMed  CAS  Google Scholar 

  42. Brown BG, Stukovsky KH, Zhao XQ: Simultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials. Curr Opin Lipidol 2006, 17:631–636.

    Article  PubMed  CAS  Google Scholar 

  43. Bays H, Rhyne J, Abby S, et al.: Lipid-lowering effects of colesevelam HCl in combination with ezetimibe. Curr Med Res Opin 2006, 22:2191–2200.

    Article  PubMed  CAS  Google Scholar 

  44. Farnier M, Freeman MW, Macdonell G, et al.: Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia. Eur Heart J 2005, 26:897–905.

    Article  PubMed  CAS  Google Scholar 

  45. Wierzbicki AS: Future approaches to reducing low-density lipoprotein cholesterol. Future Lipid 2006, 1:463–476.

    Article  CAS  Google Scholar 

  46. Cuchel M, Bloedon LT, Philippe O, et al.: Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007, 356:148–156.

    Article  PubMed  CAS  Google Scholar 

  47. de Grooth GJ, Kuivenhoven JA, Stalenhoef AFH, et al.: Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation 2002, 105:2159–2165.

    Article  PubMed  CAS  Google Scholar 

  48. Brousseau ME, Schaefer EJ, Wolfe ML, et al.: Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004, 350:1505–1515.

    Article  PubMed  CAS  Google Scholar 

  49. Burnett JR: Drug evaluation: TAK-475—an oral inhibitor of squalene synthase for hyperlipidemia. Curr Opin Investig Drugs 2006, 7:850–855.

    PubMed  CAS  Google Scholar 

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Correspondence to Anne Carol Goldberg MD.

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Goldberg, A.C. Combination therapy of dyslipidemia. Curr Treat Options Cardio Med 9, 249–258 (2007). https://doi.org/10.1007/s11936-007-0020-7

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