What Are Effective Medication Combinations for Dyslipidemia?

Home , Atorvastatin, Bile acid sequestrant, Colesevelam, Colestipol, Ezetimibe, Fenofibrate

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What are effective medication combinations for dyslipidemia? Joseph Saseen, PharmD, FCCP, Elizabeth Tweed, BSN, MLIS University of Colorado at Denver and Health Sciences Center

EVIDENCE- BASED ANSWER Many combination drug therapies are effective in effects for combined dyslipidemia (SOR: A). treating dyslipidemia. Compared with statin Most combination therapies increase the risk of monotherapy, combinations that include ezetimibe intolerance or side effects, including myopathy. (Zetia), a bile acid sequestrant, or niacin further The statin/gemfibrozil combination has the lower low-density lipoprotein (LDL) cholesterol highest risk of myopathy, whereas statin/ (strength of recommendation [SOR]: A), and ezetimibe or statin/bile acid sequestrant have the increase the likelihood of attaining National least increased risk (SOR: B). Studies evaluating Cholesterol Education Program (NCEP) LDL patient-oriented outcomes (morbidity, mortality) cholesterol goals (SOR: B). Adding ezetimibe to a with combination therapy vs monotherapy have bile acid sequestrant reduces LDL cholesterol not yet been conducted; however, combination (SOR: B). Fibrate or niacin added to statin® Dowdentherapies Health have Media demonstrated reduced athero- monotherapy provide mixed lipid-modifying sclerotic lesion progression. Copyrightor personal use only CLINICAL COMMENTARYF When statins alone don’t work, statin/fibrate combinations due to the interaction of think before writing a second prescription gemfibrozil with statins; plus, patients must forego When patients are unable to reach their lipid goal grapefruit juice with fibrates to avoid toxicity. on a single medication, they should first be Niacin has a low risk of toxicity, but fears of evaluated for dietary noncompliance before adding flushing may give patients pause (premedication another medication that can be difficult to manage. with aspirin can reduce flushing). Ezetimibe/statins Unfortunately, the older bile acid sequestrants are effective, have relatively low toxicity and are have multiple drug interactions (ie, warfarin, convenient due to availability of commercial digitalis, phenobarbital), and patients dislike them, combinations. When choosing medications, think since they must remember to take other medica- carefully about the patient before prescribing tions >1 hour before or >4 hours later (these another lipid-lowering medication. problems are not seen with colesevelam, a newer Paul Crawford, MD drug). Some physicians are reluctant to prescribe Eglin Air Force Base Family Medicine Residency, Eglin, Fla

I Evidence summary may be needed to reach LDL cholesterol Hydroxymethyl glutaryl coenzyme A goals.1–4 Ezetimibe, niacin, and bile acid (HMG CoA) reductase inhibitors, better sequestrants (cholestyramine [Questran], known as statins (atorvastatin, fluva- colesevelam [WelChol], colestipol statin, lovastatin, rosuvastatin, prava- [Colestid]) have complementary effects statin, simvastatin), have been shown to that suggest they may be appropriate for lower LDL cholesterol in the primary use in combination with a statin. and secondary prevention of cardio- Adding a bile acid sequestrant to vascular disease. Although often effective statin monotherapy does not appear as monotherapy, combination regimens to increase the risk of systemic toxicity.5

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A systematic review found that adding T ABLE colestipol or cholestyramine to a statin Commonly used combination therapies provides an additional 7% to 20% with estimated changes in lipid values absolute LDL cholesterol reduction.1 A randomized placebo-controlled trial CHANGE CHANGE CHANGE demonstrated that combination therapy COMBINATION IN LDL-C IN HDL-C IN TGD with colesevelam has similar effects. The absolute LDL cholesterol reduction of Statin/bile acid sequestrant iii h i with atorvastatin (Lipitor) alone (10 mg Statin/ezetimibe iii h i daily) increased from 38% to 48% after Statin/fibrate adding colesevelam 3.8 g daily (10% ii hh iii absolute LDL cholesterol reduction).6 Statin/niacin iii hhh iii Statin/ezetimibe combination thera- Ezetimibe/bile acid sequestrant py is FDA-approved, and provides an ii h i additional 12% to 21% absolute LDL Key: One arrow, small change; 2 arrows, moderate change; 3 arrows, large 2 change. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density cholesterol reduction. Although consid- lipoprotein cholesterol; TGD, triglycerides ered safe, adding ezetimibe increases the incidence of elevated hepatic transami- nases from 0.4% to 1.3%.7 A double- erature.5 Accordingly, the maximum blind trial randomized 769 patients on approved daily doses of lovastatin statin monotherapy who were above (Mevacor), simvastatin (Zocor), and their NCEP LDL goal to either placebo rosuvastatin (Crestor) are lowered (20, or ezetimibe 10 mg daily.3 Absolute LDL 10, and 10 mg, respectively) when used cholesterol reductions were 25.1% with with gemfibrozil. ezetimibe vs 3.7% with placebo, and Adding niacin to statin monotherapy LDL goal attainment was 71.5% with can modify combined dyslipidemia as ezetimibe vs 18.9% with placebo (sec- does a statin/fibrate combination, by low- ondary endpoint). In one retrospective ering LDL cholesterol and triglycerides, analysis, ezetimibe provided a 19% and raising HDL cholesterol to an even FAST TRACK absolute LDL cholesterol reduction when greater extent. Patients are more intoler- Ezetimibe, niacin, added to a bile acid sequestrant.8 ant to a statin/niacin combination (eg, Combinations of statins with fibrates flushing) than to a statin/fibrate combina- and bile acid (fenofibrate [Tricor], gemfibrozil [Lopid]) tion, but have a lower risk of myopathy sequestrants have can treat combined dyslipidemia by with the former.5 The combination of complementary decreasing LDL cholesterol more than statin/niacin may be more desirable than 40%, decreasing triglycerides over 50%, statin/fibrate for patients with more effects in and raising high-density lipoprotein severe mixed dyslipidemia, especially combination (HDL) cholesterol more than 20%.9 those with very low HDL cholesterol val- with a statin Prospective controlled trials have shown ues, when monotherapy regimens are not regression of atherosclerotic lesions with completely effective. A fixed combination this combination, but have also shown of lovastatin with extended-release niacin increased risks of myopathy.6,10 In an (Advicor) is commercially available.4,11 analysis of 36 controlled clinical trials (1674 patients) that evaluated statin- Recommendations from others fibrate combinations, 0.12% of patients The NCEP Adult Treatment Panel III rec- developed myopathy, but none developed ommends adding a bile acid sequestrant, rhabdomyolysis or kidney failure.10 niacin, or ezetimibe to a statin when addi- Experts believe myopathy risk is greater tional LDL cholesterol-lowering is needed with gemfibrozil than fenofibrate, based to reach NCEP-III goals, and adding on gemfibrozil’s inhibition of statin glu- niacin or a fibrate to a statin to lower curonidation, and case reports in the lit- non-HDL cholesterol for patients with

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12. Executive Summary of the Third Report of the persistently high triglycerides or low National Cholesterol Education Program (NCEP) HDL cholesterol.12,13 Expert Panel on Detection, Evaluation, and Treatment The American Association of Clinical of High Blood Cholesterol in Adults (Adult Treatment Endocrinologists also recommends using Panel III). JAMA 2001; 285:2486–2497. 13. Grundy SM, Cleeman JI, Merz CN, et al. Implications of these combinations for the following recent clinical trials for the National Cholesterol circumstances: severe dyslipidemia, inad- Education Program Adult Treatment Panel III guide- equate response to monotherapy, dose- lines. Circulation 2004; 110:227–239. dependent adverse effects, and certain 14. AACE medical guidelines for clinical practice for the 14 diagnosis and treatment of dyslipidemia and preven- mixed dyslipidemias. However, the clin- tion of atherogenesis. Endocr Pract 2000; 6:162–213. ical advisory on statins by American Heart Association/American College of Cardiology/National Heart, Lung and Blood Institute warns that statin/fibrate combinations (especially with gemfibrozil) or statin/niacin (although rare) are risk factors for statin-associated myopathy.5

REFERENCES

1. Schectman G, Hiatt J. Dose-response characteristics of cholesterol-lowering drug therapies: implications for treatment. Ann Intern Med 1996; 125:990–1000. 2. Jeu L, Cheng JW. Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor. Clin Ther 2003; 25:2352–2387. 3. Gagne C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002; 90:1084–1091. 4. Hunninghake DB, McGovern ME, Koren M, et al. A FAST TRACK dose-ranging study of a new, once-daily, dual-compo- nent drug product containing niacin extended-release Most combination and lovastatin. Clin Cardiol 2003; 26:112–118. therapies 5. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical increase risk advisory on the use and safety of statins. J Am Coll of side effects, Cardiol 2002; 40:567–572. 6. Hunninghake D, Insull W Jr, Toth P, Davidson D, including Donovan JM, Burke SK. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cho- myopathy lesterol additively. Atherosclerosis 2001; 158:407–416. 7. Zetia [package insert]. North Wales, Pa: Merck- Schering-Plough Pharmaceuticals; March 2005. 8. Xydakis AM, Guyton JR, Chiou P, Stein JL, Jones PH, Ballantyne CM. Effectiveness and tolerability of ezetimibe add-on therapy to a bile acid resin-based regi- men for hypercholesterolemia. Am J Cardiol 2004; 94:795–797. 9. Xydakis AM, Ballantyne CM. Combination therapy for combined dyslipidemia. Am J Cardiol 2002; 90(10B):21K–9K. 10. Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Pharmacother 2001; 35:908–917. 11. Insull W, Jr., McGovern ME, Schrott H, et al. Efficacy of extended-release niacin with lovastatin for hypercholesterolemia: assessing all reasonable doses with innovative surface graph analysis. Arch Intern Med 2004; 164:1121–1127.

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