EVIDENCE-BASED ANSWER
Many combination drug therapies are effective in treating dyslipidemia. Compared with statin monotherapy, combinations that include ezetimibe (Zetia), a bile acid sequestrant, or niacin further lower low-density lipoprotein (LDL) cholesterol (strength of recommendation [SOR]: A), and increase the likelihood of attaining National Cholesterol Education Program (NCEP) LDL cholesterol goals (SOR: B). Adding ezetimibe to a bile acid sequestrant reduces LDL cholesterol (SOR: B). Fibrate or niacin added to statin monotherapy provide mixed lipid-modifying effects for combined dyslipidemia (SOR: A).
Most combination therapies increase the risk of intolerance or side effects, including myopathy. The statin/gemfibrozil combination has the highest risk of myopathy, whereas statin/ezetimibe or statin/bile acid sequestrant have the least increased risk (SOR: B). Studies evaluating patient-oriented outcomes (morbidity, mortality) with combination therapy vs monotherapy have not yet been conducted; however, combination therapies have demonstrated reduced atherosclerotic lesion progression.
CLINICAL COMMENTARY
When statins alone don’t work, think before writing a second prescription
Paul Crawford, MD
Eglin Air Force Base Family Medicine Residency, Eglin, Fla
When patients are unable to reach their lipid goal on a single medication, they should first be evaluated for dietary noncompliance before adding another medication that can be difficult to manage. Unfortunately, the older bile acid sequestrants have multiple drug interactions (ie, warfarin, digitalis, phenobarbital), and patients dislike them, since they must remember to take other medications >1 hour before or >4 hours later (these problems are not seen with colesevelam, a newer drug). Some physicians are reluctant to prescribe statin/fibrate combinations due to the interaction of gemfibrozil with statins; plus, patients must forego grapefruit juice with fibrates to avoid toxicity. Niacin has a low risk of toxicity, but fears of flushing may give patients pause (premedication with aspirin can reduce flushing). Ezetimibe/statins are effective, have relatively low toxicity and are convenient due to availability of commercial combinations. When choosing medications, think carefully about the patient before prescribing another lipid-lowering medication.
Evidence summary
Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, better known as statins (atorvastatin, fluvastatin, lovastatin, rosuvastatin, pravastatin, simvastatin), have been shown to lower LDL cholesterol in the primary and secondary prevention of cardiovascular disease. Although often effective as monotherapy, combination regimens may be needed to reach LDL cholesterol goals.1-4 Ezetimibe, niacin, and bile acid sequestrants (cholestyramine [Questran], colesevelam [WelChol], colestipol [Colestid]) have complementary effects that suggest they may be appropriate for use in combination with a statin.
Adding a bile acid sequestrant to statin monotherapy does not appear to increase the risk of systemic toxicity.5 A systematic review found that adding colestipol or cholestyramine to a statin provides an additional 7% to 20% absolute LDL cholesterol reduction.1 A randomized placebo-controlled trial demonstrated that combination therapy with colesevelam has similar effects. The absolute LDL cholesterol reduction of with atorvastatin (Lipitor) alone (10 mg daily) increased from 38% to 48% after adding colesevelam 3.8 g daily (10% absolute LDL cholesterol reduction).6
Statin/ezetimibe combination therapy is FDA-approved, and provides an additional 12% to 21% absolute LDL cholesterol reduction.2 Although considered safe, adding ezetimibe increases the incidence of elevated hepatic transaminases from 0.4% to 1.3%.7 A double-blind trial randomized 769 patients on statin monotherapy who were above their NCEP LDL goal to either placebo or ezetimibe 10 mg daily.3 Absolute LDL cholesterol reductions were 25.1% with ezetimibe vs 3.7% with placebo, and LDL goal attainment was 71.5% with ezetimibe vs 18.9% with placebo (secondary endpoint). In one retrospective analysis, ezetimibe provided a 19% absolute LDL cholesterol reduction when added to a bile acid sequestrant.8