Ezetimibe is used alone or in combination with other antilipemic agents (i.e., a hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor [statin], fenofibrate) as an adjunct to dietary therapy in the treatment of primary hyperlipidemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, and/or homozygous familial sitosterolemia. Efficacy of ezetimibe, alone or in fixed combination with simvastatin, in patients with Fredrickson type I, III, IV, or V dyslipidemias has not been established.
Effects of ezetimibe on cardiovascular morbidity and mortality have not been established.
The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated.For additional details on lifestyle modifications, consult the most recent AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).
The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., ezetimibe) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. However, nonstatin drugs may be useful as adjuncts to statin therapy in high-risk patients (e.g., patients with ASCVD, low-density lipoprotein [LDL]-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly when there is evidence from randomized controlled studies suggesting that the nonstatin drug further reduces ASCVD events when added to statin therapy. When a nonstatin drug is required, selection of the nonstatin drug should be based on a favorable benefit-risk ratio (i.e., demonstrated benefit of ASCVD risk reduction outweighs risks of adverse effects and drug interactions) and patient preferences. For additional details on prevention of ASCVD, see and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).
Primary Hyperlipidemia and Mixed Dyslipidemia
Ezetimibe is used alone or in combination with a statin as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and non-high-density lipoprotein (non-HDL)-cholesterol concentrations in the treatment of primary (heterozygous familial and nonfamilial) hyperlipidemia. Ezetimibe in fixed combination with simvastatin (Vytorin) is used as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hyperlipidemia or mixed dyslipidemia. Ezetimibe also is used in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia.
Efficacy and safety of ezetimibe monotherapy in the management of primary hyperlipidemia were established in 2 multicenter, randomized, double-blind, placebo-controlled studies of 12 weeks' duration in approximately 1700 patients with primary hyperlipidemia. In these studies, patients who received ezetimibe (10 mg daily) had mean reductions of approximately 12-13% in total cholesterol, 18% in LDL-cholesterol, 15-16% in apo B, 16% in non-HDL-cholesterol, and 7-9% in triglyceride concentrations; increases in high-density lipoprotein (HDL)-cholesterol concentrations in patients receiving ezetimibe were negligible (1%). In most patients with primary hyperlipidemia, maximal or near-maximal reductions in serum lipoprotein and apolipoprotein concentrations are achieved within 2 weeks and maintained during continued therapy. Reductions in LDL-cholesterol concentrations appear to be consistent across age, gender, and baseline LDL-cholesterol concentrations.
Data from several multicenter, randomized, double-blind, placebo-controlled studies indicate that concomitant therapy with ezetimibe and a statin may produce additive antilipemic effects. In a study in patients with primary hyperlipidemia and either multiple cardiovascular risk factors or documented coronary heart disease (CHD) who had not achieved their target LDL-cholesterol goal with diet and statin monotherapy, addition of ezetimibe (10 mg daily) to existing statin therapy reduced total cholesterol, LDL-cholesterol, apo B, non-HDL-cholesterol, and triglyceride concentrations by an additional 17, 25, 19, 23, and 14%, respectively, at 8 weeks and increased HDL-cholesterol concentrations by an additional 3% compared with statin monotherapy. For patients whose LDL-cholesterol levels were above the target levels recommended by the Second Report of the National Cholesterol Education Program (NCEP) (Adult Treatment Panel [ATP] II), approximately 72% of patients receiving combination therapy achieved their target LDL-cholesterol goal compared with 19% of those receiving statin monotherapy. In 4 multicenter, randomized, double-blind, placebo-controlled studies in hyperlipidemic patients, combination therapy with ezetimibe (10 mg daily) and a statin (i.e., atorvastatin 10-80 mg daily, lovastatin 10-40 mg daily, pravastatin 10-40 mg daily, or simvastatin 10-80 mg daily), initiated concurrently and continued for 12 weeks, reduced total cholesterol, LDL-cholesterol, apo B, non-HDL-cholesterol, and triglyceride concentrations and, except for the combination of ezetimibe and pravastatin, increased HDL-cholesterol concentrations compared with monotherapy with the corresponding statin. Following combination therapy with ezetimibe and either atorvastatin, simvastatin, pravastatin, or lovastatin, total reductions in LDL-cholesterol concentrations averaged 53-61, 46-58%, 34-42, or 34-46, respectively, compared with reductions of 37-54, 27-45, 21-31, or 20-30% with atorvastatin, simvastatin, pravastatin, or lovastatin monotherapy, respectively. Results of one study in patients with known CHD or CHD risk equivalents indicated that reductions in LDL-cholesterol concentrations achieved with the combination of ezetimibe 10 mg and simvastatin 10 mg (47%) were greater than those achieved with simvastatin 20 mg alone (38%).
Similar additive antilipemic effects were observed following therapy with the fixed-combination preparation containing ezetimibe and simvastatin. Data from several randomized, double-blind studies in patients with primary hyperlipidemia indicated that reductions in LDL-cholesterol concentrations achieved with pooled doses of the fixed-combination preparation were greater than those achieved with pooled doses of atorvastatin, rosuvastatin, or simvastatin monotherapy. In one study, LDL-cholesterol concentrations were reduced by 47-59% following therapy with the fixed-combination preparation containing ezetimibe (10 mg) and simvastatin (10-80 mg) and by 36-53% following monotherapy with atorvastatin (10-80 mg daily). In another study, LDL-cholesterol concentrations were reduced by 52-61% following therapy with the fixed-combination preparation containing ezetimibe (10 mg) and simvastatin (20-80 mg) and by 46-57% following monotherapy with rosuvastatin (10-40 mg daily). In the third study, LDL-cholesterol concentrations were reduced by 45-60% following therapy with the fixed-combination preparation containing ezetimibe (10 mg) and simvastatin (10-80 mg) and by 33-49% following monotherapy with simvastatin (10-80 mg daily).
Despite its additive effects on LDL-cholesterol reduction, early findings from a randomized, double-blind, active-controlled study (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression [ENHANCE]) in patients with heterozygous familial hypercholesterolemia indicated that the fixed-combination preparation containing ezetimibe and simvastatin (10 and 80 mg daily, respectively) was not superior to simvastatin monotherapy (80 mg daily) in reducing carotid intimal-medial wall thickness (cIMT). In this study, treatment with the fixed-combination preparation for 2 years resulted in a change in cIMT (increase of 0.011 mm) that was not statistically different from the change in cIMT observed with simvastatin monotherapy (increase of 0.006 mm). However, reductions in LDL-cholesterol concentrations achieved with the fixed-combination preparation (56%) were substantially greater than those achieved with simvastatin monotherapy (39%). Although the greater reductions in LDL-cholesterol concentrations did not translate into substantial improvement in cIMT in the ENHANCE study, the cardiovascular benefits of reducing LDL-cholesterol concentrations are well established and have been demonstrated in other studies.
The addition of ezetimibe to simvastatin therapy resulted in further LDL-cholesterol lowering and improved cardiovascular outcomes in the Improved Reduction of Outcomes: Vytorin Efficacy International (IMPROVE-IT) study. IMPROVE-IT was a large randomized, double-blind study in 18,144 patients who had been hospitalized for an acute coronary syndrome in the preceding 10 days and had baseline LDL-cholesterol concentrations of 50-125 mg/dL (or 50-100 mg/dL if they were receiving lipid-lowering therapy). Patients were randomized to receive the fixed-combination preparation containing ezetimibe and simvastatin (10 and 40 mg daily, respectively) or simvastatin monotherapy (40 mg daily). After a median duration of follow-up of 6 years, the fixed-combination preparation produced a 24% further reduction in mean LDL-cholesterol concentration and also reduced the rate of the primary end point (composite of cardiovascular death, nonfatal myocardial infarction [MI], unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke) compared with simvastatin monotherapy; the absolute risk reduction for the primary composite outcome was 2% over 7 years. The treatment benefit of combined simvastatin/ezetimibe therapy began to emerge after 1 year and appeared to be particularly pronounced in patients with diabetes mellitus and geriatric patients (75 years of age or older).
The combination of ezetimibe and fenofibrate has been shown to reduce total and LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in patients with mixed dyslipidemia. In a randomized, double-blind, placebo-controlled study in patients with mixed dyslipidemia, combination therapy with ezetimibe and fenofibrate (160 mg daily) was superior to fenofibrate monotherapy in reducing total cholesterol (22 versus 11%), LDL-cholesterol (20 versus 6%), apo B (26 versus 15%), and non-HDL-cholesterol (30 versus 16%) concentrations at 12 weeks. Effects on triglyceride and HDL-cholesterol concentrations in patients receiving combination therapy were comparable to those in patients receiving fenofibrate monotherapy. Following an additional 48 weeks of combination therapy or monotherapy, changes in lipoprotein concentrations were consistent with those observed at 12 weeks of therapy. The manufacturer states that efficacy and safety of ezetimibe in combination with a fibric acid derivative other than fenofibrate have not been studied and currently is not recommended.
(See Fibric Acid Derivatives under Drug Interactions: Antilipemic Agents.)
Patients with Chronic Kidney Disease
In the Study of Heart and Renal Protection (SHARP), the fixed-combination preparation containing ezetimibe and simvastatin was shown to reduce the risk of major vascular and atherosclerotic events in patients with chronic kidney disease, a population known to be at increased risk of cardiovascular disease. More than 9000 patients with moderate to severe chronic kidney disease (33% receiving dialysis) and no known history of MI or coronary revascularization were initially randomized in a 4:4:1 ratio to receive the fixed-combination preparation containing ezetimibe and simvastatin (10 and 20 mg daily, respectively), placebo, or simvastatin alone (20 mg daily) for 1 year to assess the safety of adding ezetimibe to simvastatin; patients in the simvastatin monotherapy group were then re-randomized to the fixed-combination preparation or placebo. After a median duration of follow up of 4.9 years, the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or revascularization excluding dialysis access procedures) was reduced by 16% (based on the primary intent-to-treat analysis in patients initially randomized to the fixed-combination preparation or placebo groups) and the risk of a major atherosclerotic event (nonfatal MI or cardiac death, nonhemorrhagic stroke, or arterial revascularization excluding dialysis access procedures) was reduced by 17% (based on the total number of patients randomized at any time to the fixed-combination preparation or placebo groups) with the fixed-combination preparation compared with placebo. The treatment effect was largely driven by a substantial reduction in ischemic strokes and arterial revascularization procedures. The subgroup of patients receiving dialysis at baseline experienced a smaller risk reduction benefit compared with those not receiving dialysis. In addition, therapy with the fixed-combination preparation did not appear to slow the progression to end-stage renal disease.
Homozygous Familial Hypercholesterolemia
Ezetimibe may be used in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available.
Efficacy and safety of ezetimibe combined with atorvastatin or simvastatin for the management of homozygous familial hypercholesterolemia were established in a randomized, double-blind study of 12 weeks' duration in a limited number of patients with a clinical and/or genotypic diagnosis of homozygous familial hypercholesterolemia who were already receiving atorvastatin (40 mg daily) or simvastatin (40 mg daily), with or without concomitant LDL apheresis. In this study, patients were randomized to receive 1 of 3 regimens: atorvastatin (80 mg daily) or simvastatin (80 mg daily) monotherapy; ezetimibe (10 mg daily) with either atorvastatin (40 mg daily) or simvastatin (40 mg daily); or ezetimibe (10 mg daily) with either atorvastatin (80 mg daily) or simvastatin (80 mg daily). The addition of ezetimibe (10 mg daily) to therapy with atorvastatin (40 or 80 mg daily) or simvastatin (40 or 80 mg daily) was more effective in reducing LDL-cholesterol concentrations (21% additional reduction based on pooled data from 40-mg and 80-mg groups) than increasing the dosage of atorvastatin or simvastatin monotherapy from 40 to 80 mg daily (7% additional reduction based on pooled data from 40-mg and 80-mg groups).
In the entire group of patients receiving higher dosages (80 mg daily) of either atorvastatin or simvastatin in combination with ezetimibe (10 mg daily), LDL-cholesterol concentrations were reduced by approximately 27% compared with a 7% reduction with statin monotherapy. Comparable reductions in LDL-cholesterol concentrations were observed in the subgroup of patients with genotype-confirmed homozygous familial hypercholesterolemia.
Beneficial effects of ezetimibe combined with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia who currently are undergoing LDL apheresis compared with effects in patients not undergoing the procedure have not been established. Effects on clinical outcome and modification of other disease parameters (e.g., xanthoma formation, regression of atherosclerosis) also have not been established.
Homozygous Familial Sitosterolemia (Phytosterolemia)
Ezetimibe is used as an adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia.
Efficacy and safety of ezetimibe in the management of homozygous sitosterolemia were established in a randomized, double-blind study of 8 weeks' duration in a limited number of patients with homozygous sitosterolemia who had plasma sitosterol concentrations exceeding 5 mg/dL and were already receiving standard antilipemic therapy (dietary therapy, bile acid sequestrants, statins, ileal bypass surgery, and/or LDL apheresis). In this study, treatment with ezetimibe (10 mg daily) reduced plasma sitosterol and campesterol concentrations by 21 and 24%, respectively, compared with increases of 4 and 3% in placebo-treated patients. Reductions in sitosterol and campesterol concentrations were consistent between patients receiving ezetimibe with or without bile acid sequestrants. The effect of reducing plasma concentrations of sitosterol and campesterol on cardiovascular morbidity and mortality has not been established.
For additional information on the role of antilipemic therapy in the treatment of lipoprotein disorders, prevention of cardiovascular events, and other conditions, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.