Ezetimibe: A Selective Cholesterol Absorption Inhibitor

Edith A. Nutescu, Pharm.D.; Nancy L. Shapiro, Pharm.D.


Pharmacotherapy. 2003;23(11) 

In This Article

Clinical Evidence

The efficacy and safety of ezetimibe have been established in phase III clinical trials in which ezetimibe has been investigated as monotherapy, as an add-on to ongoing statin therapy, and as combination therapy with statins and fibrates in patients with primary hypercholesterolemia. In addition, ezetimibe has been evaluated in patients with heterozygous and homozygous familial hypercholesterolemia and in patients with sitosterolemia.

Monotherapy. Ezetimibe 10 mg/day was evaluated for efficacy and safety in two 12-week, randomized, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia (plasma LDL 130-250 mg/dl, triglycerides ≤ 350 mg/dl).[36,37] After a screening and drug washout phase of 2-12 weeks, patients were randomized to receive placebo (205 patients in study 1,[36] 226 in study 2[37]) or ezetimibe 10 mg each morning (622 patients in study 1, 666 in study 2). Most of the patients followed a National Cholesterol Education Program (NCEP) step 1 low-fat, low-cholesterol diet throughout the study. Approximately one third of all patients had a family history of coronary artery disease, and approximately one third of those in study 1 had hypertension.

In both studies, mean baseline LDL levels were 164-168 mg/dl.[36,37] The LDL levels were significantly reduced from baseline in studies 1 and 2 (-18.2% and -17.7%, respectively) after treatment with ezetimibe, compared with small increases (1.4% and 0.8%) in the respective placebo groups (p<0.01 for both). These effects were observed at 2 weeks, were sustained throughout the 12-week treatment period, and were consistent among patients regardless of risk factors, sex, age, race, or baseline lipid profile.

Ezetimibe treatment also improved total cholesterol (-12.4% and -12.5% vs 0.6% and 0.8%, respectively), high-density lipoprotein cholesterol (HDL; 1.0% and 1.3% vs -1.3% and -1.6%, respectively), and apolipoprotein B (-15.4% and -15.5% vs -1.0% and -1.4%, respectively), compared with placebo (p<0.01 for all values vs placebo).[36,37] In study 2, triglyceride levels decreased significantly compared with placebo (-5.7% vs 5.7%, p<0.01).

Ezetimibe was well tolerated by patients in both studies.[36,37] Discontinuation of therapy due to adverse events was similar between ezetimibe and placebo (2-4% of patients). Small but similar increases in the frequency of elevated creatine kinase levels were observed in both ezetimibe and placebo groups. In study 1, serum lipid-soluble vitamins, prothrombin, and baseline or stimulated cortisol were unaffected by ezetimibe treatment.[36]

Rationale for Combination Therapy with Statins. Hypercholesterolemia may not be controllable by administration of a single lipid-lowering agent, and combination therapy with agents that act through different pathways of cholesterol metabolism may be more effective.[38] In clinical practice, the most commonly prescribed combination therapy consists of a statin given with a fibrate or nicotinic acid, which raises HDL and reduces triglycerides.[3] However, limited added effect on LDL, poor tolerance of niacin, increased risk of statin-induced myopathy with gemfibrozil and possibly other fibrates, and compliance limit the use of these agents. Thus, better combination treatment regimens are needed.[38,39,40]

Because the mechanism through which ezetimibe lowers cholesterol complements the inhibitory action of statins on cholesterol biosynthesis, this agent represents an important new option for treatment in combination with statins.[41] Ezetimibe has an excellent safety and tolerability profile when administered with statins[42,43,44,45] and has a low potential for drug interactions.[22,23,24,25,26,27,30,31,35,46,47,48,49] Coadministration of ezetimibe and a statin should provide beneficial additive LDL-lowering effects.

Add-On to StatinTherapy. Many patients receiving statin therapy fail to reach their LDL goal.[4,38,50] Because its mechanism of action is complementary to that of statins, ezetimibe was studied for its potential additive lipid-lowering effects in patients already receiving statin therapy in a double-blind, placebo-controlled trial.[42] This trial involved 769 patients with primary hypercholesterolemia who had failed to achieve NCEP Adult Treatment Panel (ATP) II LDL goals. Patients were stratified into two groups -- one with LDL levels less than 18% above target, and one with LDL levels at least 18% above target.[42]

Two thirds of the patients were given simvastatin 10-80 mg/day or atorvastatin 10-80 mg/day; the rest were given lovastatin 10-40 mg/day, pravastatin 10-40 mg/day, cerivastatin 0.2-0.8 mg/day, or fluvastatin 20-80 mg/day. Patients also received a daily dose of either placebo (390 patients) or ezetimibe 10 mg (379 patients) for 8 weeks; the statin treatment regimens remained unchanged throughout the study. Most (68%) patients had CHD and/or diabetes or CHD-equivalent disease with LDL levels of at least 100 mg/dl.

Ezetimibe plus ongoing statin therapy lowered LDL levels by an additional 25.1% compared with 3.7% in the placebo-statin group (p<0.001) (Figure 2).[42] The effects were consistent regardless of which statin was administered. The response peaked by 2 weeks and was sustained throughout the 8-week treatment period. After addition of ezetimibe to statin therapy, a significant increase occurred in the proportion of patients reaching NCEP ATP II LDL goals, compared with the placebo-statin group (71.5% vs 18.9%, odds ratio 23.7, p<0.001; Figure 3). The LDL-lowering effects of ezetimibe-statin therapy were the same regardless of age, sex, race, NCEP ATP II category, body mass index, or waist circumference.

Effects on low-density lipoprotein cholesterol (LDL), triglyceride (TG), and high-density lipoprotein cholesterol (HDL) levels after the addition of ezetimibe to ongoing statin therapy. Changes in lipid levels were assessed at 8 weeks after the start of ezetimibe and were similar regardless of which statin was administered. Results were derived by pooling data across all statin dosage groups.[42] ap<0.001 vs statin plus placebo; bp<0.05 vs statin plus placebo.

Addition of ezetimibe to ongoing statin therapy significantly increased the proportion of patients who achieved their low-density lipoprotein cholesterol (LDL) goal levels. Data were calculated for patients whose LDL levels were above National Cholesterol Education Program Adult Treatment Panel II target levels at baseline.[42] ap<0.001 for ezetimibe plus statin vs statin alone.

The addition of ezetimibe to ongoing statin therapy significantly improved HDL (2.7%) and triglyceride levels (-14.0%), compared with the placebo-statin group (1.0% and -2.9%, respectively, p<0.05; Figure 2).[42] Significant improvements were also observed for other indicators of CHD risk (total cholesterol, non-HDL, apolipoprotein B, LDL:HDL ratio, and total cholesterol:HDL ratio) in patients receiving ezetimibe-statin therapy (p≤0.05).

The overall frequency of adverse events was similar for the ezetimibe-statin and placebo-statin groups (21% and 17%, respectively).[42] Hepatic- or muscle-related adverse events, laboratory safety analyses, electrocardiogram measurements, and physical examinations revealed no clinically relevant differences between treatment groups.

Combination Therapy with Statins. The efficacy and safety of ezetimibe coadministered with simvastatin (668 patients), atorvastatin (628 patients), pravastatin (538 patients), and lovastatin (548 patients) were determined in four double-blind, placebo-controlled studies.[32,44,45,51] All study patients had hypercholesterolemia (plasma LDL 145-250 mg/dl, triglycerides ≤ 350 mg/dl). After a washout period of 2-12 weeks, patients were randomized to one of the following daily treatments for 12 weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus atorvastatin 10, 20, 40, or 80 mg; pravastatin 10, 20, or 40 mg; ezetimibe 10 mg plus pravastatin 10, 20, or 40 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo.

The percentage change in direct LDL level from baseline was the primary end point; secondary efficacy end points were percentage changes from baseline of calculated LDL, HDL, and triglyceride levels. The effects of ezetimibe coadministered with each statin (pooled across all dosage groups) were compared with the effects of each statin administered alone (pooled across all dosage groups).

Compared with the respective statin monotherapy, ezetimibe coadministered with a statin caused additional reductions in LDL. Incremental reductions from baseline levels were 14%, 12%, 14%, and 15% for ezetimibe administered with simvastatin, atorvastatin, pravastatin, and lovastatin, respectively (p<0.01 compared with statin monotherapy; Table 1 ).[32,44,45,51] Reductions in LDL from baseline levels after ezetimibe combination therapy were 46%, 46%, 56%, and 58% for simvastatin 10, 20, 40, and 80 mg, respectively; 53%, 54%, 56%, and 61% for atorvastatin 10, 20, 40, and 80 mg, respectively; 34%, 40%, and 42% for pravastatin 10, 20, and 40 mg, respectively; and 34%, 41%, and 46% for lovastatin 10, 20, and 40 mg, respectively. Ezetimibe combined with a low-dose (10 mg) statin was as effective as the highest dose of the respective statin alone (Figure 4). The lipid-lowering effects of ezetimibe-statin combination therapy occurred as early as 2 weeks and were maintained throughout the study period.[32,44,45,51]

Combination therapy with ezetimibe 10 mg plus simvastatin 10 mg was as effective as high-dose (80 mg) simvastatin monotherapy.[45] LDL = low-density lipoprotein cholesterol.

Ezetimibe combined with simvastatin, atorvastatin, pravastatin, and lovastatin caused significant incremental reductions in triglyceride levels from baseline of 8%, 8%, 10%, and 11%, respectively, compared with statin monotherapy (p<0.01).[32,44,45,51] Incremental increases in HDL from baseline levels ranged from 2.4-5% with ezetimibe combined with all statins except pravastatin.

Ezetimibe-statin combination therapy was well tolerated in all four studies, and no clinically relevant differences between the ezetimibe-statin and respective statin monotherapy groups were observed with regard to adverse events or discontinuation of therapy due to adverse events.[32,44,45,51] The safety profile of ezetimibe-statin was comparable to that of statin monotherapy, with an equally low frequency of elevated hepatic enzymes and creatine kinase in both groups.

Combination Therapy with Other Lipid-Lowering Agents. Other lipid-lowering agents may provide promising treatment options in conjunction with ezetimibe. In a small, randomized, placebo-controlled trial, ezetimibe was coadministered with fenofibrate in 32 patients with primary hypercholesterolemia (baseline LDL ≥ 130 mg/dl).[48,49] Patients were randomized to one of four treatment groups: ezetimibe 10 mg, fenofibrate 200 mg, ezetimibe 10 mg plus fenofibrate 200 mg, or placebo. The treatment period was 14 days. Coadministration of ezetimibe 10 mg-fenofibrate 200 mg caused a significant (p≤0.03) reduction in LDL levels (36.3%) compared with placebo (10.1%), fenofibrate alone (22.3%), and ezetimibe alone (13.5%).

Though HDL levels decreased in all four treatment groups, the ezetimibe-fenofibrate group had the smallest reduction (2.0%).[48,49] This group also had the largest reduction (32.4%) in triglyceride levels. Ezetimibe-fenofibrate was well tolerated, and adverse-event profiles were similar among the treatment groups. These results appear encouraging in light of previous attempts to lower LDL levels with combination fibrate-statin therapy that were limited by an increased risk of myopathy and rhabdomyolysis. Larger trials are warranted to confirm the results of this study.

Other potential future options for combination therapy may involve ezetimibe and niacin with or without a statin, and ezetimibe and bile acid resins. No clinical studies have evaluated the combination of ezetimibe and niacin. A small phase I study suggests a potential drug-drug interaction with cholestyramine,[17] but the more commonly prescribed colesevelam, which has fewer drug interactions, has not been studied in combination with ezetimibe.

The efficacy of ezetimibe added to atorvastatin was determined in a 14-week, randomized, double-blind study of 621 patients with documented CHD, at least two risk factors, or heterozygous familial hypercholesterolemia (HeFH), and uncontrolled LDL (≥ 130 mg/dl).[52,53] After a run-in period of at least 4 weeks of open-label therapy with atorvastatin 10 mg/day, patients were randomized to receive concomitant ezetimibe 10 mg/day or an additional 10 mg/day of atorvastatin. The atorvastatin dose was doubled at 4 and 9 weeks if LDL levels remained above 100 mg/dl, and a maximum of atorvastatin 40 and 80 mg/day was given in the combination and monotherapy groups, respectively. The proportion of patients reaching a target LDL goal of 100 mg/dl or less at 14 weeks was the primary end point; the percentage reduction in LDL at 4 weeks was the secondary end point.

At week 4, ezetimibe 10 mg plus atorvastatin 10 mg significantly lowered LDL levels compared with atorvastatin 20 mg (-22.8% vs -8.6%, p<0.01).[52] At 14 weeks, a significantly higher percentage of patients in the ezetimibe group (22%) than in the atorvastatin monotherapy group (7%) reached their LDL goal (p<0.01).[52] In a subgroup of 362 patients, all of whom had diagnosed HeFH, similar results were observed. At week 4, ezetimibe 10 mg-atorvastatin 10 mg caused greater LDL reductions (-23.6%) in patients with HeFH than the monotherapy atorvastatin dose doubled to 20 mg (-7.4%) (p<0.01).[53] The percentage of patients with HeFH who reached LDL goal in the coadministration group was almost 4-fold greater than in the atorvastatin monotherapy group (17% vs 4%, p<0.01). Ezetimibe coadministered with atorvastatin was well tolerated and had a safety profile similar to atorvastatin alone across all study groups.

These data suggest that LDL goal attainment is enhanced by ezetimibe in high-risk patients with CHD and HeFH.

The efficacy and safety of ezetimibe was assessed in 50 patients diagnosed with homozygous familial hypercholesterolemia (HoFH).[43] During the study's lead-in phase, all patients started consuming an NCEP step 1 (or stricter) diet while receiving open-label therapy with atorvastatin 40 mg/day or simvastatin 40 mg (statin 40). Half of these patients were undergoing LDL apheresis. After the lead-in phase, patients were assigned to one of the following treatment groups: atorvastatin or simvastatin 80 mg (statin 80), ezetimibe 10 mg plus statin 40 mg, or ezetimibe 10 mg plus statin 80. The intention-to-treat primary analysis compared the statin 80 group with the group receiving ezetimibe plus either 40- or 80-mg statin (ezetimibe-statin 40/80).

At the end of 12 weeks of treatment, calculated LDL levels were significantly lower in the ezetimibe-statin 40/80 group than in the statin 80 group (-21.4% vs -6.6%, p<0.01).[43] The proportion of patients whose LDL level decreased by 15% or more was significantly higher in patients receiving combination therapy than in those receiving statin monotherapy (p≤0.001). Reduced LDL levels were detected within 2 weeks of the start of therapy and were sustained throughout the 12-week treatment period. Similar effects were observed in 35 patients with genotype-confirmed HoFH. Reductions in total cholesterol were greater in patients receiving ezetimibe-statin 40/80 (-18.7%) than statin 80 alone (-5.3%, p<0.01). However, no significant changes occurred in other lipid parameters (HDL, triglycerides, apolipoprotein A-I and B).

Ezetimibe combination therapy was well tolerated, and no differences were observed between the frequency of adverse events and data from different safety tests (laboratory results, electrocardiogram, cardiopulmonary examination) in the ezetimibe-statin 40, ezetimibe-statin 80, and statin 80 groups.[43]

Homozygous sitosterolemia is an autosomal recessive disorder characterized by hyper-absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, premature development of atherosclerosis, and abnormal hematologic and liver function test results.[54,55,56] Elevated plasma plant sterol concentrations and progressive complications are common, emphasizing the need for more effective treatment.[56] Ezetimibe was studied for its potential to lower the high plant sterol levels observed in patients with homozygous sitosterolemia since this agent inhibits intestinal absorption of cholesterol, campesterol, and sitosterol in humans.[15]

In an 8-week, multicenter, double-blind, placebo-controlled trial of 37 patients with homozygous sitosterolemia, ezetimibe 10 mg/day significantly reduced plasma sitosterol concentrations compared with placebo (-21% vs 4% reduction, between-treatment difference 25%, p<0.0001).[56] Plasma campesterol concentrations were also lower after ezetimibe therapy compared with placebo (-24.3% vs 3.2%, p<0.001). Ezetimibe was well tolerated except for reversible mild gastrointestinal adverse events. Plant sterol levels continued to fall throughout the 8-week therapy period. Thus, further trials are needed to determine the optimal sterol-lowering effects and potential of ezetimibe for preventing cardiovascular disease in these patients.


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