Ezetimibe (Zetia™)

Volume VI, Number 2 | March/April 2003
Bernadette A. Clark, Pharm. D. Candidate

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A new lipid lowering agent, ezetimibe (Zetia™; Merck/Schering Plough Pharmaceuticals), was recently approved by the Food and Drug Administration (FDA). It is indicated as 1) monotherapy or in combination with HMG-CoA Reductase Inhibitors (statins) for primary hypercholesterolemia, 2) for homozygous sitosterolemia, and 3) in combination with atorvastatin  (Lipitor®) or simvastatin (Zocor®) for homozygous familial hypercholesterolemia. Ezetimibe has a unique mechanism of action compared to other classes of lipid-lowering agents. It inhibits the absorption of dietary and biliary cholesterol decreasing the intestinal absorption by 54%. Ezetimibe does not, however, affect triglyceride absorption.

The recent cholesterol lowering guidelines, published by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), have low-density lipoprotein (LDL) goals lower than previously recommended (See Table 1). Reaching these new goals may be difficult in some patients when using the existing lipid-lowering agents; therefore, combination therapy may be needed.

Statins are currently recommended as part of the management for hypercholesterolemia. Combining statins with other available lipid-lowering drugs (e.g., fibrates, niacin, and bile acid sequestrants) to reach target goals, may lead to an increase in adverse effects or intolerable side effects. Now, however, ezetimibe is a safe and effective alternative that may be used alone or in combination with statins to reduce LDL levels to the recommended goal.

Table 1. NCEP ATP III Guidelines
Risk Category* LDL goal(mg/dL) Initiate TLCs† (mg/dL) Consider drug therapy (mg/dL)
CHD or CHD equivalents <100 > 100 > 130
2+ Risk factors <130 > 130 10 year risk‡ 10-20% > 130
0-1 Risk factor <160 > 160 > 190

Adapted from: 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(19); 2486-2536
CHD= Coronary Heart Disease
* Risk factors are described in the NCEP ATP III guidelines and consider age, smoking status, family history and HDL level.
Therapeutic Lifestyle Changes (TLC) as described in the NCEP ATP-III guidelines
‡Risk determined by Framingham scoring

Pharmacology and Pharmacokinetics

Bile acid sequestrants (e.g., cholestyramine) bind bile acids inhibiting their reabsorbtion. In turn, to produce more bile acids, the liver breaks down cholesterol. Similar to bile acid sequestrants, ezetimibe also acts in the small intestine. After oral administration, it is glucuronidated to an active metabolite (ezetimibe glucuronide), travels through the portal vessels to the bile, and is then brought back to the small intestine via enterohepatic recycling. When food is ingested, ezetimibe is excreted with the bile and acts at the brush border of the small intestine to inhibit the uptake of dietary and biliary cholesterol into the enterocytes. Furthermore, there is no inhibition of cholesterol synthesis in the liver or increase in bile acid secretion.

The exact half-life of ezetimibe has yet to be determined; however, in the product labeling, the half-life of both ezetimibe and its active metabolite is listed as approximately 22 hours. It is excreted primarily in the feces (78%). Due to unknown effects of increased exposure, ezetimibe is not recommended in patients with moderate-to-severe hepatic insufficiency. Currently, no dosage adjustment is necessary in renal insufficiency.

Selected Clinical Trials

Sudhop and colleagues conducted a randomized, double-blind, placebo-controlled, 2-period, crossover trial evaluating ezetimibe monotherapy (Circulation 2002;106:1943-8). Clinic patients (n=18) with mild-to-moderate hypercholesterolemia were administered placebo for a 2-week run-in period. Then, the patients were randomized to treatment group 1 or 2. Treatment group 1 received ezetimibe 10 mg daily for 2 weeks, followed by a 2-week washout period, and then received placebo for 2 weeks. Treatment group 2 received placebo for 2 weeks, followed by a 2-week washout period, and then received ezetimibe 10 mg daily for 2 weeks. The primary efficacy endpoint was the effect of ezetimibe on the intestinal absorption of cholesterol. Secondary endpoints included cholesterol synthesis, sterol excretion, and plasma concentrations of cholesterol and non-cholesterol sterols. Inclusion criteria for the trial were the following: 18 to 55 years of age, body mass index (BMI) between 19 and 30 kg/m2, LDL cholesterol concentrations > 130 mg/dL but < 180mg/dL, triglyceride (TG) concentrations below 250 mg/dL, and dietary cholesterol intake between 200 and 500 mg/day. Patients were excluded from the study if they received lipid-lowering drugs within 6 weeks of study entry, had a history of excessive alcohol intake, had diabetes or other endocrine disorders, had a history of hepatic disease, or gastrointestinal tract dysfunction or renal dysfunction.

Of the 18 patients enrolled, all participants were male with a mean age of 25.8 years (range: 24 to 58 years) and a mean body weight of 85 kg (range: 66 to 105 kg). For the primary efficacy endpoint, ezetimibe decreased intestinal cholesterol absorption by 54% (p<0.001). A compensatory increase in cholesterol synthesis of 89% was found to be significant with ezetimibe (1763 mg/day ± 1098) compared to placebo (931 mg/day ± 1027; p<0.001). After 2 weeks of receiving ezetimibe, the mean percent change from baseline in all patients for LDL (baseline mean: 142 mg/dL) and total cholesterol (baseline mean: 220 mg/dL) was -20.4% and -15.1%, respectively (p<0.001). Comparing ezetimibe to placebo after the 2-week period, there was a -22.3% change in LDL as well as a -13.2% change in total cholesterol (p<0.001). However, there was not a significant change in high-density lipoprotein (HDL) or triglycerides for ezetimibe as compared to placebo at the end of the 2-week period. Ezetimibe therapy was well tolerated with no serious adverse effects or critical laboratory elevations during treatment. In addition, there were no elevations of aspartate or alanine aminotranferase (AST and ALT) of three times greater than the upper limit of normal, and there were no elevations of creatinine phosphokinase (CPK) 10 times the upper limit of normal. The authors concluded that ezetimibe monotherapy in patients with mild-to-moderate hypercholesteremia is effective in reducing the intestinal absorption of cholesterol by 54%. Reductions in the total cholesterol and LDL concentrations were also associated with ezetimibe treatment.

In the Journal of the American College of Cardiology, Davidson and colleagues published a multicenter, placebo-controlled study evaluating the use of ezetimibe in combination with simvastatin in patients (n= 668) with primary hypercholesterolemia. The design of the trial was a 2 X 5 factorial which consisted of a 2- to 12-week pre-treatment washout phase, a 4-week lead-in placebo phase, and a 12-week treatment phase.

The treatment groups were the following: 1) ezetimibe 10 mg monotherapy, 2) ezetimibe 10 mg in combination with simvastatin 10-, 20-, 40- or 80-mg, 3) simvastatin 10-, 20-, 40- or 80-mg monotherapy, and 4) placebo. The objective of the trial was to determine if the co-administration of ezetimibe and simvastatin (pooled doses, n= 274) produced incremental reductions in LDL while maintaining a safety profile similar to simvastatin monotherapy (pooled doses, n=263). Secondary objectives were to evaluate changes in other lipid profile variables. Patients were included if they were at least 18 years of age and had primary hypercholesterolemia (defined as LDL > 145 mg/dL but £250 mg/dL) as well as TG < 350 mg/dL. Patients were excluded if they exhibited congestive heart failure, uncontrolled cardiac arrhythmias, history of unstable or severe peripheral artery disease within 3 months of study entry, unstable angina pectoris, myocardial infarction, coronary bypass surgery or angioplasty within six months of study entry, uncontrolled or newly diagnosed diabetes mellitus, active or chronic hepatic or hepatobiliary disease, known impairment of renal function, known coagulopathy or unstable endocrine disease. Study results were based on an intent-to-treat analysis. For the primary objective, when added to simvastatin, ezetimibe improved LDL significantly compared to simvastatin monotherapy. More specifically, the co-administration of ezetimibe and simvastatin (mean baseline direct LDL: 176.3 mg/dL) and the use of simvastatin monotherapy (mean baseline in direct LDL: 178.5 mg/dL) had a mean change in direct LDL of -49.9% and -36.1%, respectively (p<0.01). Furthermore, the co-administration was more effective than ezetimibe monotherapy, with the mean change in direct LDL from baseline of -49.9% and -18.1%, respectively (p<0.01). At the treatment endpoint, 77% (207/268) of the ezetimibe/simvastatin-treated patients were below the NCEP ATP III Guidelines target LDL levels as compared to 64% (167/261) of the simvastatin monotherapy-treated patients. Overall, when ezetimibe was added to simvastatin, there was an additional 13.8% decrease in LDL. Ezetimibe was also well tolerated. There was no incidence of elevated AST, ALT, or CPK reported. Two patients in the simvastatin monotherapy-treated group (on 20- and 40-mg doses) had elevations in CPK > 10 times the upper limit of normal (n=1 with associated muscle symptoms). Asymptomatic elevations of AST and ALT were seen in eight patients (n=6 co-administration arm and n=2 simvastatin monotherapy). The authors concluded that ezetimibe was well tolerated and possesses a safety profile similar to simvastatin and placebo.

Adverse Drug Reactions

Overall, ezetimibe is well tolerated. When used as monotherapy, the most commonly reported adverse effect is back pain (4.1%). In the majority of the studies, the adverse effects associated with ezetimibe were similar to placebo. Additionally, when it is used in combination with a statin, ezetimibe has a side effect profile similar to statin monotherapy. When ezetimibe was administered with a statin, there was a slight increase in the incidence of elevated transaminases compared to statin monotherapy.

Drug-Drug Interactions

Ezetimibe does not appear to affect the absorption of triglycerides or fat-soluble vitamins. It is not a substrate for the cytochrome (CY) P450 1A2, 2D6, 2C8/9, or 3A4, and has not been shown to induce or inhibit any of the CYP450 enzymes. Additionally, ezetimibe has no interaction with common medications that are metabolized via the CYP450 system [e.g., warfarin (Coumadin®), digoxin (Lanoxin®), cimetidine (Tagamet®), glipizide (Glucotrol®)]. It also does not have an effect on the statin bioavailability. Since cholestyramine (Questran®) decreases the area-under-the-curve (AUC) of ezetimibe by 80%, it is recommended to administer ezetimibe 2 hours before or 4 hours after the bile-acid binding resin. Finally, cyclosporine (Neoral®; Sandimmune®) and gemfibrozil (Lopid®)) may increase ezetimibe concentrations and close monitoring is recommended.

Pregnancy and Lactation

Ezetimibe is classified as pregnancy-risk category C which is defined as either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects or other) and there are no controlled studies in women, or studies in women and animals are not available. Therefore, drugs should be given only if the potential benefits justify the potential risk to the fetus. Ezetimibe has been studied in pregnant rabbits and rats, but there is no adequate data for use in pregnant women. It has also been studied in nursing rats, but it is not known whether ezetimibe is excreted into human breast milk. Therefore, ezetimibe should not be used in nursing mothers unless the benefit clearly outweighs the risk.

Monitoring Parameters

As stated previously, the adverse effects associated with ezetimibe are minimal. However, when used in combination with a statin, the incidence of elevated liver function tests (LFTs) may increase slightly. Therefore, when using ezetimibe with a statin, LFTs should be performed at the initiation of therapy and then as recommended for the statins. According to the NCEP ATP III Guidelines for monitoring statins, 1) baseline measurements should include LFTs (e.g., AST and ALT) and a CPK, 2) follow-up appointments should evaluate muscle symptoms and CPK, and 3) AST and ALT should be evaluated 12 weeks after initiation of therapy and then, annually, or more frequently, if needed. A cholesterol panel should be drawn to monitor the effectiveness of ezetimibe therapy.

Dosage and Administration

Ezetimibe is commercially available as 10 mg tablets. The recommended dose of ezetimibe is 10 mg administered by mouth once daily. It may be taken with or without food, and when using ezetimibe as an adjunct to statin therapy, it may be taken at the same time as the statin. The Average Wholesale Price (AWP) for 10 mg ezetimibe is $2.35 for each tablet, while 30 tablets is $70.64.


Ezetimibe is a therapeutically beneficial drug that works by a unique mechanism and differs from traditional lipid lowering therapies. Ezetimibe may be used alone or in combination with statins for lowering lipids. However, statins as monotherapy are more effective in lowering lipid levels than ezetimibe monotherapy. As monotherapy, ezetimibe is well tolerated having adverse effects similar to those seen with placebo. It is well known that the adverse effects associated with statins, such as myopathy, rhabdomyolysis and elevated LFTs are dose dependent. Ezetimibe may be used with a statin to increase lipid lowering without increasing the chance for adverse effects.

References Available Upon Request

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Copyright © 2000-2017 The Cleveland Clinic Foundation. All Rights Reserved.
Center for Continuing Education | 1950 Richmond Road, TR204, Lyndhurst, OH 44124