Synopsis: Ezetimibe (Zetia) is a novel, selective cholesterol absorption inhibitor. Ezetimibe blocks the absorption of dietary and biliary cholesterol within the brush-border enzyme system of the small intestine. Ezetimibe does not appear to alter or decrease the absorption of bile acids, fatty acids, fat-soluble vitamins, or triglycerides. It is labeled for use in the treatment of primary hypercholesterolemia, either as monotherapy or in combination with statins. It also is labeled for the treatment of homozygous familial hypercholesterolemia in conjunction with statins and as adjunctive therapy to diet in the treatment of homozygous sitosterolemia (a rare, inherited, plant sterol storage disease).

Safety: Ezetimibe has been studied alone and in combination with statins. To date, there have been no case reports of rhabdomyolysis. The rate of asymptomatic increases in liver transaminase levels was slightly higher in combination-treated patients, compared with those receiving a statin alone. Research to date has lasted only 12 weeks, and long-term safety data are lacking. Ezetimibe has been associated with birth defects in animals but has not been evaluated in pregnant women. It is classified FDA category C for use during pregnancy.

Tolerability: Ezetimibe appears to be well tolerated, with a side effect profile comparable to placebo. Fatigue, diarrhea, and abdominal pain were the most frequently reported side effects, but they occurred in less than 5 percent of patients. Arthralgias, back pain, and myalgias were more common when ezetimibe was given together with a statin than when used alone. In pre-marketing studies, pooled dropout rates because of adverse effects, when used alone or with a statin, were less than 5 percent and were similar to the rate in patients who received placebo.^1–5

Effectiveness: Given as monotherapy, ezetimibe reduces low-density lipoprotein (LDL) cholesterol levels by an average of 18 percent from baseline across four efficacy and safety studies (range of LDL reduction: 15 to 25 percent). Ezetimibe produces an additional effect when used in conjunction with a statin. A combined regimen of 10 mg of ezetimibe once daily plus 10 mg of simvastatin or lovastatin given once daily lowers LDL cholesterol levels to a similar extent as the maximum dose of either statin given alone.^1,2

The use of ezetimibe has not been studied in combination with fibrates. It also has not been studied to determine whether it affects patient-oriented outcomes such as death, cerebrovascular disease, or cardiovascular disease. Ezetimibe has been studied only in patients with primary hypercholesterolemia and few other comorbidities. There are no studies available examining the use of ezetimibe in patients with New York Heart Association Class III or IV heart failure, unstable or severe peripheral vascular disease, preexisting cardiovascular disease, new-onset or uncontrolled diabetes mellitus, active hepatic or renal disease, coagulopathies, or unstable endocrine disease.

Price: Ezetimibe retails for approximately $70 per month. Simvastatin is $115 at a dose of 20 mg, and for approximately $120 per month at its maximum dose of 80 mg. The cost of combined therapy of simvastatin 10 mg plus ezetimibe 10 mg will cost patients an additional $250 annually, compared with the annual cost of 80-mg simvastatin.

Simplicity: The recommended dosage of ezetimibe is 10 mg once daily, given with or without food. Ezetimibe may be used as monotherapy or in conjunction with statins. If ezetimibe is used with bile acid sequestrants, it should be given two hours before or four hours after the sequestrant. Ezetimibe should not be used in patients with moderate or severe hepatic disease. No dosage adjustments are necessary for geriatric patients, patients with renal insufficiency, or patients with mild hepatic dysfunction. Ezetimibe may be used in children 10 years and older. There is no known effect on the absorption of other medications.

Bottom line: Ezetimibe is safe and effective for lowering LDL cholesterol and triglyceride levels, but has not been shown to affect patient-oriented outcomes. It can be used as monotherapy or in combination with a low-dose statin, although the combination is more expensive than the maximum dose of the statin. Ezetimibe is reasonable adjunct therapy for patients who have not reached LDL goals on maximum statin dosage or who cannot tolerate maximum doses of statins. Ezetimibe also is an acceptable treatment option for patients with hyperlipidemia who are intolerant of statins, as long as they understand that there is no proven benefit regarding clinical outcomes.