Zetia (Ezetimibe, SCH-58235)

Pharmacy Times
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According to the American Heart Association, approximately 103 million American adults have a total cholesterol level of >200 mg/dL. Furthermore, 41 million American adults have a total cholesterol level of >240 mg/dL.1 Meta-analysis of various primary and secondary prevention studies has shown that, for every 10% reduction of total serum cholesterol, coronary artery disease mortality is reduced by 15%.2 Currently, HMG-CoA reductase inhibitors (statins) are the primary pharmacologic treatment for hypercholesterolemia. The West of Scotland Coronary Prevention Study (WOSCOPS) and the Cholesterol and Recurrent Events (CARE) study both demonstrated the use of statins for primary and secondary prevention for the reduction in coronary artery occurrences.2 Yet, cholesterol levels in some patients are not controlled despite achieving a ceiling statin dose. In addition, risk of liver toxicity increases as statin doses are increased. Consequently, researchers have investigated other lipid-lowering agents in an effort to better achieve the National Education Cholesterol Program-Adult Treatment Panel III (NCEP-ATP III) goals.3 Recently approved by the FDA, Zetia, manufactured by Merck/Scher-ing-Plough Pharmaceuticals, is the first agent of a new class used to treat hyperlipidemia.

PharmacologyZetia selectively inhibits absorption of cholesterol at the brush border of the small intestine.4 This action results in decreased cholesterol delivery to the liver. Zetia is metabolized in the liver by glucuronide conjugation and is renally excreted. It has a half-life of approximately 22 hours.Clinical Trials

A multicenter, randomized, double-blind, placebo-controlled trial conducted by Dujovne and colleagues evaluated the efficacy and safety of Zetia in 892 patients with primary hypercholesterolemia. Patients with low-density lipoprotein cholesterol (LDL-C) between 130 and 250 mg/dL and triglycerides <350 mg/dL were randomized to receive (3:1 ratio) Zetia 10 mg or placebo orally each morning for 12 weeks following >2 weeks on the NCEP step 1 or stricter diet, and a 4- to 8-week, single-blind, placebo run-in phase. The primary end point was a reduction in percentage of direct plasma LDL-C from the baseline. Results showed a 16.9% reduction of LDL-C from baseline to end point in the Zetia 10-mg group, compared with an increase of 0.4% in LDL-C (P<.01) in the placebo group. In as early as 2 weeks, patients receiving active Zetia 10 mg showed a reduction of LDL-C, which was maintained throughout the 12-week treatment period.5 A randomized, double-blind, placebo-controlled study conducted by Gagne and colleagues examined the efficacy and safety of Zetia plus ongoing statin therapy in 769 patients with primary hypercholesterolemia. Study participants were currently taking a stable dose of daily statins for 6 weeks or longer and had not achieved the NCEP-ATP II goals with diet and statin therapy alone. Efforts were made to equally distribute treatment among the 3 different statin groups, in which 1/3 took simvastatin, 1/3 took atorvastatin, and the other 1/3 took all other statins (lovastatin, pravastatin, fluvastatin, and cervastatin). Patients were randomized to orally receive (1:1 ratio) Zetia 10 mg daily or matching placebo. At 8 weeks, the results showed that patients in the treatment group (Zetia 10 mg daily plus ongoing statin therapy) experienced a 25.1% reduction in LDL-C, compared with a 3.7% LDL-C reduction in the placebo plus statin group (P<.001).6Safety

Because liver function tests are not required when Zetia is used alone, patients with active liver disease or persistent elevations in transaminases should not take Zetia in combination with other HMG-CoA reductase inhibitors. Additionally, due to lack of appropriate safety information, women who are pregnant, women who are nursing, and patients taking fibrates should avoid Zetia until future information warrants its use in these situations.7


The initial recommended dose of Zetia is 10 mg once a day alone or in combination with other statins.4 Zetia may find its role in monotherapy in patients with a contraindication to statin therapy, at risk for potential drug-to-drug interaction, or in statin failure. The clinical role of combination therapy with statins may be evident in patients who fail to achieve NCEP-ATP III goals.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. D. Campagnola, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: dcampagnola@mwc.com.

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