Pharmacology Update

Ezetimibe (Zetia—Schering): A New Cholesterol-Lowering Medication

The FDA has approved the first drug in a new class of cholesterol-lowering medications. Ezetimibe works by inhibiting the absorption of cholesterol by the small intestines and is approved for monotherapy or for use in combination with a statin. Ezetimibe will be marketed jointly by Merck and Schering-Plough under the trade name Zetia.


Ezetimibe is indicated (as monotherapy or in combination with HMG CoA reductase inhibitors) as adjunctive therapy to diet for the reduction of elevated total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B in patients with primary hypercholesterolemia. Ezetimibe is indicated in combination with atorvastatin or simvastatin in the treatment of patients with homozygous familial hypercholesterolemia. It is also indicated for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.1


The recommended dose is 10 mg once daily. It may be taken without regard to meals. Dosage adjustment is not required in patients with mild hepatic dysfunction, renal dysfunction, or in geriatric patients.1 It may be taken the same time as the HMG CoA reductase inhibitor (statin), as no significant pharmacokinetic interactions have been seen with currently marketed statins.1

Ezetimibe is available as 10-mg tablets.

Potential Advantage

Ezetimibe provides a cholesterol-lowering drug with an entirely different mechanism than currently available medications. It and/or its phenolic glucuronide acts on the brush borders of the small intestines by inhibiting the uptake of dietary and biliary cholesterol.2 Ezetimibe can effectively be combined with a statin such as atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia.1,4

Potential Disadvantages

In clinical studies, the incidence of consecutive elevations of liver enzymes (3 × ULN) was higher in combined therapy with a statin than with statin therapy alone (1.3% compared to 0.4%).1 The long-term safety and effectiveness is not known as controlled clinical trials were only up to 12 weeks in duration. The efficacy and safety of ezetimibe in non-Caucasians is not known, as the clinical evidence in this population is very limited. The safety and efficacy of concomitant use of ezetimibe and fibrates have not been established. Fenofibrate and gemfibrozil have been shown to increase ezetimibe concentration by 1.5- and 1.7-fold, respectively. In addition, the combination may increase the risk of cholelithiasis.1 Cholestyramine decreases the absorption of ezetimibe by 55%. Ezetimibe should be dosed at least 2 hours before or 4 hours or more after administration of a bile sequestering agent.1 One renal transplant patient had a 12-fold increase in ezetimibe level while on cyclosporine and other medications.1


Ezetimibe is a new cholesterol-lowering drug with an entirely new mechanism. It acts at the brush border of the small intestine, inhibiting the absorption of dietary and biliary cholesterol. The drug’s labeling is mainly based on 2 12-week, double-blind, placebo-controlled studies in 1719 patients with primary hypercholesterolemia and an 8-week study in 769 patients with coronary risk factors currently receiving statin monotherapy but have not at target LDL-C goal. As monotherapy, ezetimibe has been shown in placebo-controlled 12-week studies to produce mean reduction of total cholesterol of approximately 13%, LDL cholesterol by 18%, apolipoprotein B by 16% and triglycerides by 8%.1,2 Cholesterol reduction is similar to that achieved with a low dose statin (eg, lovastatin 10 mg, pravastatin 10 mg). The effect is seen as early as 2 weeks. In combination therapy with a statin, an additional reduction in LDL-C of 7-19% was achieved.1 The greater additive effect generally occurred with the lower doses of the statin and decreased as the dose of the statin increases.1 The drug also lowers triglycerides and raises HDL-cholesterol, but these effects are generally modest to minimal.1,5,6 Ezetimibe appeared to be well tolerated based on clinical trial data. The incidence of elevated liver enzymes may be higher when ezetimibe is combined with a statin but the combination does not appear to increase the rate of elevated creatine kinase.1 Long-term safety and efficacy has not been established. The wholesale cost of ezetimibe is $1.93 per day, which is similar to the cost of simvastatin 20 mg or atorvastatin 10 mg.

Clinical Implications

Statins are currently the most effective drugs for the lowering of total cholesterol, LDL-cholesterol, and non-HDL cholesterol. These drugs have demonstrated efficacy in primary and secondary prevention of coronary events and death.7-11 They are and should remain the first-line drugs. When lipid targets cannot be achieved with dose titration or use of a statin is limited by tolerance, other drugs, such as niacin or bile sequestering agents, are added to the regimen. The approval of ezetimibe provides an agent with a different mechanism of action to use as a complement to the action of a statin.


1. Zetia Product Information. Schering Corporation. October 2002.

2. Dujovne CA, et al. Am J Cardiol. 2002;90(10):1092-1097.

3. Sudhop T, et al. Circulation. 2002;106:1943-1948.

4. Gagne C, et al. Circulation. 2002;105:2469-7245.

5. Bays HE, et al. Clin Ther. 201;23:1209-1229.

6. Kosoglou T, et al. Br J Clin Pharmacol. 2002;54:309-319.

7. Shephard J, et al. N Engl J Med. 1995;333:1301-1307.

8. Downs JR, et al. JAMA. 1998;279:1615-1622.

9. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.

10. Sacks, et al. N Engl J Med. 1996;335:1001-1009.

11. LIPID Study Group. N Engl J Med. 1998;339:1349-1357.