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posted Nov 24, 2009, 1:03 AM by 藥物教育資源中心DERC

(Originally posted on 2004-11-11)

Ezetimibe: a new agent for the treatment of hypercholesterolaemia

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the principal agents for managing hyperlipidaemia. They act by inhibiting cholesterol production in the liver leading to a reduction in low-density lipoprotein (LDL) cholesterol and triglyceride levels, increasing high-density lipoprotein (HDL) cholesterol levels slightly and thus help to decrease the risk of coronary heart disease. Despite their established efficacy, not all patients achieve the recommended LDL cholesterol goals. Inadequate dosing due to adverse effects with high-dose, increased potential for intolerance and drug interactions with combinations of other available agents like bile acid sequestrants, fibric acid derivatives and nicotinic acid are all possible contributing factors. In addition, available statins have only modest effects on HDL. Thus, new lipid-lowering agents are needed for better clinical efficacy.

Mechanism of Action and Interactions

Ezetimibe (Ezetrol) is the first of a new class of antihyperlipidaemic agents, the selective cholesterol-absorption inhibitors. It acts by inhibiting the absorption of dietary and biliary cholesterol at the brush border of the small intestine without affecting the absorption of bile acids, fatty acids, fat soluble vitamins or triglycerides. Through inhibition of cholesterol absorption, Ezetimibe also reduce plant sterol absorption. The drug is rapidly absorbed, extensively conjugated to glucuronide in the intestine, and excreted primarily in the stool. Ezetimibe and /or its glucuronide circulate enterohepatically delivering the agent back to the intestine repeatedly. Therefore, systemic exposure is much reduced.

Ezetimibe is recommended for the treatment of Primary Hypercholesterolaemia, either in combination with statins or as monotherapy (if statins are not tolerated). It is also used for the treatment of Homozygous Familial Hypercholesterolaemia in conjunction with statins and as adjunctive therapy to diet in the treatment of Homozygous Sitosterolaemia (Phytosterolaemia). Familial Hypercholesterolaemia is caused by a mutation in the gene which codes for the receptors for LDL cholesterol. This result in absent or defective LDL receptors responsible for the clearance of LDL, and consequently in increased levels of plasma LDL. The homozygous form of the disorder results in very high concentration of cholesterol in the blood. These patients have a lower response rate to available pharmacological therapies than patients with the heterozygous form of the disease. Sitosterolaemia (Phytosterolaemia) is another genetic disorder which can cause hypercholesterolaemia through increased absorption of cholesterol and plant sterols from the gut.

Clinical Efficacy

In a multi-centre, randomized, double-blind, placebo-controlled trial involving 892 patients with Primary Hypercholesterolaemia, a 12-week course of monotherapy with Ezetimibe reduces concentration of LDL cholesterol by approximately 17% compared with an increase of 0.4% in the placebo group. The mean percentage increase in HDL cholesterol was 1.3% with Ezetimibe versus a decrease of 1.6% with placebo.

As patients with hypercholesterolaemia are often treated with an HMG-CoA reductase inhibitor, Ezetimibe has been studied in combination with these statins. In a study of 50 patients with Homozygous Familial Hypercholesterolaemia, 12 weeks of treatment with Ezetimibe and either Atorvastatin or Simvastatin had greater efficacy than statin therapy alone. Combined treatment reduced LDL cholesterol by 20.7% while high-dose (80mg/day) statin therapy reduced it by 6.7%. In a double-blind, multi-centre trial, an 8 week course of adding Ezetimibe to the treatment regimen of 37 patients with Homozygous Sitosterolaemia lowered their sitosterol concentration by 21% and their campesterol concentration by 24%.

Dosage and Precautions

The recommended dose of Ezetimibe is 10mg once daily. No dosage adjustments are required in geriatrics or in patients with renal impairment. It can be administered at any time of the day, with or without food. The drug was shown to be generally well tolerated. Adverse reactions are usually mild and transient. The overall incidence of side effects reported was similar to that reported with placebo. Although 5% of patients treated with Ezetimibe complain of myalgia, there are currently no reports of rhabdomyolysis. Other adverse effects include abdominal pain, arthralgia, back pain, cough, diarrhoea, fatigue, headache and sinusitis. Due to its minimal systemic absorption, drug interactions are few. However, caution is needed when prescribing Ezetimibe to patients who are being treated with a bile acid binding resin such as cholestyramine. These drugs interact resulting in reduced concentration of Ezetimibe. If such combination is used, Ezetimibe should be given two hours before or four hours after the bile acid sequestrants. Combined therapy with fibrates is not recommended because the safety and efficacy of the co-administration has not been established. When Ezetimibe is combined with a statin patient's liver enzyme should be checked. In patients with altered liver function, this combination is contraindicated.


Ezetimibe is a new cholesterol absorption inhibitor shown to be a safe and effective addition to the current LDL cholesterol lowering regimen. It is most useful in those patients who cannot tolerate statin or are at risk of statin interaction. The co-administration of statins (inhibiting cholesterol synthesis) and Ezetimibe (inhibiting cholesterol absorption) offers a new therapeutic option for patients with severe hypercholesterolaemia or patients who do not reach the defined treatment goals under therapy with statins alone.


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