Ezetimibe
Selective Cholesterol Absorption Inhibitor for LDL Reduction
Ezetimibe is an oral lipid-lowering agent that selectively inhibits intestinal cholesterol absorption. As the first representative of a new class of drugs, the cholesterol absorption inhibitors, ezetimibe complements statin therapy and enables additional LDL reduction through a completely different mechanism. The compound is available as a monotherapy and in fixed combinations with simvastatin (Inegy) or atorvastatin.
Ezetimibe was first approved in 2002 and is an established therapeutic agent in the treatment of primary hypercholesterolaemia and homozygous familial hypercholesterolaemia. The IMPROVE-IT trial (2015) was the first to demonstrate a cardiovascular benefit of the ezetimibe-statin combination over statin monotherapy.
Mechanism of Action
Ezetimibe selectively inhibits the transport protein NPC1L1 (Niemann-Pick C1 Like 1), which is located at the brush border of the small intestinal epithelium and is responsible for the uptake of cholesterol from the intestinal contents into the enterocytes. By blocking this transporter, ezetimibe inhibits the absorption of both dietary cholesterol and biliary cholesterol from the enterohepatic cycle.
Because less cholesterol is absorbed from the gut, the liver compensatorily upregulates LDL receptor expression on its surface. This leads to enhanced uptake of LDL cholesterol from the blood into hepatocytes. The resulting LDL reduction in monotherapy averages 15 to 20 percent. In combination with a statin, which inhibits hepatic cholesterol synthesis, additive effects are achieved: total LDL reduction is 50 to 60 percent.
Ezetimibe does not affect the absorption of fat-soluble vitamins (A, D, E, K), bile acids or other dietary lipids because it acts specifically on NPC1L1.
Indications
- Primary hypercholesterolaemia: As an adjunct to statin therapy when the LDL target is not achieved with a statin alone
- Statin intolerance: As monotherapy in patients who cannot tolerate statins (restricted indication)
- Homozygous familial hypercholesterolaemia (HoFH): In combination with statins as part of an intensified lipid-lowering regimen
- Homozygous phytosterolaemia (sitosterolaemia): To reduce elevated phytosterol levels
- Cardiovascular prevention: In high-risk patients (post-ACS, CAD, stroke) for further LDL reduction during ongoing statin therapy
Dosage and Administration
The recommended daily dose of ezetimibe is 10 mg once daily. The dose may be taken at any time of day, independently of meals. Ezetimibe may be taken simultaneously with or at any time relative to a statin, as there are no clinically meaningful pharmacokinetic interactions.
No dose adjustment is required in mild to moderate renal insufficiency. In severe hepatic insufficiency (Child-Pugh C), ezetimibe is contraindicated. In moderate hepatic insufficiency, use should be carefully considered. Ezetimibe is approved for children aged 10 years and above with familial hypercholesterolaemia.
Side Effects
Ezetimibe is generally well tolerated. Common side effects (1 to 10 percent) include headache, abdominal pain, diarrhoea and flatulence. Elevations in liver enzymes (ALT, AST) have been observed in clinical studies, particularly in combination with statins. Regular monitoring of liver values is recommended.
Muscle pain (myalgia) can occur with ezetimibe alone or in combination with statins. Severe myopathy or rhabdomyolysis is rare but has been described in case reports. If unexplained muscle pain or elevated CK levels occur, therapy should be discontinued. Allergic reactions such as rash or angioedema are rare but possible.
Drug Interactions
Cholestyramine and other bile acid sequestrants can markedly reduce the absorption of ezetimibe (reduction in AUC of up to 55 percent). Ezetimibe should therefore be taken at least 2 hours before or 4 hours after a bile acid sequestrant. Ciclosporin considerably increases ezetimibe exposure and requires close monitoring.
Concomitant use of fibrates (e.g. fenofibrate, gemfibrozil) may increase the excretion of cholesterol into bile and raise the risk of gallstone formation. Fibrate combinations are therefore not routinely recommended. When oral anticoagulants are taken concurrently, close INR monitoring is appropriate.
Special Notes
Ezetimibe is contraindicated during pregnancy and breastfeeding. Because the foetus relies on cholesterol for its development and statins are teratogenic, the entire lipid-lowering regimen should be discontinued in women of childbearing age before a planned pregnancy. Women of childbearing age should use a reliable method of contraception.
Before starting ezetimibe therapy and at regular intervals thereafter, liver values and lipid status should be monitored. A diet aimed at reducing cholesterol and saturated fatty acids should be continued alongside drug therapy.
Frequently Asked Questions
How does ezetimibe differ from statins?
Statins inhibit the body's own cholesterol synthesis in the liver by blocking the enzyme HMG-CoA reductase. Ezetimibe acts in the intestine and prevents the absorption of cholesterol from food and bile. Both mechanisms are complementary and in combination achieve a greater LDL reduction than either agent alone.
Can ezetimibe be taken alone if I cannot tolerate statins?
Yes, in documented statin intolerance, ezetimibe may be used as monotherapy. The LDL reduction is, however, lower than under statin therapy. For high-risk patients, alternative lipid-lowering therapies (e.g. PCSK9 inhibitors) may need to be considered.
Do I need to follow a special diet while taking ezetimibe?
Ezetimibe does not replace a low-cholesterol diet but complements it. A diet with reduced saturated fatty acids and cholesterol remains the foundation of any lipid-lowering therapy. Healthy eating supports the effect of medication.
How quickly does ezetimibe take effect?
The LDL-lowering effect of ezetimibe is measurable after 2 weeks. The full effect is achieved after approximately 4 to 6 weeks. A first lipid check after 4 to 6 weeks is advisable to assess efficacy and initiate further measures if necessary.
References and Further Information
- Summary of Product Characteristics for Ezetrol (current version, MSD Sharp & Dohme)
- ESC/EAS Guidelines for the Management of Dyslipidaemias (2019, 2024)
- IMPROVE-IT Trial: Cannon et al., N Engl J Med 2015
- National Care Guideline Chronic Coronary Heart Disease (AWMF)
- Federal Institute for Drugs and Medical Devices (BfArM)