Ezetimibe, also known as Zetia, is a dyslipidemic agent used to treat people with hyperlipidemia. It was FDA-approved in 2002. Ezetimibe is an inhibitor of intestinal cholesterol absorption and is indicated in reducing total cholesterol, low-density lipoprotein (LDL), apolipoprotein B (apo B), and non-high-density lipoprotein (HDL) in patients with primary hyperlipidemia, mixed hyperlipidemia, familial hypercholesterolemia (HoFH), and homozygous sitosterolemia (phytosterolemia). Clinicians can use ezetimibe as monotherapy, in combination with fenofibrate, or with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. There is a commercially marketed combination agent made up of ezetimibe and simvastatin that has been available since 2002. There is also another combination agent made up of atorvastatin and ezetimibe that has been on the market since 2012. This combination is indicated in patients with primary or mixed lipidemia as well as patients with homozygous familial hypercholesteremia. Secondary causes of hyperlipidemia should undergo evaluation before initiating ezetimibe therapy.

Atherosclerosis is one of the major causes of coronary heart disease. Therapeutic lifestyle changes, including weight reduction, increased physical activity, and dietary changes, are first-line treatments for patients with elevated cholesterol levels.[1] Patients who are at an increased risk for coronary heart disease need to have a more targeted LDL level. Drugs that help lower cholesterol include HMG-CoA reductase inhibitors (statins), bile acid sequestrants, nicotinic acid, and fibric acids.[2] Ezetimibe is different from these agents because it selectively inhibits the intestinal absorption of cholesterol. The IMPROVE-IT trial showed that lipid-lowering with ezetimibe when used in addition to statins in post-acute coronary syndrome patients, resulted in a significant improvement in cardiovascular outcomes.[3] The American College of Cardiology recommends consideration of ezetimibe therapy in addition to maximally tolerated statin therapy for both primary and secondary prevention in patients who have not achieved target reduction in their LDL levels by maximally tolerated statin therapy alone.

Cholesterol is synthesized in the liver or absorbed from the gastrointestinal tract. Ezetimibe is a synthetic 2-azetidinone agent. Ezetimibe is different from other cholesterol-lowering agents because it does not increase bile acid excretion or inhibit cholesterol synthesis in the liver. Ezetimibe inhibits the absorption of cholesterol at the brush border of the small intestine mediated by the sterol transporter, Niemann-Pick C1-Like-1 (NPC1L1).[4] 

The decrease in cholesterol absorption leads to a reduction in the delivery of cholesterol to the liver, an increase in cholesterol clearance from the blood, and a reduction in hepatic cholesterol stores. The reduction in cholesterol absorption results in a decrease in total cholesterol, triglycerides, LDL cholesterol, and an increase in HDL cholesterol. Ezetimibe has no significant effect on fat-soluble vitamins, including vitamin A, vitamin D, and vitamin E.[2] Ezetimibe causes an LDL reduction of approximately 20%.

Ezetimibe has a long half-life of about 22 hours, which is why it can be administered orally once daily with or without meals with a cholesterol-lowering diet. The dose is 10-mg daily. It may be taken at the same time as fenofibrate or HMG-CoA reductase inhibitors, but the recommendation is to dose it at least 2 hours before or 4 hours after taking bile acid sequestrants. Ezetimibe is neither a cytochrome P450 inhibitor nor a cytochrome p450 inducer, which is why metabolism with other drugs and agents is not affected.[2] Due to once-daily dosing and limited adverse effects, compliance should not be of concern.

The most common adverse effects of ezetimibe include headache, runny nose, and sore throat. Less common reactions include body aches, back pain, chest pain, diarrhea, joint pain, fatigue, and weakness.[4] There have been reports of rhabdomyolysis in combination with statin therapy and, rarely, with monotherapy.

Contraindications for the use of ezetimibe include hypersensitivity to any component of the formulation, concomitant use with an HMG-CoA reductase inhibitor in patients with active hepatic disease, or unexplained persistent elevations in serum transaminases. It is also contraindicated in pregnancy and breastfeeding when used in combination with an HMG-CoA reductase inhibitor.[4] When used as monotherapy, it is not necessary to adjust the dosage for patients with renal impairment. Ezetimibe is not recommended in patients with moderate to severe hepatic impairment.[5]