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 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. Ezetimibe may be used as monotherapy, in combination with fenofibrate, or with HMG-CoA reductase inhibitors. Vytorin is a combination agent made up of ezetimibe and simvastatin and available since 2002. Liptruzet is a combination agent made up of atorvastatin and ezetimibe and available since 2012 and indicated in patients with primary or mixed lipidemia as well as patients with homozygous familial hypercholesteremia. Secondary causes of hyperlipidemia should be evaluated 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 those patients with elevated cholesterol levels. Patients who are at an increased risk of coronary heart disease need to have a more targeted LDL level. Drugs that help lower cholesterol include hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, nicotinic acid, and fibric acids. 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. 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 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 absorption of cholesterol at the brush border of the small intestine mediated by the sterol transporter, Niemann-Pick C1-like 1 (NPC1L1). The decrease in cholesterol absorption leads to a decrease in the delivery of cholesterol to the liver, an increase in cholesterol clearance from the blood, and a reduction in hepatic cholesterol stores. The decrease in cholesterol absorption results in a decrease of 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. 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 it is recommended to take 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. Due to once-daily dosing and limited adverse effects, compliance should not be of concern.
The most common adverse effects include headache, runny nose, and sore throat. Less common reactions include body aches, back pain, chest pain, diarrhea, joint pain, fatigue, and weakness. Rhabdomyolysis has been reported 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. 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. Ezetimibe given with a statin is contraindicated in patients with hepatic impairment.
A lipid panel should be obtained at baseline and as clinically indicated thereafter. Liver function tests also need to be obtained at baseline if a combination agent is used with a statin. If patients are taking ezetimibe with cyclosporine, then cyclosporine concentrations need to be monitored.
There is a risk of skeletal muscle toxicity with concomitant use of statin increases with advanced age over 65 years old, hypothyroidism, or renal impairment. Patients taking ezetimibe with cyclosporine are at an increased risk of ezetimibe toxicity as it can result in a 2.3- to 12-fold increase in exposure. Cyclosporine concentrations should be monitored as cyclosporine can cause severe renal insufficiency.
The landmark trial for ezetimibe is called the Improved Reductions of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). It evaluated the effect of ezetimibe and simvastatin compared with simvastatin alone in patients who had an acute coronary syndrome. This double-blinded study published in 2015 followed over 18,000 hospitalized patients with acute coronary syndrome randomized to either simvastatin monotherapy or simvastatin combined with ezetimibe. The study found that the addition of ezetimibe to statin therapy lowered LDL cholesterol by 24%. The combination also lowered the risk of cardiovascular events by 2%. This trial has been a watershed moment in lipid management. Based on the trial, target LDL cholesterol of less than 70 mg per deciliter has been recommended for patients after an acute coronary syndrome. Other studies found that reducing LDL levels less than 50 mg per deciliter reduced all-cause mortality, ischemic events, and myocardial infarctions. These studies include FOURIER and ODYSSEY trials using PCSK9 inhibitors alirocumab and evolocumab. It is important for physicians to understand the importance and the efficacy of additional agents in lowering LDL cholesterol in addition with dietary and lifestyle modifications.
Another trial known as the SHARP (Study of Heart and Renal Protection) trial published in 2011 found that patients with chronic kidney disease receiving simvastatin and ezetimibe had reduced atherosclerotic events. With this publication, the Kidney Disease: Improving Global Outcomes (KDIGO) organization updated their practical guidelines in 2013, stating that all adults over the age of 50 years old with chronic kidney disease should be treated with a statin. Moreover, ezetimibe and a statin is recommended in patients with chronic kidney disease stage 3-5. People with chronic kidney disease are at an increased risk of cardiovascular disease and so lipid assessment and treatment is important in this patient population.