Ezetimibe


Article Author:
Omeed Sizar


Article Editor:
Raja Talati


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
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Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
5/16/2019 2:11:08 PM

Indications

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[1]. 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[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 by maximally tolerated statin therapy alone.

Mechanism of Action

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).[4] 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.[2] Ezetimibe causes an LDL reduction of approximately 20%.

Administration

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.[2] Due to once-daily dosing and limited adverse effects, compliance should not be of concern.

Adverse Effects

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.[4] Rhabdomyolysis has been reported in combination with statin therapy and, rarely, with monotherapy.

Contraindications

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]. Ezetimibe given with a statin is contraindicated in patients with hepatic impairment.

Monitoring

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[6]. When ezetimibe is prescribed with patients taking cyclosporine, lower dose of 5mg ezetimibe needs to be initiated[6]

Toxicity

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.[6] Cyclosporine concentrations should be monitored as cyclosporine can cause severe renal insufficiency.

Enhancing Healthcare Team Outcomes

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%[3]. 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.[3] 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[7]. 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.[8] 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.


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Ezetimibe - Questions

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Which drug can lower cholesterol levels by preventing absorption from the intestines?



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A 56-year-old male with recent myocardial infarction with two stents placed three months ago presents to the clinic for follow up. His LDL levels remain 150 mg/dL even with a high-intensity statin. It is decided to place the patient on another agent to reduce LDL below 70 mg/dL. What is the mechanism of action of the preferred agent?



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Which of the following antilipemic agents is a cholesterol absorption inhibitor?



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A 65-year-old female with history of hypertension, gout, and coronary artery disease with a stent placed nine months ago presents to the clinic for follow up. The patient was recently placed on ezetimibe in addition to high dose statin with LDL measuring 72 mg/dL. The patient is planning on traveling and will not be back to the clinic for 12 months. Which of the following should be monitored in patients taking ezetimibe?



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A 53-year-old female with history of type 2 diabetes mellitus, hyperlipidemia, and hypertension presents to the clinic for follow up. Recent LDL measuring 160 mg/dL and patient reports intolerance to statin despite trying atorvastatin and rosuvastatin. Patient started on ezetimibe due to statin intolerance. Which of the following is true about ezetimibe?



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Which of the following is the brand name for ezetimibe?



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A 65-year-old male comes to the office for follow-up. He had a stent placed in his right coronary artery two years ago for unstable angina. He reports that he exercises regularly and is compliant with a heart healthy diet. His current medications include atorvastatin 80 mg daily for dyslipidemia. The lipid profile shows total cholesterol is 195, HDL is 33, LDL is 110, and triglycerides are 120. Which of the following drugs has been shown to improve cardiovascular outcomes when added to statins for secondary prevention?



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Which of the following drugs primarily acts by inhibiting the absorption of cholesterol in the small intestine?



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A 65-year old is about to be discharged after an uneventful coronary artery bypass procedure. Prior to discharge, the cardiologist starts him on a drug that decreases cholesterol absorption from the intestine. What is this drug?



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Ezetimibe - References

References

Cannon CP,Blazing MA,Giugliano RP,McCagg A,White JA,Theroux P,Darius H,Lewis BS,Ophuis TO,Jukema JW,De Ferrari GM,Ruzyllo W,De Lucca P,Im K,Bohula EA,Reist C,Wiviott SD,Tershakovec AM,Musliner TA,Braunwald E,Califf RM, Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England journal of medicine. 2015 Jun 18     [PubMed]
Brar KS, Ezetimibe (Zetia). Medical journal, Armed Forces India. 2004 Oct     [PubMed]
Patel J,Sheehan V,Gurk-Turner C, Ezetimibe (Zetia): a new type of lipid-lowering agent. Proceedings (Baylor University. Medical Center). 2003 Jul     [PubMed]
Koshman SL,Lalonde LD,Burton I,Tymchak WJ,Pearson GJ, Supratherapeutic response to ezetimibe administered with cyclosporine. The Annals of pharmacotherapy. 2005 Sep     [PubMed]
Baigent C,Landray MJ,Reith C,Emberson J,Wheeler DC,Tomson C,Wanner C,Krane V,Cass A,Craig J,Neal B,Jiang L,Hooi LS,Levin A,Agodoa L,Gaziano M,Kasiske B,Walker R,Massy ZA,Feldt-Rasmussen B,Krairittichai U,Ophascharoensuk V,Fellström B,Holdaas H,Tesar V,Wiecek A,Grobbee D,de Zeeuw D,Grönhagen-Riska C,Dasgupta T,Lewis D,Herrington W,Mafham M,Majoni W,Wallendszus K,Grimm R,Pedersen T,Tobert J,Armitage J,Baxter A,Bray C,Chen Y,Chen Z,Hill M,Knott C,Parish S,Simpson D,Sleight P,Young A,Collins R, The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet (London, England). 2011 Jun 25     [PubMed]
Sabatine MS,De Ferrari GM,Giugliano RP,Huber K,Lewis BS,Ferreira J,Kuder JF,Murphy SA,Wiviott SD,Kurtz CE,Honarpour N,Keech AC,Sever PS,Pedersen TR, Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease. Circulation. 2018 Aug 21;     [PubMed]
Bhardwaj SS,Chalasani N, Lipid-lowering agents that cause drug-induced hepatotoxicity. Clinics in liver disease. 2007 Aug;     [PubMed]
Skolnik N,Jaffa FM,Kalyani RR,Johnson E,Shubrook JH, Reducing CV risk in diabetes: An ADA update. The Journal of family practice. 2017 May;     [PubMed]

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