Continuing Education Activity

Ezetimibe is a medication used in the management and treatment of hypercholesterolemia. It is among a novel class of selective cholesterol-absorption inhibitors. It is indicated to reduce 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). This activity describes the indications, actions, and contraindications for ezetimibe as a valuable agent in treating hypercholesterolemia. In addition, this activity highlights the administration and monitoring principles that the interprofessional team should employ to manage patients with hypercholesterolemia using ezetimibe.

Objectives:

• Identify the indications for initiating ezetimibe therapy.
• Review the contraindications for ezetimibe therapy.
• Summarize the common and less common adverse effects of ezetimibe therapy.
• Explain the importance of collaboration and communication amongst the interprofessional team to ensure appropriate monitoring of patients receiving ezetimibe.

Indications

Ezetimibe is a dyslipidemic agent used to treat people with hyperlipidemia. It was FDA-approved in 2002. Ezetimibe is the most commonly used nonstatin agent, which lowers LDL-C levels by 13% to 20%.[1] Ezetimibe is an inhibitor of intestinal cholesterol absorption. It is indicated to reduce 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. A fixed-dose combination of ezetimibe and simvastatin has been available since 2002. Another combination agent, made up of atorvastatin and ezetimibe, was approved in 2012. Currently, it is no longer commercially marketed in the USA.[2] 

However, the FDA approved ezetimibe and rosuvastatin's FDC (Fixed-Dose Combination). Combination therapy of ezetimibe plus statin is indicated in patients with primary or mixed lipidemia and homozygous familial hypercholesterolemia. Secondary causes of hyperlipidemia should undergo evaluation before initiating ezetimibe therapy.[3]

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 management for elevated cholesterol levels.[4] Patients at an increased risk for coronary heart disease need a more targeted LDL level. Drugs that help lower cholesterol include HMG-CoA reductase inhibitors (statins), bile acid sequestrants, nicotinic acid, and fibric acids.[5] 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, combined with statins in post-acute coronary syndrome patients, significantly improved cardiovascular outcomes.[6] 

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. Another study found that lipid-lowering treatment in those over age 75 was just as effective in decreasing cardiovascular events as those less than 75 years of age.[7]

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 cholesterol absorption at the brush border of the small intestine mediated by the sterol transporter Niemann-Pick C1-Like-1 (NPC1L1).[8]

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. This consequent reduction n cholesterol absorption results in a decrease in total cholesterol, triglycerides, and LDL cholesterol and an increase in HDL cholesterol. Ezetimibe does not significantly affect fat-soluble vitamins, including vitamins A, D, and E.[5] Ezetimibe causes a reduction in LDL levels of 13-20%.[1] 

Pharmacokinetics

Absorption: According to the manufacturer's labeling, after oral administration of ezetimibe, it is absorbed and conjugated to a pharmacologically active ezetimibe-glucuronide. Mean peak plasma concentrations are attained within 4 to 12 hours. However, ezetimibe-glucuronide peak plasma concentrations are achieved between 1 and 2 hours. Cmax of ezetimibe is increased by 38% with consumption of high-fat meals; however, administration of food with ezetimibe does not affect the extent of absorption. Consequently, ezetimibe Tablets can be administered without regard to food.

Distribution: Ezetimibe and ezetimibe-glucuronide complex are more than 90% protein bound.

Metabolism: In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe(10 to 20%) and ezetimibe-glucuronide(80 to 90%) are detected in plasma. In addition, plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. The CYP450 metabolizes ezetimibe, but it has a negligible effect on other drugs' pharmacokinetics because it is rapidly conjugated and excreted in the bile as a glucuronide.[9]

Excretion: Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours. Ezetimibe is primarily excreted in feces, while Ezetimibe-glucuronide is excreted in the urine.

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 the recommendation is to dose it at least 2 hours before or 4 hours after taking bile acid sequestrants. Due to once-daily dosing and limited adverse effects, compliance should not be of concern.

Use in Specific Patient Population

Patients with Renal Impairment: No dose adjustment is required for patients with renal disease, according to the manufacturer's product labeling. However, as renal impairment increases the risk of statin-associated myopathy, simvastatin exceeding 20 mg should be used with caution when administered concomitantly with ezetimibe in patients with moderate to severe renal impairment.

Patients with Hepatic Impairment: Ezetimibe is not recommended in patients with moderate to severe hepatic impairment.[10]

Pregnancy Considerations:  In preclinical studies, ezetimibe increased the risk of congenital anomalies. However, there are no adequate and well-controlled studies of ezetimibe in pregnant women. Therefore, ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Ezetimibe comes under FDA former Pregnancy Category C. Additionally,  no well-controlled clinical studies of ezetimibe in pregnant women have been conducted. Therefore,  Ezetimibe should be used during pregnancy only if the potential benefit outweighs the risk to the fetus. Bile acid sequestrants are currently the preferred drug in pregnancy for managing dyslipidemia.[11] 

Breastfeeding Considerations: Information regarding using ezetimibe during breastfeeding is unavailable. It is not known whether ezetimibe is excreted into human breast milk. Ezetimibe should be avoided during breastfeeding. An alternate drug is preferred, especially while nursing a newborn or preterm infant. Clinicians should avoid ezetimibe and statin (e.g.simvastatin) in nursing mothers.[12]

Adverse Effects

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.[8] There have been reports of rhabdomyolysis in combination with statin therapy and, rarely, with monotherapy. Hepatotoxicity with ezetimibe can present with hepatocellular or cholestatic patterns, and cases of autoimmune hepatitis and vanishing bile duct syndrome have been reported.[9]

Contraindications

Contraindications for using 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.[8]  As discussed above, ezetimibe is not recommended in patients with moderate to severe hepatic impairment.[10]  Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with ezetimibe.[13]

Monitoring

A lipid panel is necessary at baseline and as clinically indicated after that. If patients take ezetimibe with cyclosporine, then cyclosporine concentrations need to be monitored, as cyclosporine can cause severe renal insufficiency.[14] Consequently, When prescribing ezetimibe in patients taking cyclosporine, a lower dose of 5 mg of ezetimibe is suggested.[14] Obtain liver function tests at baseline and monitor LFTs during therapy due to the potential for hepatotoxicity as described above. Monitor for signs of myopathy, especially when ezetimibe is combined with a statin, and discontinue therapy immediately if rhabdomyolysis is suspected.[15]

Toxicity

According to the manufacturer's product labeling, administration of ezetimibe in doses up to 40-50 mg daily was generally well tolerated in clinical trials. In addition, one patient with homozygous sitosterolemia had an accidental overdose of ezetimibe 120 mg/day for 28 days with no significant clinical or laboratory adverse events. There is no specific antidote to ezetimibe. In an overdose with ezetimibe, clinicians should provide symptomatic and supportive care. In addition, clinicians should obtain LFTs if hepatotoxicity is suspected, as autoimmune hepatitis associated with ezetimibe requires treatment with corticosteroid therapy.[9] The incidence of skeletal muscle toxicity related to ezetimibe and concomitant statin treatment increases with age over 65, 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 drug exposure.[14]

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 with acute coronary syndrome. This double-blinded study published in 2015 followed over 18,000 hospitalized patients with acute coronary syndrome randomized to simvastatin monotherapy or simvastatin combined with ezetimibe. The study found that adding 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, a target LDL cholesterol of less than 70 mg per deciliter is recommended for patients after acute coronary syndrome.[6] Other studies found that reducing LDL levels to 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.[16] Clinicians need to understand the importance and the efficacy of additional agents in lowering LDL cholesterol in addition to dietary and lifestyle modifications.

Another trial, known as the SHARP (Study of Heart and Renal Protection), published in 2011, found that patients with chronic kidney disease receiving simvastatin and ezetimibe had reduced atherosclerotic events.[17] With this publication, the Kidney Disease: Improving Global Outcomes (KDIGO) organization updated its practical guidelines in 2013, stating that all adults over 50 years with chronic kidney disease should receive treatment with a statin. Moreover, ezetimibe and statin are recommended in patients with chronic kidney disease stages 3 through 5. People with chronic kidney disease demonstrate an increased risk of cardiovascular disease, so lipid assessment and treatment are essential in this patient population.

According to AHA(American Heart Association)/ACC (American College of Cardiology)/NLA (National Lipid Association) joint guidelines, patients with clinical ASCVD (atherosclerotic cardiovascular disease) on maximally tolerated statin therapy have a very high risk and have an LDL-C≥70 mg/dL; it is useful to add ezetimibe therapy.[1][6] [Level IIa] In addition, for patients between 20 to 75 years of age with an LDL-C≥190 mg/dL and a 50% reduction in LDL-C while receiving maximally tolerated statin therapy or having an LDL-C≥100 mg/dL, clinicians should consider ezetimibe therapy.[18][6] [Level IIa]

Ezetimibe therapy is most effective when the entire interprofessional healthcare team is involved. The prescribing clinician can work with the pharmacist to ensure that dosing is appropriate and that there are no medications that will interact and result in adverse events, particularly rhabdomyolysis. Nursing involvement will include verifying compliance, monitoring for adverse events, and providing counsel regarding administration and what to look for as potential side effects. Both pharmacy and nursing will report any concerns to the prescriber promptly. This interprofessional team approach will maximize treatment effectiveness and minimize adverse events, resulting in better patient outcomes. [Level 5]

Review Questions

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References

1.

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Jun 25;73(24):3168-3209. [PubMed: 30423391]

2.

Goldenberg MM. Pharmaceutical approval update. P T. 2013 Jul;38(7):389-403. [PMC free article: PMC3776487] [PubMed: 24049424]

3.

Palacio-Portilla EJ, Roquer J, Amaro S, Arenillas JF, Ayo-Martín O, Castellanos M, Freijo MM, Fuentes B, García-Pastor A, Gomis M, Gómez-Choco M, López-Cancio E, Martínez-Sánchez P, Morales A, Rodríguez-Yáñez M, Segura T, Serena J, Vivancos-Mora J, de Leciñana MA., Comité ad hoc del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Española de Neurología. Dyslipidemias and stroke prevention: recommendations of the Study Group of Cerebrovascular Diseases of the Spanish Society of Neurology. Neurologia (Engl Ed). 2022 Jan-Feb;37(1):61-72. [PubMed: 33160722]

4.

Skolnik N, Jaffa FM, Kalyani RR, Johnson E, Shubrook JH. Reducing CV risk in diabetes: An ADA update. J Fam Pract. 2017 May;66(5):300-308. [PubMed: 28459890]

5.

Patel J, Sheehan V, Gurk-Turner C. Ezetimibe (Zetia): a new type of lipid-lowering agent. Proc (Bayl Univ Med Cent). 2003 Jul;16(3):354-8. [PMC free article: PMC1200795] [PubMed: 16278712]

6.

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., IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. [PubMed: 26039521]

7.

Gencer B, Marston NA, Im K, Cannon CP, Sever P, Keech A, Braunwald E, Giugliano RP, Sabatine MS. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2020 Nov 21;396(10263):1637-1643. [PMC free article: PMC8015314] [PubMed: 33186535]

8.

Brar KS. Ezetimibe (Zetia). Med J Armed Forces India. 2004 Oct;60(4):388-9. [PMC free article: PMC4923440] [PubMed: 27407681]

9.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Dec 1, 2021. Ezetimibe. [PMC free article: PMC547852] [PubMed: 31643425]

10.

Bhardwaj SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis. 2007 Aug;11(3):597-613, vii. [PMC free article: PMC2048990] [PubMed: 17723922]

11.

Lewek J, Banach M. Dyslipidemia Management in Pregnancy: Why Is It not Covered in the Guidelines? Curr Atheroscler Rep. 2022 Jul;24(7):547-556. [PubMed: 35499807]

12.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Oct 19, 2020. Ezetimibe. [PubMed: 30000696]

13.

Lu T, Grewal T. Ezetimibe: An Unusual Suspect in Angioedema. Case Rep Med. 2020;2020:9309382. [PMC free article: PMC7063208] [PubMed: 32180811]

14.

Koshman SL, Lalonde LD, Burton I, Tymchak WJ, Pearson GJ. Supratherapeutic response to ezetimibe administered with cyclosporine. Ann Pharmacother. 2005 Sep;39(9):1561-5. [PubMed: 16030077]

15.

Wen Z, Liang Y, Hao Y, Delavan B, Huang R, Mikailov M, Tong W, Li M, Liu Z. Drug-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug reaction management. Drug Discov Today. 2019 Jan;24(1):9-15. [PMC free article: PMC7050640] [PubMed: 29902520]

16.

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: Analysis From FOURIER. Circulation. 2018 Aug 21;138(8):756-766. [PubMed: 29626068]

17.

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., SHARP Investigators. 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. 2011 Jun 25;377(9784):2181-92. [PMC free article: PMC3145073] [PubMed: 21663949]

18.

Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, Braunwald E, Sabatine MS. Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis. JAMA. 2016 Sep 27;316(12):1289-97. [PubMed: 27673306]

Disclosure: Omeed Sizar declares no relevant financial relationships with ineligible companies.

Disclosure: Ali Nassereddin declares no relevant financial relationships with ineligible companies.

Disclosure: Raja Talati declares no relevant financial relationships with ineligible companies.