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ezetimibe (Zetia)

Indications: - hypercholesterolemia - alone or in combination with statin (see EASE trial) - homozygous familial hypercholesterolemia - beta sitosterolemia [7] - cardiovascular risk reduction (NICE [NGC]) - in combination with statin, reduces cardiovascular events in high-risk patients (33% vs 35% for statin alone) [8] - in combination with statin, reduces cardiovascular events & mortality 7 years after acute coronary syndrome (33% vs 35% for statin alone)* [9] - despite a lesser lipid-lowering efficacy of ezetimibe vs statins, widespread use on a population level in conjunction with optimized statin therapy may be associated with further meaningful reductions in cardiovascular risk [17] - ezetimibe 10 mg 1st line for addition to high potency statin to achieve LDL cholesterol < 70 mg/dL [16] - ezetimibe 10 plus moderate intensity statin (10 mg rosuvastatin) may be alternative in patients intolerant of high intensity statin [18] * no mortality benefit Contraindications: - does NOT slow atherosclerosis - inferior to niacin in combination with statin [6] Benefit/risk: - number needed to treat: - 50 high-risk patients for 7 years for prevent 1 adverse cardiovascular event [8] - 50 for 7 years after acute coronary syndreom for prevent 1 adverse cardiovascular event* [9] * no mortality benefit Dosage: 10 mg PO QD (with or without food) Adverse effects: 1) well tolerated 2) GI upset (4%), diarrhea, abdominal pain 3) other: < 5% - arthralgia, sinusitis, dizziness, headache, pelvic pain, 4) postmarketing reports - anaphylaxis, cholecystitis, hepatitis, angioedema, rash, pancreatitis, rhabdomyolysis, thrombocytopenia, myalgia, myopathy, myositis, urticaria Drug interactions: - bile acid sequestrants may decrease ezetimibe bioavailability - elevated serum transaminases in combination with statins Mechanism of action: 1) works on brush border of intestinal microvillae to prevent absorption of cholesterol - inhibits Niemann-Pick C1-like protein 1 (NPC1L1) [4] 2) 18-25% reduction in LDL cholesterol a) additive effect to statin b) 44-57% reduction in LDL cholesterol in combination with simvastatin compared with 27-44% with simvastatin alone [2] c) 46-61% reduction in LDL cholesterol in combination with simvastatin compared with 31-46% with simvastatin alone [3] (also see EASE trial) d) 20% reduction in LDL cholesterol as monotherapy 3) 10% reduction in triglycerides 4) slightly increased HDL cholesterol; NO effect [3,6] 5) does NOT slow atherosclerosis Clinical trials: - IMPROVE-IT [8] - in combination with statin, reduces cardiovascular events in high-risk patients (33% vs 35% for statin alone) - no benefit for all-cause mortality or cardiovascular mortality - may benefit patients with diabetes more than those without [11] - may benefit high-risk patients more than low-risk patients [11] - funded by Merck & Co, maker Vytorin (simvastatin plus ezetimibe)

Interactions

drug adverse effects of anti-hyperlipidemic agents

Related

ezetimibe add-on to statin for effectiveness (EASE) trial

General

cholesterol absorption inhibitor

Properties

Database Correlations

PUBCHEM cid=150311

References

  1. Prescriber's Letter 9(11):62 2002
  2. Journal Watch 23(4):30-31, 2003 Davidson MH et al, J Am Coll Cardiol 40:2125, 2002 Sacks FM, J Am Coll Cardiol 40:2135, 2002
  3. Journal Watch 24(13):103, 2004 Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB; Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2004 May;79(5):620-9. PMID: 15132403
  4. UniProt :accession Q9UHC9
  5. Merck/Schering-Plough Pharmaceuticals Enhance study. abstract submitted to 2008 Meeting of the American College of Cardiology New York Times - Kastelein JJP et al for the ENHANCE investigators Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008, 358:1504 PMID: 18376000 - Brown BG and Taylor AJ Does ENHANCE diminish confidence in lowering LDL or in ezetimibe? N Engl J Med 2008, 358:1431 PMID: 18376002 - Drazen JM et al Cholesterol lowering and ezemtimibe. N Engl J Med 2008, 358:1507 PMID: 18376000
  6. Taylor AJ et al Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness N Engl J Med. 2009 Nov 26;361(22):2113-22. Epub 2009 Nov 15. PMID: 19915217 doi:10.1056/NEJMoa0907569. http://content.nejm.org/cgi/content/full/NEJMoa0907569 - O'Riordan M ARBITER 6-HALTS: HDL raising with niacin superior to ezetimibe. November 15, 2009. Heartwire http://www.theheart.org/article/1022265.do - Prescriber's Letter 16(12): 2009 COMMENTARY: Ezetimibe vs. Niacin for Atherosclerosis: The ARBITER 6-HALTS Study PATIENT HANDOUT: What You Should Know About Niacin Detail-Document#: 251212 (subscription needed) http://www.prescribersletter.com
  7. Deprecated Reference
  8. IMPROVE-IT investigators Cholesterol-lowering drug with different action adds to statin's reduction of cardiovascular risk. American Heart Association Meeting Report Abstract LBCT.02 November 17, 2014 http://newsroom.heart.org/news/cholesterol-lowering-drug-with-different-action-adds-to-statins-reduction-of-cardiovascular-risk
  9. Cannon CP et al; IMPROVE-IT Investigators Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. June 3, 2015 372:2387 PMID: 26039521 http://www.nejm.org/doi/full/10.1056/NEJMoa1410489
  10. Stiles S Medscape: Feb 16, 2016 FDA Says No to Ezetimibe Secondary-Prevention Indication. http://www.medscape.com/viewarticle/858944 - Merk Newsroom. Monday, February 15, 2016 5:30 pm ES Merck Receives Complete Response Letter from the U.S. FDA for ZETIA (ezetimibe) and VYTORIN (ezetimibe and simvastatin). http://www.mercknewsroom.com/news-release/prescription-medicine-news/merck-receives-complete-response-letter-us-fda-zetia-ezetimi
  11. Giugliano RP, Cannon CP, Blazing MA et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with vs. without diabetes: Results from IMPROVE-IT. Circulation 2017 Dec 20; PMID: 29263150 http://circ.ahajournals.org/content/early/2017/12/18/CIRCULATIONAHA.117.030950
  12. Kato ET, Cannon CP, Blazing MA et al Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). J Am Heart Assoc. 2017 Nov 18;6(11). PMID: 29151034 Free PMC Article
  13. Bohula EA, Wiviott SD, Giugliano RP et al Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2017 Dec 19;136(25):2440-2450. Epub 2017 Sep 30. PMID: 28972004
  14. Pokharel Y, Chinnakondepalli K, Vilain K et al Impact of Ezetimibe on the Rate of Cardiovascular-Related Hospitalizations and Associated Costs Among Patients With a Recent Acute Coronary Syndrome: Results From the IMPROVE-IT Trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circ Cardiovasc Qual Outcomes. 2017 May;10(5). pii: e003201. PMID: 28506979
  15. Medical Knowledge Self Assessment Program (MKSAP) 18, American College of Physicians, Philadelphia 2018
  16. Aguilar-Salinas CA, Gomez-Diaz RA, Corral P. New therapies for primary hyperlipidemia. J Clin Endocrinol Metab. 2022;107:1216-1224. PMID: 34888679
  17. Kovach CP, Mesenbring EC, Gupta P et al Projected Outcomes of Optimized Statin and Ezetimibe Therapy in US Military Veterans with Coronary Artery Disease. JAMA Netw Open. 2023;6(8):e2329066 PMID: 37638630 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808802
  18. Lee SJ, Cha JJ, Choi WG et al Moderate-Intensity Statin With Ezetimibe Combination Therapy vs High-Intensity Statin Monotherapy in Patients at Very High Risk of Atherosclerotic Cardiovascular Disease. A Post Hoc Analysis From the RACING Randomized Clinical Trial. JAMA Cardiol. 2023;8(9):853-858 PMID: 37531130 PMCID: PMC10398545 (available on 2024-08-02) https://jamanetwork.com/journals/jamacardiology/fullarticle/2807851

Component-of

atorvastatin/ezetimibe (Liptruzet) ezetimibe/rosuvastatin (Roszet) ezetimibe/simvastatin (Vytorin)