Research Article| Volume 201, P247-252, December 15, 2015

Safety and efficacy of ezetimibe: A meta-analysis



      The addition of ezetimibe to statin therapy has been widely demonstrated to significantly reduce low-density lipoprotein cholesterol levels. However, the efficacy of ezetimibe in reducing CV events and its safety has been less investigated. The aim of the current meta-analysis was to report efficacy and safety of ezetimibe from randomized clinical trials.


      Randomized clinical trials with a follow-up of at least 24 weeks, enrolling more than 200 patients, comparing ezetimibe versus placebo or ezetimibe plus another hypolipidemic agent versus the same hypolipidemic drug alone and reporting at least one event among all-cause and CV mortality, myocardial infarction (MI), stroke and new onset of cancer were included in the analysis.


      7 trials enrolling 31,048 patients (median follow-up 34.1 ± 26.3 months; 70% women; mean age 61 ± 8 years) were included in the analysis. Compared to control therapy, ezetimibe significantly reduced the risk of MI by 13.5% (RR: 0.865, 95% CI: 0.801 to 0.934, p < 0.001) and the risk of any stroke by 16.0% (RR: 0.840, 95% CI: 0.744 to 0.949, p = 0.005), without any effect on all-cause and CV mortality (RR: 1.003, 95% CI: 0.954 to 1.055, p = 0.908; RR: 0.958, 95% CI: 0.879 to 1.044, p = 0.330; respectively) and risk of new cancer (RR: 1.040, 95% CI: 0.965 to 1.120, p = 0.303).


      Ezetimibe significantly reduces the risk of MI and stroke without any effect on all-cause and CV mortality and risk of cancer.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to International Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Scandinavian Simvastatin Survival Study Group
        Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
        Lancet. 1994; 344: 1383-1389
        • Heart Protection Study Collaborative Group
        MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo controlled trial.
        Lancet. 2002; 360: 7-22
        • Baigent C.
        • Keech A.
        • Kearney P.M.
        • et al.
        Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
        Lancet. 2005; 366: 1267-1278
        • Cholesterol Treatment Trialists C
        • Baigent C.
        • Blackwell L.
        • et al.
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Cannon C.P.
        • Braunwald E.
        • McCabe C.H.
        • et al.
        Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
        N. Engl. J. Med. 2004; 350: 1495-1504
        • de Lemos J.A.
        • Blazing M.A.
        • Wiviott S.D.
        • et al.
        Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
        JAMA. 2004; 292: 1307-1316
        • LaRosa J.C.
        • Grundy S.M.
        • Waters D.D.
        • et al.
        Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
        N. Engl. J. Med. 2005; 352: 1425-1435
        • Pedersen T.R.
        • Faergeman O.
        • Kastelein J.J.
        • et al.
        High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
        JAMA. 2005; 294: 2437-2445
        • Cannon C.P.
        • Steinberg B.A.
        • Murphy S.A.
        • Mega J.L.
        • Braunwald E.
        Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy.
        J. Am. Coll. Cardiol. 2006; 48: 438-445
        • Preiss D.
        • Seshasai S.R.
        • Welsh P.
        • et al.
        Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
        JAMA. 2011; 305: 2556-2564
        • The ACCORD Study Group
        Effects of combination lipid therapy in type 2 diabetes mellitus.
        N. Engl. J. Med. 2010; 362: 1563-1574
        • Boden W.E.
        • Probstfield J.L.
        • Anderson T.
        • et al.
        Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
        N. Engl. J. Med. 2011; 365: 2255-2267
        • Landray M.J.
        • Haynes R.
        • Hopewell J.C.
        • et al.
        Effects of extended-release niacin with laropiprant in high-risk patients.
        N. Engl. J. Med. 2014; 371: 203-212
        • Schwartz G.G.
        • Olsson A.G.
        • Abt M.
        • et al.
        Effects of dalcetrapib in patients with a recent acute coronary syndrome.
        N. Engl. J. Med. 2012; 367: 2089-2099
        • Dietschy J.M.
        Theoretical considerations of what regulates low-density-lipoprotein and high-density-lipoprotein cholesterol.
        Am. J. Clin. Nutr. 1997; 65: 1581S-1589S
        • Turley S.D.
        • Dietschy J.M.
        The intestinal absorption of biliary and dietary cholesterol as a drug target for lowering the plasma cholesterol level.
        Prev. Cardiol. 2003; 6 (64): 29-33
        • Sudhop T.
        • Lutjohann D.
        • Kodal A.
        • et al.
        Inhibition of intestinal cholesterol absorption by ezetimibe in humans.
        Circulation. 2002; 106: 1943-1948
        • Kosoglou T.
        • Meyer I.
        • Veltri E.P.
        • et al.
        Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin.
        Br. J. Clin. Pharmacol. 2002; 54: 309-319
        • Ballantyne C.M.
        • Blazing M.A.
        • King T.R.
        • Brady W.E.
        • Palmisano J.
        Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia.
        Am. J. Cardiol. 2004; 93: 1487-1494
        • Morrone D.
        • Weintraub W.S.
        • Toth P.P.
        • et al.
        Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials.
        Atherosclerosis. 2012; 223: 251-261
        • Stone N.J.
        • Robinson J.
        • Lichtenstein A.H.
        • et al.
        2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
        Circulation. 24 2014; 129: S1-S45
        • Rossebø A.B.
        • Pedersen T.R.
        • Boman K.
        • et al.
        SEAS investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.
        N. Engl. J. Med. 2008; 359: 1343-1356
        • Peto R.
        • Emberson J.
        • Landray M.
        • et al.
        Analyses of cancer data from three ezetimibe trials.
        N. Engl. J. Med. 2008; 359: 1357-1366
        • Nissen S.E.
        Analyses of cancer data from three ezetimibe trials.
        N. Engl. J. Med. 2009; 360: 86-87
        • Collins R.
        • Peto R.
        Analyses of cancer data from three ezetimibe trials.
        N. Engl. J. Med. 2009; 360 (authors reply 87)
        • Battaggia A.
        • Donzelli A.
        • Font M.
        • Molteni D.
        • Galvano A.
        Clinical efficacy and safety of ezetimibe on major cardiovascular endpoints: systematic review and meta-analysis of randomized controlled trials.
        PLoS One. Apr 27 2015; 10: e0124587
        • Blazing M.A.
        • Giugliano R.P.
        • Cannon C.P.
        • et al.
        Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population.
        Am. Heart J. 2014; 168 (e1): 205-212
        • Califf R.M.
        • Lokhnygina Y.
        • Cannon C.P.
        • et al.
        An update on the IMProved reduction of outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design.
        Am. Heart J. 2010; 159: 705-709
        • Cannon C.P.
        • Giugliano R.P.
        • Blazing M.A.
        • et al.
        Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes.
        Am. Heart J. 2008; 156: 826-832
        • Cannon C.P.
        • Blazing M.A.
        • Giugliano R.P.
        • et al.
        Ezetimibe added to statin therapy following acute coronary syndrome.
        N. Engl. J. Med. 2015; 372: 2387-2397
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        J. Clin. Epidemiol. 2009; 62: 1006-1012
        • Detsky A.
        • Naylor C.
        • O'Rourke K.
        • McGeer A.
        • L'Abbé K.
        Incorporating variations in the quality of individual randomized trials into meta-analysis.
        J. Clin. Epidemiol. 1992; 45: 255-265
        • Sharp S.
        • Sterne J.
        in: Stata Technical Bulletin Reprints. 7. 1998: 100-108
        • Raudenbush S.W.
        Analyzing effect sizes: random-effects models.
        in: Cooper H.M. Hedges L.V. Valentine J.C. The Handbook of Research Synthesis and Meta-Analysis. Russell SAGE Foundation, New York, USA2009: 306-307
      1. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Identifying and measuring heterogeneity.
        • Tobias A.
        Assessing the influence of a single study in meta-analysis.
        STB. 1999; 47: 15-17
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629
        • Kastelein J.J.
        • Akdim F.
        • Stroes E.S.
        • ENHANCE Investigators
        Simvastatin with or without ezetimibe in familial hypercholesterolemia.
        N. Engl. J. Med. 2008; 358: 1431-1443
        • Kouvelos G.N.
        • Arnaoutoglou E.M.
        • Matsagkas M.I.
        • et al.
        Effects of rosuvastatin with or without ezetimibe on clinical outcomes in patients undergoing elective vascular surgery: results of a pilot study.
        J. Cardiovasc. Pharmacol. Ther. 2013; 18: 5-12
        • McKenney J.M.
        • Farnier M.
        • Lo K.W.
        • et al.
        Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia.
        J. Am. Coll. Cardiol. 2006; 47: 1584-1587
        • Baigent C.
        • Landray M.J.
        • Reith C.
        • 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; 377: 2181-2192
        • Landray M.
        • Baigent C.
        • Leaper C.
        • et al.
        The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD.
        Am. J. Kidney Dis. 2006; 47: 385-395
        • Myocardial Infarction Genetics Consortium Investigators
        • Stitziel N.O.
        • Won H.H.
        • et al.
        Inactivating mutations in NPC1L1 and protection from coronary heart disease.
        N. Engl. J. Med. 2014; 371: 2072-2082