BACKGROUND: Ezetimibe-statin combination therapy has been found to reduce low density lipoprotein cholesterol levels and the risk of major adverse cardiovascular events (MACEs) in large trials. We sought to examine the differential effect of ezetimibe on MACEs when added to statins according to the presence of diabetes. METHODS: Randomized clinical trials with a sample size of at least 50 participants and at least 24 weeks of follow-up that compared ezetimibe-statin combination therapy with a statin- or placebo-controlled arm and reported at least one MACE, stratified by diabetes status, were included in the meta-analysis and meta-regression. RESULTS: A total of seven trials with 28,191 enrolled patients (mean age, 63.6 years; 75.1% men; 7,298 with diabetes [25.9%]; mean follow-up, 5 years) were analysed. MACEs stratified by diabetes were obtained from the published data (two trials) or through direct contact (five trials). No significant heterogeneity was observed among studies (I²=14.7%, P=0.293). Ezetimibe was associated with a greater reduction of MACE risk in subjects with diabetes than in those without diabetes (pooled relative risk, 0.84 vs. 0.93; P(heterogeneity)=0.012). In the meta-regression analysis, the presence of diabetes was associated with a greater reduction of MACE risk when ezetimibe was added to statins (β=0.87, P=0.038). CONCLUSION: Ezetimibe-statin combination therapy was associated with greater cardiovascular benefits in patients with diabetes than in those without diabetes. Our findings suggest that ezetimibe-statin combination therapy might be a useful strategy in patients with diabetes at a residual risk of MACEs.

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

Cardiovascular Research Institute and Cardiovascular Genome Center Yonsei University College of Medicine Seoul Korea

Department of Biostatistics The Catholic University of Korea Seoul Korea

Department of Cardiovascular Medicine Graduate School of Medical Sciences Kumamoto University Kumamoto Japan

Department of Medicine and Radiology University of Virginia Health System Charlottesville VA USA

Division of Cardiology Department of Internal Medicine Yonsei University College of Medicine Seoul Korea

Division of Endocrinology and Metabolism Department of Internal Medicine Yonsei University College of Medicine Seoul Korea

Graduate School Yonsei University College of Medicine Seoul Korea

Institute of Endocrine Research Yonsei University College of Medicine Seoul Korea

Musashino Tokusyu Hospital Tokyo Japan

Vascular Surgery Unit Department of Surgery University of Ioannina Ioannina Greece

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Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, 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. PubMed

Cholesterol Treatment Trialists' (CTT) Collaboration. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, 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. PubMed PMC

Gerstein HC, Yusuf S. Dysglycaemia and risk of cardiovascular disease. Lancet. 1996;347:949–950. PubMed

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, 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. J Am Coll Cardiol. 2014;63(25 Pt B):2889–2934. PubMed

ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, 3rd, Leiter LA, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574. PubMed PMC

Park SW. Intestinal and hepatic niemann-pick c1-like 1. Diabetes Metab J. 2013;37:240–248. PubMed PMC

Sudhop T, Lutjohann D, Kodal A, Igel M, Tribble DL, Shah S, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106:1943–1948. PubMed

Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–2397. PubMed

Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. 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. PubMed PMC

Moher D, Liberati A, Tetzlaff J, Altman DG PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. PubMed PMC

Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. PubMed PMC

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. PubMed PMC

Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–612. PubMed PMC

Sedgwick P. Meta-analyses: heterogeneity and subgroup analysis. BMJ. 2013;346:f4040 PubMed

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634. PubMed PMC

West AM, Anderson JD, Meyer CH, Epstein FH, Wang H, Hagspiel KD, et al. The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis. 2011;218:156–162. PubMed PMC

Kovarnik T, Mintz GS, Skalicka H, Kral A, Horak J, Skulec R, et al. Virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibe administration: HEAVEN study. Circ J. 2012;76:176–183. PubMed

Kouvelos GN, Arnaoutoglou EM, Matsagkas MI, Kostara C, Gartzonika C, Bairaktari ET, 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. PubMed

Suzuki H, Watanabe Y, Kumagai H, Shuto H. Comparative efficacy and adverse effects of the addition of ezetimibe to statin versus statin titration in chronic kidney disease patients. Ther Adv Cardiovasc Dis. 2013;7:306–315. PubMed

Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K, et al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol. 2015;66:495–507. PubMed

Savarese G, De Ferrari GM, Rosano GM, Perrone-Filardi P. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201:247–252. PubMed

Fei Y, Guyatt GH, Alexander PE, El Dib R, Siemieniuk RA, Vandvik PO, et al. Addition of Ezetimibe to statins for patients at high cardiovascular risk: systematic review of patient-important outcomes. J Eval Clin Pract. 2018;24:222–231. PubMed

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. 2015;10:e0124587. PubMed PMC

Thomopoulos C, Skalis G, Michalopoulou H, Tsioufis C, Makris T. Effect of low-density lipoprotein cholesterol lowering by ezetimibe/simvastatin on outcome incidence: overview, meta-analyses, and meta-regression analyses of randomized trials. Clin Cardiol. 2015;38:763–769. PubMed PMC

Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37:2999–3058. PubMed

Committee for the Korean Guidelines for the Management of Dyslipidemia. 2015 Korean guidelines for the management of dyslipidemia: executive summary (English translation) Korean Circ J. 2016;46:275–306. PubMed PMC

Nayor M, Vasan RS. Recent update to the US cholesterol treatment guidelines: a comparison with international guidelines. Circulation. 2016;133:1795–1806. PubMed PMC

Ravid Z, Bendayan M, Delvin E, Sane AT, Elchebly M, Lafond J, et al. Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors. Am J Physiol Gastrointest Liver Physiol. 2008;295:G873–G885. PubMed

Lally SE, Owens D, Tomkin GH. Sitosterol and cholesterol in chylomicrons of type 2 diabetic and non-diabetic subjects: the relationship with ATP binding cassette proteins G5 and G8 and Niemann-Pick C1-like 1 mRNA. Diabetologia. 2007;50:217–219. PubMed

Vaverkova H, Farnier M, Averna M, Missault L, Viigimaa M, Dong Q, et al. Lipid-altering efficacy of ezetimibe/simvastatin 10/20 mg compared to rosuvastatin 10 mg in high-risk patients with and without type 2 diabetes mellitus inadequately controlled despite prior statin monotherapy. Cardiovasc Ther. 2012;30:61–74. PubMed

Leiter LA, Betteridge DJ, Farnier M, Guyton JR, Lin J, Shah A, et al. Lipid-altering efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in patients with and without diabetes: an analysis of pooled data from 27 clinical trials. Diabetes Obes Metab. 2011;13:615–628. PubMed

Koh KK, Oh PC, Sakuma I, Kim EY, Lee Y, Hayashi T, et al. Vascular and metabolic effects of ezetimibe combined with simvastatin in patients with hypercholesterolemia. Int J Cardiol. 2015;199:126–131. PubMed

Tie C, Gao K, Zhang N, Zhang S, Shen J, Xie X, et al. Ezetimibe attenuates atherosclerosis associated with lipid reduction and inflammation inhibition. PLoS One. 2015;10:e0142430. PubMed PMC

Patel SB. Ezetimibe: a novel cholesterol-lowering agent that highlights novel physiologic pathways. Curr Cardiol Rep. 2004;6:439–442. PubMed PMC

Qin L, Yang YB, Yang YX, Gong YZ, Li XL, Li GY, et al. Inhibition of smooth muscle cell proliferation by ezetimibe via the cyclin D1-MAPK pathway. J Pharmacol Sci. 2014;125:283–291. PubMed

Hussein O, Minasian L, Itzkovich Y, Shestatski K, Solomon L, Zidan J. Ezetimibe's effect on platelet aggregation and LDL tendency to peroxidation in hypercholesterolaemia as monotherapy or in addition to simvastatin. Br J Clin Pharmacol. 2008;65:637–645. PubMed PMC

Peto R, Emberson J, Landray M, Baigent C, Collins R, Clare R, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008;359:1357–1366. PubMed

Drazen JM, D'Agostino RB, Ware JH, Morrissey S, Curfman GD. Ezetimibe and cancer: an uncertain association. N Engl J Med. 2008;359:1398–1399. PubMed