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• W2897872959 abstract "HomeCirculationVol. 138, No. 17Letter by Koh Regarding Article, “Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Koh Regarding Article, “Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)” Kwang Kon Koh, MD, PhD Kwang Kon KohKwang Kon Koh Department of Cardiovascular Medicine, Heart Center, Gachon University, Incheon, Korea. Gil Medical Center, Incheon, Korea. Gachon Cardiovascular Research Institute, Incheon, Korea. Search for more papers by this author Originally published22 Oct 2018https://doi.org/10.1161/CIRCULATIONAHA.118.035512Circulation. 2018;138:1914–1915To the Editor:Giugliano et al1 report that all patients with type 2 diabetes mellitus demonstrated benefit with 40 mg ezetimibe/simvastatin regardless of risk. In contrast, among patients without type 2 diabetes mellitus, those with a high risk score experienced a significant (18%) relative reduction in the composite of cardiovascular death, myocardial infarction, and ischemic stroke with ezetimibe/simvastatin in comparison with placebo/simvastatin, whereas patients without type 2 diabetes mellitus at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin.Statins are important for preventing adverse cardiovascular events in patients with both a high risk and a low risk of vascular disease, by reducing the levels of low-density lipoprotein cholesterol (LDL-cholesterol).2 However, statins dose-dependently increase adverse effects and increase the risk of type 2 diabetes mellitus.2,3 Therefore, to compensate the untoward effect of statins, other therapies are needed on statins.Ezetimibe is a promising alternative drug added to statins. In addition to lowering LDL-cholesterol by 20% more, ezetimibe reduced visceral fat with beneficial effects on adiponectin and insulin resistance. Indeed, experimental studies demonstrated that ezetimibe improves liver steatosis and insulin sensitivity in a rat model of metabolic syndrome. We observed that ezetimibe combined with simvastatin significantly decreased insulin levels and increased adiponectin levels and insulin sensitivity, and reduced visceral fat and blood pressure quite differently from simvastatin alone in patients with hypercholesterolemia.4Our observations were the same regardless of type 2 diabetes mellitus. Recently, in a rabbit model of spontaneous atherothrombotic occlusion without plaque rupture, ezetimibe, but not rosuvastatin, significantly decreased thrombotic occlusion of arteries accompanied with accelerated reendothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels.5 Therefore, ezetimibe added on to statins would be expected to significantly reduce cardiac events, in particular, in patients with type 2 diabetes mellitus.Indeed, the current study confirms the multiple effects of ezetimibe added on to statins in patients with type 2 diabetes mellitus. However, a raised question is why ezetimibe combined with simvastatin did not show benefit in patients without type 2 diabetes mellitus at low or moderate risk despite the further reduction of LDL-cholesterol levels. Participants in this study were patients with coronary artery disease. A recent study demonstrated that reduction of LDL-cholesterol levels, irrespective of intervention modalities including statins, similarly resulted in the reduction of major adverse cardiovascular events. Also, this finding is quite different from a recent study reporting that patients randomly assigned to atorvastatin+ezetimibe therapy experienced a greater reduction in percent atheroma volume than those randomly assigned to atorvastatin alone, despite a similar reduction of LDL-cholesterol levels, because this difference may be caused by the pleiotropic effects of ezetimibe. Based on these experimental and clinical studies, the lack of benefit in patients without type 2 diabetes mellitus at low or moderate risk might have occurred by an unexplained bias, such as statistical methods, patients’ biological differences.Sources of FundingThis work was supported by a grant of the Korean Society of CardioMetabolic Syndrome.DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circReferences1. Giugliano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalán R, Špinar J, Park JG, White JA, Bohula EA, Braunwald E; IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).Circulation. 2018; 137:1571–1582. doi:10.1161/CIRCULATIONAHA.117.030950LinkGoogle Scholar2. Cho KI, Sakuma I, Sohn IS, Hayashi T, Shimada K, Koh KK. Best treatment strategies with statins to maximize the cardiometabolic benefits.Circ J. 2018; 82:937–943. doi:10.1253/circj.CJ-17-1445CrossrefMedlineGoogle Scholar3. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients.J Am Coll Cardiol. 2010; 55:1209–1216. doi:10.1016/j.jacc.2009.10.053CrossrefMedlineGoogle Scholar4. Koh KK, Oh PC, Sakuma I, Kim EY, Lee Y, Hayashi T, Han SH, Park YM, Shin EK. Vascular and metabolic effects of ezetimibe combined with simvastatin in patients with hypercholesterolemia.Int J Cardiol. 2015; 199:126–131. doi:10.1016/j.ijcard.2015.07.016CrossrefMedlineGoogle Scholar5. Honda K, Matoba T, Antoku Y, Koga JI, Ichi I, Nakano K, Tsutsui H, Egashira K. Lipid-lowering therapy with ezetimibe decreases spontaneous atherothrombotic occlusions in a rabbit model of plaque erosion: a role of serum oxysterols.Arterioscler Thromb Vasc Biol. 2018; 38:757–771. doi:10.1161/ATVBAHA.117.310244LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails October 23, 2018Vol 138, Issue 17 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.035512PMID: 30354661 Originally publishedOctober 22, 2018 PDF download Advertisement SubjectsCardiovascular DiseaseDiabetes, Type 2Primary PreventionRisk FactorsSecondary Prevention" @default.
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