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Ezetimibe Therapy for Dyslipidemia: An Update Niki Katsiki1, Eleni Theocharidou1, Asterios Karagiannis1, Vasilios G. Athyros1 and Dimitri P. Mikhailidis2* 1
Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece; 2Department of Clinical Biochemistry (Vascular Disease Prevention Clinic) and Department of Surgery, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK Abstract: Ezetimibe, an inhibitor of intestinal cholesterol absorption, can decrease total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TGs) and apolipoprotein (apo) B levels and increase high-density lipoprotein cholesterol (HDL-C) levels. Apart from lipid-lowering, ezetimibe may exert certain off-target actions (e.g. anti-inflammatory, anti-atherogenic and antioxidant) thus contributing to a further decrease of cardiovascular disease (CVD) risk. Ezetimibe trials resulted in controversial outcomes with some studies reporting atherosclerosis regression and reductions in CVD events following ezetimibe therapy in combination with a statin while others reported negative results. The results of the ongoing IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) which compares ezetimibe plus simvastatin with simvastatin monotherapy with regard to CVD outcomes after acute coronary syndromes should further elucidate the effect of ezetimibe on CVD events. This review presents the results of up-to-date clinical trials with ezetimibe and summarizes its potential pleiotropic effects. Furthermore, we comment on the administration of ezetimibe in treating high-risk patients [i.e. with diabetes mellitus (DM), metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), peripheral artery disease (PAD) or carotid disease]. The use of ezetimibe either as monotherapy or as add-on therapy in daily clinical practice is also discussed.
Keywords: Ezetimibe, clinical trials, dyslipidemia, pleiotropic actions, drug combinations, cholesterol. INTRODUCTION Ezetimibe is a lipid-lowering drug that selectively blocks the absorption of biliary and dietary cholesterol in the small intestine by inhibiting the Niemann Pick C1-like1 transporter (NPC1L1), a critical protein in cholesterol transmembrane transport in enterocytes [1]. Ezetimibe is minimally absorbed in the systemic circulation, whereas it is involved in an enterohepatic cycle thus allowing once daily administration [2]. The mechanisms of action of ezetimibe are described in detail in a recent review [3]. Ezetimibe was previously shown to beneficially affect lipids by decreasing total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TGs) and apolipoprotein (apo) B levels and increasing high-density lipoprotein cholesterol (HDL-C) levels [4, 5]. It is generally regarded as a safe and well tolerated drug since cases of myopathy and mild increases in liver tests have been rarely reported and mainly when ezetimibe was coadministered with a statin [6]. Although an increased risk of cancer was observed in patients with mild-to-moderate asymptomatic aortic stenosis on simvastatin plus ezetimibe compared with placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study [7], this was not seen in other studies [8, 9]. Ezetimibe was approved (in 2002) by the United States Food and Drug Administration (FDA) for the treatment of both primary (heterozygous familial and non-familial) and homozygous familial hypercholesterolemia (FH) either as monotherapy or combined with a statin, in conjunction with other lipid-reducing interventions such as diet or LDL apheresis [10]. This review presents the results of up-to-date clinical trials with ezetimibe and summarizes its potential pleiotropic effects. Furthermore, we comment on the administration of ezetimibe in treating *Address correspondence to this author at the Department of Clinical Biochemistry (Vascular Disease Prevention Clinic), Royal Free Hospital Campus, University College, London Medical School, University College, London (UCL), Pond Street, London NW3, 2QG, United Kingdom; Tel: +44 20 7830 2258; Fax: +44 20 7830 2235; E-mail:
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high-risk patients such as those with diabetes mellitus (DM), metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), peripheral artery disease (PAD) or carotid disease. The use of ezetimibe either as monotherapy or as add-on therapy in daily clinical practice is also discussed. RANDOMIZED CLINICAL TRIALS THAT ASSESSED THE EFFECT OF EZETIMIBE ON CAROTID INTIMA-MEDIA THICKNESS OR VASCULAR EVENTS The results of randomized clinical trials with ezetimibe were published during the last decade; however, these studies have been the subject of substantial criticism regarding their design and interpretation [3, 11-16]. In a double-blind, randomized trial, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial [17], ezetimibe plus simvastatin (10 + 80 mg/day) did not change carotid intima-media thickness (cIMT) compared with simvastatin monotherapy (80 mg/day) in patients with FH (n = 720; duration = 24 months); in contrast, LDL-C, TGs and CRP were significantly reduced in both groups with significantly greater changes in the combination group [17]. It is important to mention that the findings of the ENHANCE trial have been criticized as baseline cIMT measurements were low (i.e. 0.70 mm), thus limiting any measurable decrease [3, 12, 15]. This was also the case for atorvastatin net effect in cIMT in the Carotid Atorvastatin Study in Hyperlipidemic post-Menopausal Women: A Randomized Evaluation (CASHMERE) trial (baseline cIMT = 0.69 mm) that compared atorvastatin 80 mg/day vs placebo [18]. In contrast, in the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial [19], where a significant reduction in cIMT was reported following intensive treatment with atorvastatin compared with simvastatin, baseline cIMT value was higher, i.e. 0.925 mm. Furthermore, the vast majority of patients in the ENHANCE study had been on statin therapy [12]. Interestingly, a beneficial effect of ezetimibe plus statin treatment on cIMT has been documented in other studies mainly attrib© 2013 Bentham Science Publishers
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uted to greater improvements in lipids compared with statin monotherapy [15, 20-24]. In this context, 2 meta-analyses found that the addition of ezetimibe to a statin resulted in significantly greater reductions in LDL-C levels, thus more patients achieved their LDLC targets [25, 26]. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial [7] was a randomized, double-blind trial comparing ezetimibe plus simvastatin (10 + 40 mg/day) vs placebo in patients with aortic stenosis (n = 1,873; median follow-up = 52.2 months). A significant reduction in ischemic CVD events was observed in the ezetimibe plus simvastatin group compared with placebo [hazard ratio (HR): 0.78; 95% confidence intervals (CI): 0.63 to 0.97; p = 0.02], whereas no effect was found in terms of aortic valve events [7]. A subanalysis of SEAS showed that the degree of lipid lowering by ezetimibe plus simvastatin may predict the decrease in ischemic cardiovascular events (ICE)in patients with mild Aortic Stenosis but it does not affect valve-related events [27]. The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) trial [28], an open-label, randomized study, compared statin (mainly atorvastatin or simvastatin at a mean dose of 42 mg/day) combination with ezetimibe (10 mg/day) or extended-release niacin (2,000 mg/day) in patients with coronary heart disease (CHD) or CHD equivalent (n = 315 patients; follow-up = 14 months for 208 patients and 7 ± 3 months for another 107 after treatment). Patients were already on statin therapy with baseline LDL-C and HDL-C levels
