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Cardiovascular Risk Ezetimibe in the Treatment of Patients with Metabolic Diseases Mayssam A Nehme 1 and Ashish Upadhyay 2 1. Resident in Internal Medicine; 2. Assistant Professor of Medicine, Renal Section, Department of Medicine, Boston Medical Center and Boston University School of Medicine Abstract Dyslipidaemia is an established risk factor for cardiovascular disease. While statin therapy remains the most important component of dyslipidaemia management, a substantial proportion of patients on statin monotherapy fails to achieve guideline-recommended lipid levels. Ezetimibe is a second-line lipid-lowering agent that reduces sterol absorption and has a favourable effect on lipid profile. This article reviews studies examining the role of ezetimibe on lipid profile, metabolic biomarkers and cardiovascular outcomes in individuals with metabolic diseases. Special focus is given to studies in patients with dyslipidaemia, Type 2 diabetes and the metabolic syndrome. The controversy surrounding the role of ezetimibe in mitigating atherosclerosis is also highlighted. The article concludes that the ezetimibe–statin combination improves lipid parameters and helps attain guideline-recommended lipid goals in patients with metabolic diseases. However, further research is needed to better understand the role of ezetimibe monotherapy, and the impact of ezetimibe on clinical cardiovascular outcomes. Keywords Dyslipidaemia, ezetimibe, metabolic diseases, atherosclerosis Disclosure: The authors have no conflicts of interest to declare. Received: 7 February 2013 Accepted: 28 February 2013 Citation: European Endocrinology 2013;9(1):48–53 Correspondence: Ashish Upadhyay, Renal Section, Department of Medicine, Boston Medical Center and Boston University School of Medicine, 72 E Concord Street, Evans 124, Boston, MA 02118, US. E: ashishu@bu.edu Dyslipidaemia along with hypertension, obesity and cigarette smoking are established risk factors for premature heart disease. 1 The third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) recommends a low-density lipoprotein cholesterol (LDL-C) goal of <2.6 mmol/l (<100 mg/dl) for patients with high risk of coronary artery disease (CAD) or CAD risk equivalent and <3.4 mmol/l (<130 mg/dl) for patients with moderate risk of CAD. 2,3 Although statins have been shown to be effective in lowering LDL-C and decreasing mortality, 4 40–80 % of individuals on statin monotherapy fail to achieve guideline-recommended LDL-C levels, with the lowest success rate for LDL-C goal achievement seen in patients with the highest risk of CAD. 5,6 Heterogeneity in response may partly be due to genetic variation, with poor statin responders having a higher baseline cholesterol absorption, 7 or increased compensatory cholesterol absorption during therapy. 8 Although statins can reduce LDL-C levels by 30–50 %, doubling of dose, for those who do not attain a goal LDL-C, only yields an additional reduction of 5–7 %. 9 In addition, there is a residual risk of CAD despite statin therapy even in individuals who have achieved the recommended LDL-C level. This residual risk may be from a low high- density lipoprotein cholesterol (HDL-C) level, high triglyceride level, high baseline apolipoprotein B (ApoB) level or from the influence of other co-existing vascular risk factors. 10–14 It is also important to note that while only a small proportion of patients on statins do not tolerate treatment, 15 some subgroups have a higher risk of drug toxicity and statin-induced myopathy, 16 particularly patients with chronic kidney disease or patients with HIV receiving protease inhibitors. 17,18 Therefore, adding a second-line lipid-lowering agent such as ezetimibe may help in reducing the dose of statin, lowering the risk of side effects, attaining the recommended LDL-C goals and ameliorating 48 the residual cardiovascular risk in patients on statin monotherapy. In this article, we will look at studies examining the use of ezetimibe in metabolic diseases. What is Ezetimibe? Ezetimibe is a lipid-lowering agent that prevents sterol absorption by selectively inhibiting the Niemann Pick C1 Like 1 Protein (NPC1L1) at the jejunal brush border. 19 Decreased sterol absorption leads to the over-expression of hepatic LDL-C receptors with further reduction in the blood LDL-C level. 20 A combination therapy of 10 mg of ezetimibe and 10 mg of simvastatin results in a similar degree of LDL-C lowering as an 80 mg simvastatin monotherapy. 21 In addition, ezetimibe has been shown to increase the HDL-C level, 22 and decrease triglyceride and ApoB levels. 23–25 Ezetimibe also has a favourable metabolic profile with limited drug–drug interactions as it does not induce nor inhibit cytochrome P450 system. It is primarily metabolised by the liver and excreted in faeces, and usually no severe side effects are noted with its use. Despite these salutary effects and the approval for use by regulatory agencies based on its efficacy in improving lipid profile, 26 evidence from recent trials examining carotid intima-media thickness (CIMT) as a surrogate for atherosclerosis have raised questions about the added beneficial role of ezetimibe in the treatment of atherosclerotic vascular diseases. 27,28 Tables 1, 2 and 3 summarise clinical studies examining the impact of ezetimibe treatment in various populations. Ezetimibe and Cardiovascular Events Two trials (see Table 1) have assessed the efficacy of ezetimibe and statin combination therapy in reducing major cardiovascular events. No trial has evaluated the impact of ezetimibe monotherapy on clinical outcomes. © To uch ME d ica l ME di a 2013