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      Cholesteryl ester transfer protein inhibitors for dyslipidemia: focus on dalcetrapib

      ,

      Drug Design, Development and Therapy

      Dove Medical Press

      dalcetrapib, CETP inhbitor, HDL, cardiovascular disease

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          Abstract

          Among the noteworthy recent stories in the management and prevention of atherosclerotic cardiovascular disease (CVD) is the saga of the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP). Inhibiting CETP significantly raises plasma concentrations of high-density lipoprotein cholesterol, which has long been considered a marker of reduced CVD risk. However, the first CETP inhibitor, torcetrapib, showed a surprising increase in CVD events, despite a dramatic increase in high-density lipoprotein cholesterol levels. This paradox was explained by putative off-target effects not related to CETP inhibition that were specific to torcetrapib. Subsequently, three newer CETP inhibitors, namely dalcetrapib, anacetrapib, and evacetrapib, were at various phases of clinical development in 2012. Each of these had encouraging biochemical efficacy and safety profiles. Dalcetrapib even had human arterial imaging results that tended to look favorable. However, the dalcetrapib development program was recently terminated, presumably because interim analysis of a large CVD outcome trial indicated no benefit. These events raise important questions regarding the validity of the mechanism of CETP inhibition and the broader issue of whether pharmacological raising of high-density lipoprotein cholesterol itself is a useful strategy for CVD risk reduction.

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          Author and article information

          Journal
          Drug Des Devel Ther
          Drug Des Devel Ther
          Drug Design, Development and Therapy
          Dove Medical Press
          1177-8881
          2012
          24 September 2012
          : 6
          : 251-259
          Affiliations
          Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
          Author notes
          Correspondence: Robert A Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada, N6A 5K8, Tel +1 519 931 5271, Fax +1 519 931 5218, Email hegele@ 123456robarts.ca
          Article
          dddt-6-251
          10.2147/DDDT.S34976
          3460676
          23055695
          © 2012 Goldberg and Hegele, publisher and licensee Dove Medical Press Ltd.

          This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

          Categories
          Review

          Pharmacology & Pharmaceutical medicine

          cardiovascular disease, hdl, dalcetrapib, cetp inhbitor

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