Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/112558
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Type: Journal article
Title: Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib
Author: Nicholls, S.
Ruotolo, G.
Brewer, H.
Kane, J.
Wang, M.
Krueger, K.
Adelman, S.
Nissen, S.
Rader, D.
Citation: Journal of the American College of Cardiology, 2015; 66(20):2201-2210
Publisher: Elsevier
Issue Date: 2015
ISSN: 0735-1097
1558-3597
Statement of
Responsibility: 
Stephen J. Nicholls, Giacomo Ruotolo, H. Bryan Brewer, John P. Kane, Ming-Dauh Wang, Kathryn A. Krueger, Steven J. Adelman, Steven E. Nissen, Daniel J. Rader
Abstract: Background: Potent cholesteryl ester transfer protein (CETP) inhibitors have been shown to substantially increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels as monotherapy and combined with statins. However, data on the effects of this class of drugs on macrophage cholesterol efflux capacity (CEC), a functional assay that characterizes a key step in the process of reverse cholesterol transport, are limited. Objectives: This study assessed the impact of evacetrapib, statins, or combination therapy on CEC. Methods: We analyzed samples from 377 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C levels who were enrolled in a phase 2 trial of evacetrapib. Percent changes from baseline in CEC (total, non-ABCA1-, and ABCA1-specific) and HDL subpopulations were evaluated after 12 weeks of treatment with placebo, statin monotherapy, evacetrapib monotherapy, or evacetrapib combined with statins. Pre-beta-1 HDL levels were quantified by immunofixation and nondenaturing 2-dimensional gel electrophoresis (2DGE). Results: Relative to placebo, evacetrapib monotherapy increased dose-dependent total and non-ABCA1-specific CEC up to 34% and 47%, respectively. Evacetrapib monotherapy also increased ABCA1-specific CEC up to 26%. Relative to statin monotherapy, evacetrapib with statins also increased total, non-ABCA1-, and ABCA1-specific CEC by 21%, 27%, and 15%, respectively. In contrast, rosuvastatin and simvastatin significantly reduced total and ABCA1-specific CEC, whereas atorvastatin had no significant effect. Consistent with ABCA1-specific CEC, evacetrapib monotherapy and evacetrapib combined with statins significantly increased pre-beta-1 HDL levels as measured by either method. Conclusions: Evacetrapib, as monotherapy and combined with statins, not only increased total CEC, but also increased ABCA1-specific CEC and pre-beta-1 HDL. The mechanisms by which potent CETP inhibition increases ABCA1-specific CEC and pre-beta-1 HDL require further study.
Keywords: Apolipoproteins; cholesterol; lipoproteins
Rights: © 2015 by the American College of Cardiology Foundation. Published by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
RMID: 0030041858
DOI: 10.1016/j.jacc.2015.09.013
Appears in Collections:Medicine publications

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