Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib

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• 作者：Stephen J. Nicholls ; MD ; PhD^&lowast ; ; Giacomo Ruotolo ; MD ; PhD^&dagger ; ; H. Bryan Brewer ; MD^&Dagger ; ; John P. Kane ; MD ; PhD^§ ; ; Ming-Dauh Wang ; PhD^&dagger ; ; Kathryn A. Krueger ; MD^&dagger ; ; Steven J. Adelman ; PhD^‖ ; Steven E. Nissen ; MD^¶ ; ; Daniel J. Rader ; MD^# ; ^{rader@mail.med.upenn.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：apolipoproteins ; cholesterol ; lipoproteins
• 刊名：Journal of the American College of Cardiology
• 出版年：2015
• 出版时间：17-24 November 2015
• 年：2015
• 卷：66
• 期：20
• 页码：2201-2210
• 全文大小：772 K

文摘

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. (A Study of LY2484595 in Patients With High LDL-C or Low HDL-C; NCT01105975)