Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib

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

Research output: Contribution to journalArticle

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

LanguageEnglish
Pages2201-2210
Number of pages10
JournalJournal of the American College of Cardiology
Volume66
Issue number20
DOIs
Publication statusPublished - 1 Jan 2015

Keywords

  • apolipoproteins
  • cholesterol
  • lipoproteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Nicholls, Stephen J. ; Ruotolo, Giacomo ; Brewer, H. Bryan ; Kane, John P. ; Wang, Ming Dauh ; Krueger, Kathryn A. ; Adelman, Steven J. ; Nissen, Steven E. ; Rader, Daniel J. / Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib. In: Journal of the American College of Cardiology. 2015 ; Vol. 66, No. 20. pp. 2201-2210.
@article{b719e9c933274cdea4a8d13b8d710f71,
title = "Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib",
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. (A Study of LY2484595 in Patients With High LDL-C or Low HDL-C; NCT01105975)",
keywords = "apolipoproteins, cholesterol, lipoproteins",
author = "Nicholls, {Stephen J.} and Giacomo Ruotolo and Brewer, {H. Bryan} and Kane, {John P.} and Wang, {Ming Dauh} and Krueger, {Kathryn A.} and Adelman, {Steven J.} and Nissen, {Steven E.} and Rader, {Daniel J.}",
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language = "English",
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Nicholls, SJ, Ruotolo, G, Brewer, HB, Kane, JP, Wang, MD, Krueger, KA, Adelman, SJ, Nissen, SE & Rader, DJ 2015, 'Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib', Journal of the American College of Cardiology, vol. 66, no. 20, pp. 2201-2210. https://doi.org/10.1016/j.jacc.2015.09.013

Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib. / Nicholls, Stephen J.; Ruotolo, Giacomo; Brewer, H. Bryan; Kane, John P.; Wang, Ming Dauh; Krueger, Kathryn A.; Adelman, Steven J.; Nissen, Steven E.; Rader, Daniel J.

In: Journal of the American College of Cardiology, Vol. 66, No. 20, 01.01.2015, p. 2201-2210.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib

AU - Nicholls, Stephen J.

AU - Ruotolo, Giacomo

AU - Brewer, H. Bryan

AU - Kane, John P.

AU - Wang, Ming Dauh

AU - Krueger, Kathryn A.

AU - Adelman, Steven J.

AU - Nissen, Steven E.

AU - Rader, Daniel J.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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. (A Study of LY2484595 in Patients With High LDL-C or Low HDL-C; NCT01105975)

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

KW - apolipoproteins

KW - cholesterol

KW - lipoproteins

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U2 - 10.1016/j.jacc.2015.09.013

DO - 10.1016/j.jacc.2015.09.013

M3 - Article

VL - 66

SP - 2201

EP - 2210

JO - Journal of the American College of Cardiology

T2 - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 20

ER -