Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E

Authors

John S. Millar, University of Pennsylvania
Michael E. Lassman, Merck & Co.
Tiffany Thomas, Columbia University
Rajasekhar Ramakrishnan, Columbia University
Patricia Jumes, Merck & Co.
Richard L. Dunbar, University of Pennsylvania
Emil M. deGoma, University of Pennsylvania
Amanda L. Baer, University of Pennsylvania
Wahida Karmally, Columbia University
Daniel S. Donovan, Columbia University
Hashmi Rafeek, University of Pennsylvania
John A. Wagner, Merck & Co.
Stephen Holleran, Columbia University
Joseph Obunike, CUNY New York City College of Technology
Yang Liu, Merck & Co.
Soumia Aoujil, University of Pennsylvania
Taylor Standiford, University of Pennsylvania
David E. Gutstein, Merck & Co.
Henry N. Ginsberg, Columbia University
Daniel J. Rader, University of Pennsylvania
Gissette Reyes-Soffer, Columbia University

Document Type

Article

Publication Date

3-17-2017

Abstract

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.

Comments

This article originally appeared in Journal of Lipid Research, available at DOI https://doi.org/10.1194/jlr.M074880

Final version free via Creative Commons CC-BY license.