Anacetrapib
Anacetrapib lowers VLDL triglyceride only on a statin background, by boosting the catabolic rate of VLDL-TG (J Lipid Res 2017)
Original title: Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E
To explain how CETP inhibition with anacetrapib lowers triglycerides, this study measured the kinetics of VLDL triglyceride and apoC-II, apoC-III, and apoE in mildly hypercholesterolemic subjects randomized to placebo (n equals 10) or atorvastatin 20 mg/d (n equals 29) for 4 weeks, followed by 8 weeks of anacetrapib 100 mg/d, using stable isotope studies to determine fractional catabolic rates (FCRs) and production rates (PRs) after each period. On the atorvastatin background, anacetrapib reduced the VLDL-TG pool through an increased VLDL-TG FCR (29%, P equals 0.002). As anacetrapib monotherapy, the VLDL-TG FCR also rose (41%, P equals 0.11), but the VLDL-TG pool was unchanged because the VLDL-TG production rate rose in parallel (39%, P equals 0.014). ApoC-II, apoC-III, and apoE pool sizes all increased with anacetrapib, through mechanisms that differed by treatment group, indicating anacetrapib lowers VLDL-TG mainly by enhancing lipolytic clearance of VLDL, an effect only realized when combined with a statin.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.