Evacetrapib
Evacetrapib more than doubled circulating ApoA5 in the ACCELERATE and ACCENTUATE trials, explaining how CETP inhibitors lower triglycerides (J Clin Lipidol 2025)
Original title: Cholesteryl ester transfer protein activity correlates inversely with apolipoprotein A5 levels
CETP inhibitors modestly lower triglycerides despite blocking the transfer of triglycerides out of ApoB-containing lipoproteins, a paradox this study set out to explain by studying the relationship between CETP and apolipoprotein A5 (ApoA5), which lowers triglycerides by suppressing ANGPTL3/8-mediated inhibition of lipoprotein lipase. CETP-overexpressing transgenic mice had increased triglycerides, normal ANGPTL3/8 levels, but dramatically reduced ApoA5. The CETP inhibitor evacetrapib had no effect on ANGPTL3/8 in CETP-overexpressing mice or in humans, but increased ApoA5 concentrations in both species. In human subjects, evacetrapib treatment raised circulating ApoA5 by 160.1% in the ACCELERATE study and 204.7% in the ACCENTUATE study. The results identify a previously unrecognised CETP-ApoA5 link: CETP overexpression lowers ApoA5 while CETP inhibition raises it, offering a mechanistic explanation for the triglyceride-lowering effect of the drug class.
Original abstract
Background: Cholesteryl ester transfer protein (CETP) mediates the exchange of triglycerides (TG) from apolipoprotein B (ApoB)-containing lipoproteins to high-density lipoproteins (HDL) and the reciprocal exchange of cholesterol (C) from HDL to ApoB-containing lipoproteins. CETP inhibition increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C) while modestly decreasing TG. Considering that CETP inhibitors block removal of TG from TG-rich lipoproteins (TRL), it is interesting that CETP inhibition decreases TG concentrations. TG levels are largely regulated by lipoprotein lipase (LPL), the enzyme primarily responsible for hydrolyzing TG. The angiopoietin-like 3/8 complex (ANGPTL3/8) is the most potent circulating LPL inhibitor, while the TG-lowering apolipoprotein A5 (ApoA5) acts by suppressing ANGPTL3/8-mediated LPL inhibition.
Methods: To better understand CETP biology, we studied the effects of CETP overexpression and CETP inhibition on the levels of ANGPTL3/8 and ApoA5 in circulation using dedicated immunoassays.
Results: CETP-overexpressing transgenic mice had increased TG and normal ANGPTL3/8 levels but manifested dramatically reduced ApoA5 concentrations. Administration of the CETP inhibitor evacetrapib had no effect on ANGPTL3/8 levels in CETP-overexpressing mice or in humans. However, evacetrapib administration increased ApoA5 concentrations in both species. In human subjects, evacetrapib treatment increased circulating ApoA5 levels in the late-stage ACCELERATE and ACCENTUATE studies by 160.1% and 204.7%, respectively.
Conclusions: Our results uncover a previously unrecognized link between CETP and ApoA5 by showing that CETP overexpression reduces ApoA5 levels while CETP inhibition increases ApoA5 concentrations.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.