Anacetrapib impairs endothelial function in CETP-transgenic mice despite raising HDL-C fivefold, while evacetrapib does not (Atherosclerosis 2017)

Original title: Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C increase

Atherosclerosis · 16 January 2017 · 7

Simic B, Mocharla P, Crucet M, Osto E, Kratzer A, Stivala S, Kühnast S, Speer T, Doycheva P, Princen HM, van der Hoorn JW, Jukema JW et al.

E3L.CETP mice on a high-cholesterol diet were treated with anacetrapib (3 mg/kg/day), evacetrapib (3 mg/kg/day), or placebo, with triglycerides and cholesterol measured at weeks 5, 14, and 21, cholesterol efflux and paraoxonase-1 activity assessed after 3 weeks on normal chow, and endothelial function analyzed in isolated aortic rings at week 21. Both inhibitors raised HDL-C (5-fold with anacetrapib, 3.4-fold with evacetrapib) and reduced triglycerides (-39% versus placebo, P equals 0.0174), but total cholesterol fell only with anacetrapib (-32%, P equals 0.0386). Evacetrapib increased cholesterol efflux and paraoxonase-1 activity (plus 45% and plus 35%, P less than 0.005) and reduced aortic reactive oxygen species (-49%, P equals 0.020), while anacetrapib, but not evacetrapib, impaired endothelium-dependent vasorelaxation (P less than 0.05); no such effects appeared in mice lacking the human CETP transgene. These findings suggest anacetrapib carries unfavorable endothelial effects beyond CETP inhibition itself, potentially explaining the neutral clinical trial results seen despite HDL-C elevation.

Original abstract

Background And Aims: High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and evacetrapib on triglycerides, cholesterol and lipoproteins, cholesterol efflux, paraoxonase activity (PON-1), reactive oxygen species (ROS), and endothelial function in E3L and E3L.CETP mice.

Methods: Triglycerides and cholesterol were measured at weeks 5, 14 and 21 in E3L.CETP mice on high cholesterol diet and treated with anacetrapib (3 mg/kg/day), evacetrapib (3 mg/kg/day) or placebo. Cholesterol efflux was assessed ex-vivo in mice treated with CETP inhibitors for 3 weeks on a normal chow diet. Endothelial function was analyzed at week 21 in isolated aortic rings, and serum lipoproteins assessed by fast-performance liquid chromatography.

Results: Anacetrapib and evacetrapib increased HDL-C levels (5- and 3.4-fold, resp.) and reduced triglycerides (-39% vs. placebo, p = 0.0174). Total cholesterol levels were reduced only in anacetrapib-treated mice (-32%, p = 0.0386). Cholesterol efflux and PON-1 activity (+45% and +35% vs. control, p < 0.005, resp.) were increased, while aortic ROS production was reduced with evacetrapib (-49% vs. control, p = 0.020). Anacetrapib, but not evacetrapib, impaired endothelium dependent vasorelaxation (p < 0.05). In contrast, no such effects were observed in E3L mice for all parameters tested.

Conclusions: Notwithstanding a marked rise in HDL-C, evacetrapib did not improve endothelial function, while anacetrapib impaired it, suggesting that CETP inhibition does not provide vascular protection. Anacetrapib exerts unfavorable endothelial effects beyond CETP inhibition, which may explain the neutral results of large clinical trials in spite of increased HDL-C.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.