Evacetrapib raises large and medium HDL but cuts the functionally important preβ-1 HDL by 36%, a clue to why raising HDL-C didn't help (Atherosclerosis 2019)

Original title: Evacetrapib reduces preβ-1 HDL in patients with atherosclerotic cardiovascular disease or diabetes

Atherosclerosis · 14 April 2019 · 7

Chen Y, Dong J, Zhang X, Chen X, Wang L, Chen H, Ge J, Jiang XC

CETP inhibitors raise HDL cholesterol without protecting against cardiovascular disease, and this study investigated whether the effect on HDL subclasses could explain the disconnect. Patients with atherosclerotic cardiovascular disease or diabetes on atorvastatin 40 mg received evacetrapib 130 mg (n = 70) or placebo (n = 30), with HDL separated into large, medium, small and preβ-1 subclasses by native polyacrylamide gel electrophoresis at baseline and 3 months. Relative to placebo, evacetrapib dramatically increased large and medium HDL, but significantly reduced small HDL by 27% and preβ-1 HDL, the primary acceptor for ABCA1-driven cholesterol efflux, by 36%. Evacetrapib also reduced total LDL while producing a more polydisperse LDL population, with particles both larger and smaller than in the placebo group. The authors note preβ-1 HDL and medium HDL are negatively interrelated, and propose this shift away from the most functionally active small HDL subclasses as a clue to why CETP inhibitors have not translated HDL-C increases into cardiovascular benefit.

Original abstract

Background And Aims: Cholesteryl ester transfer protein (CETP) inhibitor-mediated induction of HDL-cholesterol has no effect on the protection from cardiovascular disease (CVD). However, the mechanism is still unknown. Data on the effects of this class of drugs on subclasses of HDL are either limited or insufficient. In this study, we investigated the effect of evacetrapib, a CETP inhibitor, on subclasses of HDL in patients with atherosclerotic cardiovascular disease or diabetes.

Methods: Baseline and 3-month post-treatment samples from atorvastatin 40 mg plus evacetrapib 130 mg (n = 70) and atorvastatin 40 mg plus placebo (n = 30) arms were used for this purpose. Four subclasses of HDL (large HDL, medium HDL, small HDL, and preβ-1 HDL) were separated according to their size and quantified by densitometry using a recently developed native polyacrylamide gel electrophoresis (PAGE) system.

Results: Relative to placebo, while evacetrapib treatment dramatically increased large HDL and medium HDL subclasses, it significantly reduced small HDL (27%) as well as preβ-1 HDL (36%) particles. Evacetrapib treatment reduced total LDL, but also resulted in polydisperse LDL with LDL particles larger and smaller than the LDL subclasses of the placebo group.

Conclusion: Evacetrapib reduced preβ-1 HDL and small HDL in patients with ASCVD or diabetes on statin. Preβ-1 HDL and medium HDL are negatively interrelated. The results could give a clue to understand the effect of CETP inhibitors on cardiovascular outcomes.

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