In CETP mice, obicetrapib plus ezetimibe on top of atorvastatin regresses established atherosclerosis by 44% via LDL-receptor-driven VLDL clearance (J Lipid Res 2026)

Original title: Obicetrapib and ezetimibe enhance LDL receptor-mediated VLDL clearance and regress atherosclerosis on atorvastatin background

J Lipid Res · 25 March 2026 · 4

Inia JA, Zhang LH, Keijzer N, Worms N, van Nieuwkoop-van Straalen A, Ditmarsch M, de Kleer M, Jukema JW, Kastelein JJP, Szarek M, van den Hoek AM, Stokman G et al.

In APOE*3-Leiden.CETP mice on a Western-type diet, obicetrapib alone cut non-HDL-C by 53% and blocked CETP activity by 99%, raising HDL-C by 286%; combined with ezetimibe non-HDL-C fell by 75%. Both increased VLDL clearance (plasma half-life fell 44% and 57%) and LDL receptor expression (up 63% and 74%) without raising liver lipids. After 28 weeks, atherosclerotic lesion area fell by 90% (obicetrapib) and 98% (combination), driven by non-HDL-C exposure rather than HDL-C. In mice with established lesions, obicetrapib plus ezetimibe added to atorvastatin for 24 weeks regressed lesion area by 44% versus baseline. Preclinical mechanistic work supporting the rationale for combination regimens such as TANDEM.

Original abstract

The selective cholesteryl ester transfer protein (CETP) inhibitor obicetrapib is in clinical evaluation for dyslipidemia and cardiovascular risk reduction. This study investigated how obicetrapib alone and with ezetimibe reduces non-HDL-C, affects atherosclerotic lesion progression, and regression when added to background atorvastatin intervention. APOE∗3-Leiden.CETP mice received a Western-type diet (WTD) or this diet supplemented with obicetrapib, ezetimibe, or both. After 8 weeks, all interventions reduced non-HDL-C levels (obicetrapib: -53%; ezetimibe: -19%; combination: -75%). Obicetrapib mono and combination treatment blocked CETP activity (-99% and -98%), thereby increasing HDL-C levels (+286% and +256%). Very low-density lipoprotein (VLDL) cholesterol production was not affected, while obicetrapib and the combination with ezetimibe increased VLDL clearance (plasma half-life [14C]-cholesteryloleate: -44% and -57%) and LDL receptor expression (+63% and +74%), without increasing liver lipids. Atherosclerosis progression was evaluated after 28 weeks. All interventions reduced atherosclerotic lesion area (obicetrapib: -90%; ezetimibe: -50%; combination: -98%) and severity due to almost complete reductions in severe lesions (obicetrapib: -80%; combination: -98%). Non-HDL-C exposure (P < 0.001) was independently associated with lesion area, in contrast to HDL-C (P = 0.336). Combination treatment synergistically reduced non-HDL-C and atherosclerosis. For atherosclerosis regression, mice with advanced and established atherosclerosis received obicetrapib and ezetimibe on top of atorvastatin for 24 weeks. Triple therapy regressed lesion area (-44% vs. baseline) and increased healthy vessel segments, indicating potential for complete atherosclerosis resolution. In summary, obicetrapib, alone or combined with ezetimibe, lowers non-HDL cholesterol by enhancing LDL receptor-mediated VLDL clearance, thereby synergistically reducing atherosclerosis progression, while triple treatment with atorvastatin induces regression of established atherosclerotic lesions.

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