Journal of Lipid Research · Mar 25, 2026

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

By Inia JA, Zhang LH, Keijzer N et al.

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.

doi.org/10.1016/j.jlr.2026.101028Open accessPubMed 41887531Interventions