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

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 [ 14 C]-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