Cholesteryl Ester Transfer Protein Inhibition and High-Density Lipoprotein Particle Composition: Consequences for Atherogenesis and Neurodegeneration

Low activity or inhibition of cholesteryl ester transfer protein (CETP), the protein required for transferring triglyceride from very-low-density lipoprotein in exchange for cholesteryl ester from high-density lipoprotein (HDL)—also involved in lipophilic antioxidant exchange—has been shown to influence several distinct disorders. We aimed to determine the effects of the next generation potent CETP inhibitor, obicetrapib, on lipoprotein disposition of plasma and cerebrospinal fluid (CSF) antioxidant markers. Therefore, we measured apolipoprotein (apo)A1, monomeric apoA1 (m-apoA1), apoE, apoM, sphingosine-1-phosphate (S1P), lipoprotein lipophilic antioxidants, and oxidized LDL (oxLDL) in plasma from a Phase 2 trial of 2.5, 5, and 10 mg/d obicetrapib or placebo taken for 8 weeks by Japanese participants (n=12); and plasma and CSF lipoprotein antioxidants from a proof-of-concept study of obicetrapib 10 mg/d taken for 24 weeks by apoE4-positive early Alzheimer’s disease patients (n=13). In the Japanese dose-range study, obicetrapib robustly increased all antioxidant levels in the HDL fraction and decreased plasma levels of oxLDL at all doses. HDL subfractions tested only in the 2.5 mg group, indicated obicetrapib also raised HDL2 cholesterol, apoA1, S1P, apoM, and apoE. In particular, m-apoA1 was found in the HDL2 and HDL3 fractions and was markedly increased and correlated with apoM and S1P in the HDL2 fraction. In the Alzheimer’s disease study, HDL2 and CSF carotenoid and tocopherol levels were increased upon obicetrapib therapy. These results are key to unraveling the mechanisms of obicetrapib’s effects on HDL metabolism and function, which has implications for atherogenesis and neurodegeneration. One Sentence Summary: Obicetrapib increased levels of plasma, HDL, and CSF lipophilic antioxidants, decreased plasma oxidized LDL, and altered HDL apolipoprotein and S1P distribution.