CETP Inhibitors: Back With a New Target

CETP (cholesteryl ester transfer protein) plays an important role in lipid metabolism, facilitating the exchange of esterified cholesterol for triglycerides between lipoproteins. Genetic and cohort studies have demonstrated the presence of low CETP associates with lower rates of cardiovascular disease, diabetes, and neurodegeneration. However, early development programs of pharmacological CETP inhibitors proved disappointing with evidence of off-target toxicity, clinical futility, or marginal cardiovascular benefit with adipose tissue accumulation. Subsequent investigation of these programs and genomic studies has identified a pathway for drug development, in which promoting the ability of CETP inhibitors to lower levels of atherogenic lipids and lipoproteins and exerting a favorable impact on glycemic control may translate to reductions in cardiovascular risk, as opposed to the original motivation to raise HDL (high-density lipoprotein) cholesterol levels. Obicetrapib is a highly selective CETP inhibitor with evidence of favorable effects on atherogenic lipids and lipoproteins, glycemic control, and biomarkers of beta-amyloid pathology in preclinical Alzheimer disease. The ongoing potential for CETP inhibition as an effective tool in the prevention clinic and other emerging applications will be reviewed.