The two faces of cholesteryl ester transfer protein inhibitors

PURPOSE OF REVIEW: The causal role of LDL in atherosclerotic cardiovascular disease (ASCVD) is well established, but the contribution of HDL has proven more complex. CETP inhibitors were originally developed to increase HDL-cholesterol (HDL-C), but the failure of clinical trials and genetic evidence have changed our understanding of CETP biology. With the development of obicetrapib, a next-generation CETP inhibitor, there has been renewed interest in its therapeutic potential. This review summarizes the latest findings on CETP inhibition and highlights the evolving perspectives from lipid modulation to broader clinical applications. RECENT FINDINGS: Clinical trials and Mendelian randomisation consistently show that increasing HDL-C alone does not reduce cardiovascular risk, while lowering apoB-containing lipoproteins is associated with benefit. Off-target effects, modest efficacy or insufficient follow-up limited previous CETP inhibitors. Obicetrapib, in contrast, achieves a significant LDL-C and apoB reduction, a marked HDL-C increase and favourable safety. Beyond ASCVD, CETP inhibition may also have an impact on diabetes risk, cognitive function and possibly other conditions, although data are still preliminary. SUMMARY: The therapeutic focus has shifted from HDL-C elevation to apoB lowering as the determinant of cardiovascular benefit. Obicetrapib shows promise, with ongoing trials designed to define its role in ASCVD management.