Outcomes trials
CETP inhibitor trials reframe the HDL hypothesis around apoB lowering rather than HDL-C raising (Drugs 2026)
Original title: Reframing the High-density Lipoprotein (HDL) Hypothesis in Light of Clinical Trials of Cholesterol Ester Transfer Protein (CETP) Inhibitors
This review reassesses the HDL hypothesis, that raising HDL cholesterol reduces cardiovascular events, in light of clinical trial data from CETP inhibitors, which raise HDL cholesterol with variable effects on LDL cholesterol and apolipoprotein B. Trial outcomes were heterogeneous, with several showing neutral or adverse clinical results despite robust HDL-C increases, and this pattern, together with Mendelian randomisation evidence, suggests low HDL-C is a risk marker rather than a causal driver of atherosclerotic cardiovascular disease. The favourable outcomes seen with certain CETP inhibitors are argued to be more consistently explained by reductions in apoB-containing lipoproteins, including LDL-C and non-HDL-C, than by HDL-C increases themselves, shifting the HDL hypothesis toward apoB-containing lipoproteins as the more plausible causal treatment pathway and toward HDL quality rather than quantity.
Original abstract
High-density lipoprotein cholesterol (HDL-C) has been inversely associated with atherosclerotic cardiovascular disease (ASCVD) risk. This relationship is the foundation of the "HDL hypothesis," which states that increasing plasma HDL-C levels would result in a decrease in cardiovascular events. The recent surge in clinical testing of cholesteryl ester transfer protein (CETP) inhibitors provides valuable data for this hypothesis. The CETP inhibitors increase plasma HDL-C along with variable effects on low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). The clinical outcomes of randomized controlled trials were heterogeneous, with several studies showing either neutral or adverse clinical outcomes despite robust increases in HDL-C values. These observations along with Mendelian randomization studies suggest that low HDL-C is a risk marker, not a causal mediator of ASCVD. New evidence points to HDL functionality, specifically cholesterol efflux potential and particle composition, instead of HDL-C concentration as a more relevant determinant of ASCVD risk. The favorable clinical outcomes observed with certain CETP inhibitors are more consistently explained by reductions in apoB-containing lipoproteins (including LDL-C and non-HDL-C), rather than increases in HDL-C itself. This distinction reframes the HDL hypothesis where HDL-C is merely a biomarker of ASCVD while apoB-containing lipoproteins are the more plausible causal treatment pathway. These findings have shifted the focus of the HDL hypothesis from the "quantity" to the "quality" of HDL.
the classHDL biologyLDL and apoBoutcomes trials
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.