Safety and Efficacy of Cholesteryl Ester Transfer Protein Inhibition: from Genetics to Outcome Trials

Therapeutic Area ASCVD/CVD Risk Assessment Background To investigate the associations between HDL-C levels with mortality and cardiovascular (CV) events; the safety of increased HDL-C due to CETP inhibition; and the efficacy of CETP as a target of lipid-altering therapy. Methods The cumulative rates of major coronary events, CV mortality, and non-CV mortality were compared among participants in the UK Biobank (n∼445,000) who were randomized by nature to different levels of lifetime exposure to HDL-C (Mendelian randomization [MR]) using an instrumental variable genetic score. The cumulative rates of major coronary events among participants randomized by nature to CETP, HMG CoA reductase, and PCSK9 inhibition was compared for the same absolute reduction in apoB among participants in the UK Biobank or CARDloGRAMplusC4D consortium (n=630,070). A Meta-analysis of RCTs adjusted for magnitude and duration of therapy was used to estimate the association between CETP inhibition induced changes in plasma HDL-C and the risk of both all-cause and CV mortality (n=58,412); and between CETP inhibition and the risk of major CV events, CV mortality, and all-cause mortality (n=42,541). Results There was no compelling unconfounded evidence from observational studies, MR studies, or RCTs that very high plasma HDL-C levels increase risk of all-cause, non-CV, or CV mortality. CETP inhibition is associated with a modestly lower risk of all-cause and CV mortality. There was consistent randomized evidence from MR and RCTs that CETP inhibition reduces risk of major CV events proportional to the achieved reduction in plasma apoB, and by approximately the same amount as statins and PCSK9 inhibitors for the same achieved reduction in apoB. Conclusions Neither naturally occurring elevated HDL-C or therapeutically increased HDL-C due to CETP inhibition are associated with increased all-cause, CV, or non-CV mortality. ApoB reduction induced by CETP inhibition reduces CV risk by approximately the same degree as reductions induced by statins and PCSK9 inhibitors.