Outcomes trials
Drug-target Mendelian randomization confirms CETP as an effective target for coronary heart disease with an on-target macular degeneration risk (Nat Commun 2021)
Original title: Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
To distinguish whether past CETP inhibitor failures reflect compound problems or a flawed drug target, researchers compared clinical trial evidence with drug-target Mendelian randomization of CETP protein concentration, benchmarked against PCSK9. Between-compound heterogeneity in trial effects on lipids, blood pressure and clinical outcomes indicated previous CETP inhibitor failures were likely compound-related rather than target-related. On-target CETP inhibition was expected to reduce risk of coronary heart disease, heart failure, diabetes and chronic kidney disease, while increasing risk of age-related macular degeneration, contrasting with lower PCSK9 concentration, which was linked to reduced coronary heart disease, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis and stroke risk but potentially higher Alzheimer's disease and asthma risk. The authors conclude CETP is genetically validated as an effective target for coronary heart disease prevention, with joint CETP and PCSK9 inhibition potentially offering added benefit given their distinct lipoprotein effects.
Original abstract
Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer's disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.
the classgeneticsoutcomes trialspcsk9
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.