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.
Highlights
Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines
The reduction in LDL-C was −38% for anacetrapib, −37% for evacetrapib, −20% for torcetrapib, and −1% for dalcetrapib
The multivariable MR (MVMR) model for LDL-C and high-density lipoprotein cholesterol (HDL-C) (Fig. 6 and Supplemental Table 7) indicated that the CHD decreasing effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) were convincingly mediated by lower LDL-C (OR per SD decrease in LDL-C: 0.66, 95% confidence interval (95% CI): 0.58–0.75), for CETP we found evidence for HDL-C mediation instead (OR per SD increase in HDL-C: 0.85, 95% CI: 0.82–0.88)
Summary
Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. 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. The causal role of low-density lipoprotein cholesterol (LDLC) in coronary heart disease (CHD) has been established through randomized controlled trials (RCTs) of different LDL-C lowering drug classes[1,2,3,4] and by Mendelian randomization (MR) studies[5]. Compound-related failures can be addressed by developing improved CETP inhibitors, whereas target failure would affect all CETP inhibitors To address these uncertainties, we performed a drug target MR study of CETP, focusing on variants within and around the encoding gene (acting in cis) that are associated with circulating CETP concentration, to directly model the effects of pharmacological action on this target by a clean drug with no off-target actions. Drug target MR analyses of CETP and PCSK9 (an archetypal LDL-C lowering drug target) were compared for their effects on the same outcomes to differentiate anticipated effects of CETP versus PCSK9 inhibition
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