Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

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.

Fig. 1. Differences in CETP-inhibitor effects on lipids, blood pressure, and clinical endpoints.

N.B Results are based on a fixed effect compound-specific meta-analyses with differences between compounds tested using a Q-test (Heterogeneity). *** indicates a p-value < 0.001 for a two-sided Cochrane’s Q-test, without adjustment for multiplicity. The p-values are provided, to 2 dp, in Supplemental Fig. 3 as “Heterogeneity p-value”. LDL: LDL-C, HDL: HDL-C, TG: triglycerides, ApoA1: apolipoprotein A1, ApoB: apolipoprotein B, S/DBP: systolic/diastolic blood pressure, ACM: all-cause mortality, CVD: cardiovascular disease, FCVD: fatal-CVD, MI myocardial infarction, FMI: fatal-MI, ST: any stroke, IST: Ischemic stroke, HST: hemorrhagic stroke, HF: heart failure. Error bars reflect 95% confidence intervals, and the central dot represents the odds ratio (RHS) or mean difference (LHS). The total number of subjects and events used in each analysis are provided in Supplemental Fig. 3.

Fig. 2. Drug target Mendelian randomization estimates of lower CETP and PCSK9 weighted by genetic associations with protein concentration or downstream lipid.

N.B The rows represent the quantitative outcomes and the columns represent the intermediate variable (approximating) drug target concentration. Cells are colored by effect direction times −log₁₀(p-value), with the mean difference (the slope coefficient), provide for MR results with a p-value smaller than 0.05. The p-values were truncated at 10⁻¹⁶ ensuring sufficient variation in the color code. p-values were calculated from two-sided Z-test statistics, without multiplicity correction. Effects were orientated toward the canonical drug target effect direction: decreasing for CETP concentration, PCSK9 concentration, LDL-C, and for TG, and increasing for HDL-C.

Fig. 3. The drug target Mendelian randomization effects of lower CETP and PCSK9 concentration on clinical end-points.

N.B CHD: coronary heart disease, HF: heart failure, AF: atrial fibrillation, T2DM: type 2 diabetes mellitus, CKD: chronic kidney disease, IBD: inflammatory bowel disease, CD: Crohn’s disease, UC: ulcerative colitis, MS: multiple sclerosis, AMD: age-related macular degeneration. Error bars reflect 95% confidence intervals, where the central dot represents the odds ratio. The number of events and total samples are provided in the figure as “Events/Total”.

Fig. 4. The drug target Mendelian randomization effects of lower CETP and PCSK9 concentration on NMR-measured metabolites.

N.B Results are provided as −log₁₀(p-values) times effect direction, with the x-axis limits set to ±16. Bars are semi-transparent and plotted on top of each other to directly compare the two drug targets in their NMR measured lipids effect estimates. The vertical lines at ±1.3 represent the traditional p-value threshold of 0.05. p-values were calculated from two-sided Z-test statistics, without multiplicity correction. Analyses were based on a sample size of 33,029 subjects.

Fig. 5. A cluster analysis comparing the on-target Mendelian randomization effect of lower CETP concentration to effects from CETP inhibiting compounds.

N.B CETP (MR estimates) and drug compound are ordered by columns, with specific outcomes listed in the rows. Effects are presented as −log10(p-values) × effect direction, where the CETP effect is orientated towards the CETP decreasing direction. p-values were calculated from two-sided Z-test statistics, without multiplicity correction. We note that p-values can be mapped to z-statistics, for example for a p-value of 0.05 we have −log₁₀(0.05) = 1.3, which can be mapped to a z-statistic of 1.96. Clustering was performed on the square root of the −log₁₀(p-values) × effect direction, with the p-value truncated to 10⁻⁶⁰ to ensure enough difference between the CETP compound effect on changes in lipids. Associations with a p-value below 0.05 are indicated with a star. The dendrograms represent clustering by outcome (rows) and compound/drug target (columns). Point estimates (OR, MD), confidence intervals, and p-values are presented in Supplemental Tables 3, 6, and 7.

Fig. 6. The multivariable drug target MR assessing the possible LDL-C and HDL-C mediating effects of CETP and PCSK9 concentration on the incidence of clinical events.

N.b. Results are colored by −log₁₀(p-values) × effect direction, with starred tiles indicating results with a p-value > 0.05. p-values were calculated from two-sided Z-test statistics, without multiplicity correction. Effects were orientated towards the canonical drug target effect direction: decreasing for LDL-C and increasing for HDL-C.