Cholesteryl Ester Transfer Protein as a Drug Target for Cardiovascular Disease

Drug development of cholesteryl ester transfer protein (CETP) inhibition to prevent coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and Mendelian randomization (MR) results. Findings from meta-analyses of CETP inhibitor trials (≥ 24 weeks follow-up) were used to judge between-compound heterogeneity in treatment effects. Genetic data were extracted on 190 + pharmacologically relevant outcomes; spanning 480,698 − 21,770 samples and 74,124-4,373 events. Drug target MR of protein concentration was used to determine the on-target effects of CETP inhibition and compared to that of PCSK9 modulation. Fifteen eligible CETP inhibitor trials of four compounds were identified, enrolling 79,961 participants. There was a high degree of heterogeneity in effects on lipids, lipoproteins, blood pressure, and clinical events. For example, dalcetrapib and evacetrapib showed a neutral effect, torcetrapib increased, and anacetrapib decreased cardiovascular disease (CVD); heterogeneity p-value < 0.001. In drug target MR analysis, lower CETP concentration (per \(\mu\)g/ml) was associated with CHD (odds ratio 0.95; 95%CI 0.91; 0.99), heart failure (0.95; 95%CI 0.92; 0.99), chronic kidney disease (0.94 95%CI 0.91; 0.98), and age-related macular degeneration (1.69; 95%CI 1.44; 1.99). Lower PCSK9 concentration was associated with a lower risk of CHD, heart failure, atrial fibrillation and stroke, and increased risk of Alzheimer’s disease and asthma. In conclusion, previous failures of CETP inhibitors are likely compound related. CETP inhibition is expected to reduce risk of CHD, heart failure, and kidney disease, but potentially increase risk of age-related macular disease.

Cholesteryl Ester Transfer Protein as a Drug Target for Cardiovascular Disease

Background: Drug development of cholesteryl ester transfer protein (CETP) inhibition to prevent coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and Mendelian randomization (MR) results. Methods: Findings from meta-analyses of CETP inhibitor trials (≥ 24 weeks follow-up) were used to judge between-compound heterogeneity in treatment effects. Genetic data were extracted on 190+ pharmacologically relevant outcomes; spanning 480,698-21,770 samples and 74,124-4,373 events. Drug target MR of protein concentration was used to determine the on-target effects of CETP inhibition and compared to that of PCSK9 modulation. Results: Fifteen eligible CETP inhibitor trials of four compounds were identified, enrolling 79,961 participants. There was a high degree of heterogeneity in effects on lipids, lipoproteins, blood pressure, and clinical events. For example, dalcetrapib and evacetrapib showed a neutral effect, torcetrapib increased, and anacetrapib decreased cardiovascular disease (CVD); heterogeneity p-value < 0.001. In drug target MR analysis, lower CETP concentration (per ug/ml) was associated with CHD (odds ratio 0.95; 95%CI 0.91; 0.99), heart failure (0.95; 95%CI 0.92; 0.99), chronic kidney disease (0.94 95%CI 0.91; 0.98), and age-related macular degeneration (1.69; 95%CI 1.44; 1.99). Lower PCSK9 concentration was associated with a lower risk of CHD, heart failure, atrial fibrillation and stroke, and increased risk of Alzheimer's disease and asthma. Conclucion: Previous failures of CETP inhibitors are likely compound related. CETP inhibition is expected to reduce risk of CHD, heart failure, and kidney disease, but potentially increase risk of age-related macular disease.

CETP inhibition and ADCY9 genotype: evidence of a qualitative pharmacogenetic interaction in cardiovascular disease?

BackgroundCETP inhibitors raise circulating concentrations of HDL-cholesterol, and potent inhibitors also lower non-HDL-cholesterol and risk of vascular disease. Previous genome-wide pharmacogenetic analysis of a phase III randomized controlled trial (RCT) of the CETP inhibitor, dalcetrapib, found variants in ADCY9 to associate with response to treatment. More recently, findings from a pharmacogenetic analysis of the CETP inhibitor evacetrapib reported a lack of such an association.AimsTo clarify the totality of evidence on whether ADCY9 genotype modifies the treatment response to CETP inhibition on risk of major adverse cardiac events through systematic review and meta-analysis.MethodsWe searched PubMed on 22nd May 2018 to identify RCTs of CETP inhibition that reported vascular disease effect estimates stratified by ADCY9 genotype. Stratum-specific estimates were pooled using fixed effect meta-analysis. Tests of heterogeneity between, and trend across, genotypic strata were assessed using Chi2.ResultsNine studies were identified from PubMed, of which two (dal-OUTCOMES and ACCELERATE) were RCTs reporting the treatment response to CETP inhibition by ADCY9 genotype, and fulfilled the inclusion criteria. In meta-analysis of dal-OUTCOMES and ACCELERATE, treatment with a CETP inhibitor was associated with a relative risk (RR) for major adverse cardiac events of RR 0.80 (95%CI, 0.65-0.99) in carriers of ADCY9 rs1967309 AA. For carriers of AG, the corresponding estimate was a RR of 1.01 (95%CI, 0.89-1.13), and for GG carriers, it was RR 1.21 (95%CI, 1.06-1.40). We identified evidence of heterogeneity (P=0.004) and a trend (P=0.0009) across genotypic groups.ConclusionsIn contrast to the interpretation provided by authors of the analysis based in the ACCELERATE trial, the available evidence lends weak support to a potential interaction of CETP treatment by ADCY9 genotype on risk of major adverse cardiac events. Additional data, e.g. from the ongoing dal-GenE trial focused explicitly on this interaction, should provide further clarity regarding the robustness of this pharmacogenetic effect.