Lipid-lowering therapies for aortic stenosis: a drug-target Mendelian randomization study

• DOI: 10.1093/ehjcvp/pvae092
• Publication Date: 2024-11-29T10:33:44Z
• Authors: Jonathan L Ciofani; Daniel Han; Karan Rao; Dipender Gill; Benjamin Woolf; Kazem Rahimi; Usaid K Allahwala; Ravinay Bhindi
• Keywords: Mendelian Randomization; Mendelian inheritance

Abstract Introduction Large observational and Mendelian randomization (MR) studies have demonstrated a strong association between both elevated LDL cholesterol (LDL-c) triglycerides (TG) with risk of aortic stenosis (AS), although randomized trials showed no benefit statins for AS. It consequently remains uncertain whether lipid-lowering therapies role to prevent or treat We used drug-target MR approach investigate the genetically predicted effect on Methods results collected summary statistics LDL-c, TG, AS from genome-wide (GWAS) including 1 320 016, 253 277, 412 181 European participants Global Lipids Genetics Consortium FinnGen study, respectively. identified genetic proxies PCSK9 inhibitors, statins, bempedoic acid, ezetimibe as single nucleotide polymorphisms in within 200 kb target genes (PCSK9, HMGCR, ACLY, NPC1L1, respectively), which were also significantly associated LDL-c at P < 5 × 10−8. similar identify TG-lowering agents fenofibrates, APOC3 ANGPTL3 inhibitors using PPARA, APOC3, ANGPTL3, Inverse variance-weighted was primary analysis method. Sensitivity analyses included weighted median, mode, MR-Egger, followed by outlier-exclusion approaches MR-PRESSO Cook's distance. performed multivariable evaluate inhibition may be mediated lipoprotein(a). replication negative control GWAS height 653 867 408 112 participants, Genetically proxied reduced (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.52–0.72, 0.0001) main, replication, all sensitivity analyses. (OR 0.49, CI 0.31–0.78, = 0.003), acid 0.0054, 0.0002–0.12, 0.0009), 0.46–0.81, 0.0006) similarly risk, latter not significant Amongst agents, 0.78, 0.70–0.88, 0.0001), but fenofibrate 0.64, 0.09–4.53, 0.65) 1.05, 0.77–1.43, 0.74) not. Conclusions are Early initiation sustained administration progression warrants further research clinical trial setting.