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

Abstract

Introduction: Large observational and Mendelian randomization (MR) studies have demonstrated a strong association between both elevated LDL cholesterol (LDL-c) and triglycerides (TG) with risk of aortic stenosis (AS), although randomized trials showed no benefit of statins for AS. It consequently remains uncertain whether lipid-lowering therapies have a role to prevent or treat AS. We used a drug-target MR approach to investigate the genetically predicted effect of lipid-lowering therapies on risk of AS.

Methods and results: We collected summary statistics for LDL-c, TG, and AS from genome-wide association studies (GWAS) including 1 320 016, 1 253 277, and 412 181 European participants from the Global Lipids Genetics Consortium and FinnGen study, respectively. We identified genetic proxies for PCSK9 inhibitors, statins, bempedoic acid, and ezetimibe as single nucleotide polymorphisms in or within 200 kb of the target genes (PCSK9, HMGCR, ACLY, and NPC1L1, respectively), which were also significantly associated with LDL-c at P < 5 × 10-8. We used a similar approach to identify genetic proxies for the TG-lowering agents fenofibrates, APOC3 inhibitors, and ANGPTL3 inhibitors using the target genes PPARA, APOC3, and ANGPTL3, respectively. Inverse variance-weighted was the primary analysis method. Sensitivity analyses included weighted median, weighted mode, and MR-Egger, followed by the outlier-exclusion approaches MR-PRESSO and Cook's distance. We also performed multivariable analyses to evaluate whether the predicted effect of PCSK9 inhibition may be mediated by lipoprotein(a). We performed replication and negative control analyses using GWAS of AS and height including 653 867 and 408 112 participants, respectively. Genetically proxied PCSK9 inhibition was significantly associated with reduced AS risk (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.52-0.72, P < 0.0001) on main, replication, and all sensitivity analyses. Genetically proxied ezetimibe (OR 0.49, 95% CI 0.31-0.78, P = 0.003), bempedoic acid (OR 0.0054, 95% CI 0.0002-0.12, P = 0.0009), and statins (OR 0.61, 95% CI 0.46-0.81, P = 0.0006) were similarly associated with reduced AS risk, although the latter were not significant on replication analyses. Amongst the TG-lowering agents, genetically proxied APOC3 inhibition was associated with reduced AS risk (OR 0.78, 95% CI 0.70-0.88, P < 0.0001), but fenofibrate (OR 0.64, 95% CI 0.09-4.53, P = 0.65) and ANGPTL3 inhibitors (OR 1.05, 95% CI 0.77-1.43, P = 0.74) were not.

Conclusions: Genetically proxied lipid-lowering therapies are significantly associated with reduced risk of AS. Early initiation and sustained administration of lipid-lowering therapies may prevent AS progression and warrants further research in the clinical trial setting.

Keywords: Aortic stenosis; Epidemiology; Genetic epidemiology; Lipid-lowering therapy; Mendelian randomization; Valvular heart disease.

Figure 1

Drug target Mendelian randomization study design. LDL-c, LDL cholesterol; TG, triglyceride. Adapted from Ciofani et al. 2023.

Figure 2

Conventional Mendelian randomization (MR) analyses for the effect of one standard deviation increase in genetically proxied LDL cholesterol (LDL-c), triglycerides (TG), and lipoprotein(a) (Lp(a)) on risk of aortic stenosis. Primary inverse variance-weighted (IVW) and sensitivity analyses are presented; outliers excluded based on Cook's distance method.

Figure 3

Drug-target Mendelian randomization (MR) analyses. Top panel: genetically proxied effects of PCSK9, HMGCoA reductase, NPC1L1, and ACLY inhibition on risk of aortic stenosis per standard deviation decrease in LDL cholesterol. Bottom panel: genetically proxied effects of APOC3, ANGPTL3, and PPARA inhibition on risk of aortic stenosis per standard deviation decrease in triglycerides. Primary inverse variance-weighted (IVW) and sensitivity analyses are presented; outliers excluded based on Cook's distance method.