Glucagon-like peptide-1 receptor activation, inflammation and heart failure: Insights from genetic analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce heart failure (HF) risk, but the underlying mechanisms remain unclear. OBJECTIVES: To assess the causal effect of GLP-1R pathway activation on HF risk and identify inflammatory mediators using genetic approaches. METHODS: We conducted two-sample and two-step Mendelian randomization (MR). Cis-eQTL SNPs for GLP1R expression (P 〈 5 × 10⁻⁸, F 〉 10) were selected from the eQTLGen Consortium to proxy the GLP-1R pathway, with positive control against type 2 diabetes mellitus (T2DM). The primary analysis used inverse-variance weighted (IVW) method, with four MR methods as sensitivity analyses. Using two-step MR, we assessed 95 inflammatory biomarkers as mediators, with significant ones validated externally using an independent dataset. Mediation effects were calculated via Delta and parametric Bootstrap methods. RESULTS: Genetic instruments showed a strong association with reduced T2DM risk (OR = 0.8217, 95% CI 0.7852 to 0.8598, P = 2.32 × 10⁻¹⁷). Genetically proxied GLP1R expression was associated with lower HF risk (OR = 0.9327, 95% CI 0.8715 to 0.9981, P = 0.0439). Among 95 biomarkers, matrix metalloproteinase-1 (MMP-1) reduction showed a significant indirect effect (-0.0196, Delta 95% CI -0.0342 to -0.0050, P = 0.0084; Bootstrap -0.0356 to -0.0066), accounting for 28% of the total effect. External validation confirmed this mediation (indirect effect -0.0148, Delta 95% CI -0.0266 to -0.0030, P = 0.0140; Bootstrap 95% CI -0.0275 to -0.0039), explaining 21% of the total effect. CONCLUSION: This study provides genetic evidence that GLP-1R activation protects against HF and identifies MMP-1 reduction as a partial mediator, illuminating an anti-inflammatory mechanism underlying GLP-1RA efficacy.