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.