Association of glucagon-like peptide-1 receptor agonists with atrial fibrillation, cardiac arrest, and ventricular fibrillation: Casual evidence from a drug target Mendelian randomization

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown benefits for cardiorenal outcomes in patients with type 2 diabetes mellitus. Although some observational studies suggest that GLP-1RAs protect against arrhythmias, the evidence remains inconclusive.

Methods: This study aimed to assess the causal relationship between GLP-1RAs and arrhythmias, including atrial fibrillation (AF), cardiac arrest, and ventricular fibrillation. We performed a two-sample Mendelian randomization (MR) analysis to examine the associations between genetically proxied GLP-1RAs and the risk of arrhythmias. Genetic instruments for GLP-1RAs were obtained from the cis-expression quantitative trait loci of the GLP1R gene, on the basis of data from the eQTLGen Consortium. Genome-wide association study (GWAS) data for AF were sourced from FinnGen10, whereas data for cardiac arrest and ventricular fibrillation came from the GWAS Catalog. Bayesian colocalization and multivariable Mendelian randomization (MVMR) analyses were conducted as supplementary analyses.

Results: Twelve independent single nucleotide polymorphisms were identified as genetic instruments for GLP-1RAs. MR analysis indicated that genetically proxied GLP-1RAs were associated with a reduced risk of AF (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.71-0.85, p = 4.45E-08, posterior probability of hypothesis 4 [PP.H4] = 0.007) and a lower risk of cardiac arrest and ventricular fibrillation (OR = 0.60, 95% CI = 0.42-0.85, p = 0.0039, PP.H4 = 0.018). Bayesian colocalization analysis revealed that genetically proxied GLP-1RAs did not share genetic variation with arrhythmias. MVMR analysis revealed that, after adjusting for body mass index and type 2 diabetes mellitus, genetically proxied GLP-1RAs did not have a significant effect on the risk of arrhythmias.

Conclusions: Our findings suggest that genetically proxied GLP-1RAs are causally associated with a reduced risk of AF, cardiac arrest, and ventricular fibrillation. Further randomized controlled trials are needed to confirm these results.

Keywords: Atrial fibrillation; Cardiac arrest; Glucagon-like peptide-1 receptor agonists; Mendelian randomization; Ventricular fibrillation.

Fig. 1

Study design overview. The flowchart of evaluating the effects of genetically proxied glucagon-like peptide-1 receptor (GLP-1R) agonists on arrhythmias. eQTL: expression quantitative trait locus; MAF: minor allele frequency; SNPs: single nucleotide polymorphisms; T2DM: type 2 diabetes mellitus; BMI: body mass index; MR: Mendelian randomization; IVW: inverse-variance weighted; MR-PRESSO: Mendelian Randomization Pleiotropy RESidual Sum and Outlier. MVMR: multivariable Mendelian randomization (Created in BioRender. Zhang, Y. (2025) https://BioRender.com/m93p747).

Fig. 2

The colocalization of genetically proxied glucagon-like peptide-1 receptor agonists and arrhythmias. (A) Atrial fibrillation (AF); (B) Cardiac arrest and ventricular fibrillation (VF). Scatter plots (left) depict − log10(P) values for associations between genetic variants and GLP1R expression versus AF and cardiac arrest and VF, highlighting the variant rs9283907. Regional association plots (right) show the locus around rs9283907 on chromosome 6, illustrating genetic signals for both GLP1R expression and arrhythmias