Genetic insights into SGLT2 inhibition and atrial fibrillation: exploring the mediating role of inflammatory proteins.

Background: This study aimed to employ Mendelian randomization (MR) analysis to investigate the causal relationship between sodium-glucose cotransporter 2 (SGLT2) inhibition and atrial fibrillation (AF), as well as assess the potential mediating role of inflammatory proteins in this association.

Methods: A two-sample MR analysis was conducted using summary-level data from the genome-wide association study (GWAS) were used to evaluate the genetic prediction of SGLT2 inhibition and AF. Additionally, a two-step MR approach was applied to explore the causal mediation effects of inflammatory proteins in the SGLT2-AF pathway.

Results: Genetically predicted SGLT2 inhibition was associated with a significantly lower risk of AF (odds ratio [OR] = 0.51; 95% confidence interval [CI]: 0.27-0.97; p = 0.039). Mendelian randomization analysis further identified FGF-23 (OR = 0.88; 95% CI: 0.79, 0.98; p = 0.024) and PD-L1 (OR = 0.90; 95% CI: 0.82, 0.96; p = 0.023) as significant mediators, accounting for 21.28% and 17.69% of the total effect, respectively.

Conclusions: These findings provide potential protective role of SGLT2 inhibition against AF, mediated by inflammatory proteins. Further mechanistic and clinical investigations are warranted to elucidate the underlying pathways and therapeutic implications.