Genetic variation in anti-diabetic drug targets and risk of atrial fibrillation: a drug-target mendelian...

Atrial fibrillation (AF) is a common cardiac arrhythmia with limited options for upstream prevention. While several anti-diabetic drugs have shown cardiovascular benefits, their potential role in modifying AF risk remains unclear.

This study aimed to evaluate the causal relationship between genetically proxied antidiabetic drug targets and the risk of AF using a drug-target Mendelian randomization (MR) approach.

A two-sample MR analysis was conducted to investigate the association between genetic variants related to antidiabetic drug targets and AF. Thirty-eight FDA-approved glucose-lowering agents were identified, and their targets were extracted from the ChEMBL (Chemical Biology Database and Information System) database. Protein quantitative trait loci (pQTL) data from a large plasma proteome GWAS (Genome-Wide Association Study) were used to construct instrumental variables. Positive control testing was conducted to confirm that the selected drug targets were significantly associated with diabetes, using summary statistics from the UK Biobank, FinnGen, and other GWAS datasets. Causal effects on AF were evaluated using multiple independent GWAS cohorts for replication. MR methods included inverse-variance weighted (IVW), MR-Egger, and weighted median approaches with sensitivity analyses for pleiotropy and heterogeneity.

The alpha-glucosidase inhibitor miglitol was causally associated with a reduced risk of AF. Specifically, miglitol was shown to inhibit lactase (LCT), a protein whose elevated levels were associated with increased AF risk (IVW, OR = 1.013; 95%CI, 1.007-1.018; P = 2.37 × 10⁻⁵). This association was confirmed using MR-Egger and weighted median methods and validated across multiple datasets. Sensitivity analyses did not reveal evidence of pleiotropy or confounding factors, supporting the robustness of the findings.

This study provides novel genetic evidence suggesting that miglitol may reduce AF risk through lactase inhibition. These findings highlight a potential opportunity for drug repurposing for cardiovascular prevention, particularly for clinical pharmacists managing patients with higher risks in cardiovascular outcomes meanwhile with type 2 diabetes. Further mechanistic and clinical studies are warranted to confirm these observations and explore their translational value in practice.