Unraveling the Genetic Links: The Impacts of Antidiabetic Drugs on Stroke Risk

Background: Diabetes is widely recognized as a major contributor to stroke risk. Certain antidiabetic medications have demonstrated promising effects on reducing stroke incidence and improving outcomes. Methods: To evaluate the potential impacts of antidiabetic drugs comprehensively, we developed an analytical framework that incorporates summary-based Mendelian randomization (SMR), two-sample Mendelian randomization (TSMR), and colocalization analyses. Summary statistics from the largest genome-wide association study (GWAS) of stroke and known subtypes were utilized, along with gene expression data from the blood, aorta, coronary artery, and tibial artery provided by the eQTLGen or GTEx V8 consortia. Results: Elevated expression levels of the solute carrier family 5 member 2 (SLC5A2) gene, which is targeted by sodium–glucose co-transporter 2 (SGLT2) inhibitors, in the tibial artery and the potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene, which is targeted by sulfonylureas, in the blood were linked to an increased risk of any ischemic stroke (AIS) (KCNJ11: odds ratio (OR) = 1.11, 95% confidence interval (CI) = 1.01–1.21; p = 0.033; SLC5A2: OR = 1.05, 95% CI = 1.01–1.10; p = 0.017, respectively), according to the SMR analysis. Additionally, the upregulation of insulin receptor (INSR) expression in the tibial artery was associated with a reduction in stroke incidence in patients with large-artery atherosclerotic stroke (LAS) (OR = 0.66, 95% CI = 0.46–0.95; p = 0.026). The TSMR results were consistent with these findings. Furthermore, the expressions of SLC5A2 and INSR, which are associated with AIS and LAS, respectively, were colocalized in the tibial artery. Conclusion: Our findings suggest that SGLT2 inhibitors and sulfonylureas may influence the risk of AIS. Additionally, activation of the insulin receptor may reduce the risk of LAS. These results increase our understanding of medication options for stroke patients who require hypoglycemic agents and provide a basis for the strategic repurposing of antidiabetic drugs.