Sodium-glucose cotransporter 2 Inhibition, Primary open-angle glaucoma, Mendelian randomization, Drug target, Pharmacological mechanism, Medicine, Science

Abstract This study aimed to evaluate the causal effect of sodium-glucose cotransporter protein 2 (SGLT2) inhibition on primary open-angle glaucoma (POAG) and explore potential mechanisms. A drug-targeted Mendelian randomization (MR) study was conducted using genetic variation related to SGLT2 inhibition, based on SGLT2 gene expression and glycated hemoglobin levels. Genetic summary statistics for POAG were obtained from the FinnGen consortium and a multi-ancestry genome-wide association study. Glaucomatous endophenotype data were also incorporated. A two-step MR analysis was performed to examine whether pathways related to obesity, blood pressure, lipid levels, oxidative stress, and inflammation mediated the association between SGLT2 inhibition and POAG. Genetically predicted SGLT2 inhibition was associated with a reduced risk of POAG (OR: 0.28; 95% CI: 0.12 to 0.63; P = 2.22 × 10− 3), confirmed in a multi-ancestry validation cohort. It was also associated with decreased optic cup area, reduced vertical cup-disc ratio, and increased optic disc area. Mediation analysis indicated that the effect of SGLT2 inhibition on POAG was partly mediated by diastolic blood pressure (4.8%). This study suggests that SGLT2 inhibition is a promising therapeutic target for POAG. However, further large-scale randomized controlled trials are required to confirm these findings.