Exploring the effect of SGLT2 inhibitors on the risk of primary open-angle glaucoma using Mendelian randomization analysis

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.

Keywords: Drug target; Mendelian randomization; Pharmacological mechanism; Primary open-angle glaucoma; Sodium-glucose cotransporter 2 Inhibition.

Fig. 1

Overview of the research design in this study. (A) Flowchart for assessing the effect of SGLT2 inhibition on POAG risk using MR. (B) The utilization of MR to investigate the impact of SGLT2 inhibition on POAG (total effect). (C) The application of a two-step MR framework was employed to investigate potential mediators in the SGLT2 inhibition and POAG association pathways, and to calculate indirect effects.

Fig. 2

The forest plot illustrates the causal effect of SGLT2 inhibition on POAG risk in the discovery phase and validation phase.

Fig. 3

The forest plot illustrates the causal effect of SGLT2 inhibition on glaucoma endophenotypes.

Fig. 4

Meta-analysis of the causal association between glucose traits and POAG. (A) Meta-analysis of the causal association between fasting glucose level and POAG. (B) Meta-analysis of the causal association between HbA1c level and POAG.