Association of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists With Risk of Cataract

Purpose: To evaluate the risk of age-related cataract (ARC) among patients with type 2 diabetes mellitus (T2DM) using sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RA) as second-line antihyperglycemic agents.

Design: Population-based retrospective cohort study.

Participants: Adults aged over 40 years with a diagnosis of T2DM between January 2015 and June 2025 were identified from the TriNetX Global Network. The patients were categorized into three cohorts: (1) SGLT2i plus metformin, (2) GLP-1 RA plus metformin, and (3) metformin monotherapy. Patients with aphakia or pseudophakia, orbital injuries, secondary cataracts, or congenital ocular malformations were excluded.

Methods: Pairwise comparisons were performed with a 3-year follow-up. Baseline characteristics were balanced using 1:1 propensity score matching for demographics, comorbidities, T2DM severity, and cataract risk factors. Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Main outcome measures: The primary outcome was the incidence of ARC events, defined as a diagnosis of ARC or cataract surgery, with stratified analyses conducted by demographics, glycemic control, and comorbidities.

Results: After matching, three pairwise comparisons included 34,259 (SGLT2i vs metformin; mean age, 62.8 years; 35.1% female), 50,877 (GLP-1 RA vs metformin; mean age, 58.3 years; 54.8% female), and 23,022 (SGLT2i vs GLP-1 RA; mean age, 61.0 years; 40.8% female) patients. Adjunctive SGLT2i or GLP-1 RA was associated with a reduced risk of ARC events (SGLT2i, HR: 0.82, 95% CI: 0.76-0.89; GLP-1 RA, HR: 0.93, 95% CI: 0.87-0.99). The protective effect of SGLT2i was greater than that of GLP-1 RA (HR: 0.84, 95% CI: 0.76-0.92). However, in patients with advanced age, obesity, or diabetic retinopathy, the association attenuated. When analyzed as separate outcomes, adjunctive use of SGLT2i and GLP-1 RA remained associated with a reduced risk of ARC diagnosis, while the risk of cataract surgery did not differ significantly (SGLT2i, HR: 1.14, 95% CI: 0.95-1.34; GLP-1 RA, HR: 1.01, 95% CI: 0.79-1.26).

Conclusions: Adjunctive use of SGLT2i or GLP-1 RA was associated with a lower risk of ARC, with a stronger effect for SGLT2i; however, neither agent reduced the risk of cataract surgery. Further studies are needed to clarify the underlying biological pathways and validate our findings.