To evaluate whether GLP-1 RA therapy is associated with an increased risk of NAION in a large, diverse real-world population.

This retrospective cohort study utilized the TriNetX U.S. Collaborative Network from 2015 to 2024. Adults (≥18 years) with type 2 diabetes mellitus (T2DM) were identified and grouped as GLP-1 RA users versus other antidiabetic users and GLP-1 RA users versus sodium-glucose cotransporter-2 inhibitors (SGLT-2 i) users. Patients with preexisting optic neuropathy or severe ocular disease were excluded. Propensity score matching (1:1) was applied to balance baseline characteristics. The primary outcome was incident NAION, defined by ICD-10 codes. Cox proportional hazards models and Kaplan–Meier analyses were used to estimate hazard ratios (HRs) and cumulative probabilities.

After matching, 799 036 GLP-1 RA users were compared with 799 036 other antidiabetic users, and 429 985 GLP-1 RA users were compared with 429 985 SGLT-2i users. Over 9 years, GLP-1 RA users showed higher cumulative NAION incidence vs other agents (0.21% vs 0.17%; HR 1.38; 95% CI, 1.23–1.55) and vs SGLT-2i users (0.20% vs 0.20%; HR 1.30; 95% CI, 1.11–1.52). Kaplan–Meier curves demonstrated consistent early separation favoring higher risk among GLP-1 RA users. Sensitivity analyses yielded similar patterns.

GLP-1 RA therapy was associated with a modest but statistically significant increased risk of NAION. While the absolute risk remains low, clinicians should consider ophthalmic risk assessment—particularly in patients with anatomical susceptibility or vascular risk factors—as GLP-1 RA use expands for diabetes and obesity management. Further mechanistic and prospective research is warranted.