Importance: Anecdotal experience raised the possibility that semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA) with rapidly increasing use, is associated with nonarteritic anterior ischemic optic neuropathy (NAION).

Objective: To investigate whether there is an association between semaglutide and risk of NAION.

Design, setting, and participants: In a retrospective matched cohort study using data from a centralized data registry of patients evaluated by neuro-ophthalmologists at 1 academic institution from December 1, 2017, through November 30, 2023, a search for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code H47.01 (ischemic optic neuropathy) and text search yielded 16 827 patients with no history of NAION. Propensity matching was used to assess whether prescribed semaglutide was associated with NAION in patients with type 2 diabetes (T2D) or overweight/obesity, in each case accounting for covarying factors (sex, age, systemic hypertension, T2D, obstructive sleep apnea, obesity, hyperlipidemia, and coronary artery disease) and contraindications for use of semaglutide. The cumulative incidence of NAION was determined with the Kaplan-Meier method and a Cox proportional hazards regression model adjusted for potential confounding comorbidities. Data were analyzed from December 1, 2017, through November 30, 2023.

Exposures: Prescriptions for semaglutide vs non-GLP-1 RA medications to manage either T2D or weight.

Main outcomes and measures: Cumulative incidence and hazard ratio of NAION.

Results: Among 16 827 patients, 710 had T2D (194 prescribed semaglutide; 516 prescribed non-GLP-1 RA antidiabetic medications; median [IQR] age, 59 [49-68] years; 369 [52%] female) and 979 were overweight or obese (361 prescribed semaglutide; 618 prescribed non-GLP-1 RA weight-loss medications; median [IQR] age, 47 [32-59] years; 708 [72%] female). In the population with T2D, 17 NAION events occurred in patients prescribed semaglutide vs 6 in the non-GLP-1 RA antidiabetes cohort. The cumulative incidence of NAION for the semaglutide and non-GLP-1 RA cohorts over 36 months was 8.9% (95% CI, 4.5%-13.1%) and 1.8% (95% CI, 0%-3.5%), respectively. A Cox proportional hazards regression model showed higher risk of NAION for patients receiving semaglutide (hazard ratio [HR], 4.28; 95% CI, 1.62-11.29); P < .001). In the population of patients who were overweight or obese, 20 NAION events occurred in the prescribed semaglutide cohort vs 3 in the non-GLP-1 RA cohort. The cumulative incidence of NAION for the semaglutide vs non-GLP-1 RA cohorts over 36 months was 6.7% (95% CI, 3.6%-9.7%) and 0.8% (95% CI, 0%-1.8%), respectively. A Cox proportional hazards regression model showed a higher risk of NAION for patients prescribed semaglutide (HR, 7.64; 95% CI, 2.21-26.36; P < .001).

Conclusions and relevance: This study's findings suggest an association between semaglutide and NAION. As this was an observational study, future study is required to assess causality.