Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy.

Summary

Across 14 databases including 37.1 million people with T2D, semaglutide use was associated with a modestly increased NAION risk: SCCS IRR 1.32 (95% CI 1.14–1.54). In active-comparator analyses, risk was not higher than several non-GLP-1 comparators under a sensitive definition, but was higher versus empagliflozin under a more specific definition.

Key Findings

• NAION incidence among semaglutide users was 14.5 per 100,000 person-years.
• Active-comparator hazard ratios were not different vs non-GLP-1RAs under a sensitive NAION definition; higher risk only vs empagliflozin under a specific definition (HR 2.27, 95% CI 1.16–4.46).
• SCCS meta-analysis showed increased NAION risk during semaglutide exposure (IRR 1.32, 95% CI 1.14–1.54).

Clinical Implications

Clinicians should discuss a small but nonzero NAION risk with semaglutide, particularly in patients with optic nerve vulnerability, while balancing cardiometabolic benefits. Consider ophthalmic symptom vigilance and comparator selection in high-risk individuals.

Limitations

• Observational design with reliance on diagnosis codes; residual confounding and misclassification possible.
• Definition-dependent results (sensitive vs specific NAION definitions) complicate effect-size interpretation.
• Exposure timing and ophthalmic phenotype granularity limited without chart validation in all databases.

Future Directions

Prospective ophthalmic safety surveillance and mechanistic studies are needed to define susceptible subgroups, dose–response, and biological plausibility; linkage with imaging/clinical adjudication would refine case definitions.