Research Summary

Semaglutide Initiation Linked to Higher Risk of NAION in US Veterans With Type 2 Diabetes

Edited by:
Ashton L. Stahl

Key Highlights

  • Semaglutide initiation was associated with a 2.33-fold higher risk of incident NAION compared with SGLT2 inhibitors.
  • Overlap-weighted cumulative NAION incidence was 0.29% with semaglutide vs 0.13% with SGLT2 inhibitors.
  • Median follow-up was 2.1 years, with a maximum follow-up of 7.5 years.
  • Absolute NAION incidence remained low despite the relative risk increase.

Initiation of semaglutide for type 2 diabetes (T2D) was associated with a significantly higher risk of new-onset nonarteritic anterior ischemic optic neuropathy (NAION) compared with sodium-glucose cotransporter-2 inhibitors (SGLT2i) in a large cohort of US veterans, according to a brief report published in JAMA Ophthalmology. While the relative risk was elevated, investigators emphasized that the absolute incidence of NAION was low.

The study emulated a target trial using nationwide Veterans Health Administration data from March 1, 2018, through March 1, 2025. Eligible participants were veterans aged 18 years or older with T2D who were receiving metformin and newly initiated semaglutide or an SGLT2i. Patients with prior GLP-1 receptor agonist or SGLT2i use, other non-metformin antidiabetic medications, insulin use of 30 days or more in the prior 10 years, or prior NAION or related optic nerve conditions were excluded. The primary outcome was incident NAION identified by ICD-10 or SNOMED codes. Overlap propensity score weighting was used to balance baseline covariates, and hazard ratios were estimated using Cox proportional hazards models under an intention-to-treat framework.

Study Findings

Among 102,361 eligible veterans, 11,478 initiated semaglutide and 90,883 initiated an SGLT2i, predominantly empagliflozin. After overlap weighting, baseline characteristics were well balanced, including age (mean 60.1 years), body mass index (37.8), and hemoglobin A1c (7.0%).

During a median follow-up of 2.1 years, encompassing 239,333 person-years, 173 incident NAION events occurred. Thirty cases occurred among semaglutide initiators (incidence rate 123 per 100,000 person-years) compared with 143 among SGLT2i initiators (67 per 100,000 person-years). In unweighted analyses, semaglutide was associated with an increased NAION hazard (HR, 1.84; 95% CI, 1.24-2.73; P = .002). After overlap weighting, the hazard ratio increased to 2.33 (95% CI, 1.53-3.54; P < .001). Over a maximum of 7.5 years of follow-up, the overlap-weighted cumulative incidence was 0.29% for semaglutide initiators versus 0.13% for SGLT2i initiators, corresponding to an absolute risk difference of 0.16 percentage points.

Clinical Implications

According to the study authors, semaglutide initiators had a twofold higher risk of NAION compared with SGLT2i initiators, although the absolute risk was low. The investigators noted that clinicians should counsel patients about NAION as a rare but serious cause of vision loss and encourage prompt evaluation of visual symptoms. They also advised ophthalmologists to identify patients' use of semaglutide when presenting with NAION and to communicate with prescribing clinicians.

Expert Commentary

“…veterans with T2D taking metformin who initiated semaglutide had a 2-fold higher NAION risk than those who initiated SGLT2i, although absolute risk was low. This study supports medical counseling about NAION risk and implications for vision loss after semaglutide initiation,” the researchers concluded.

Reference

Heberer K, Bress AP, Cogill S, et al. New-onset nonarteritic anterior ischemic optic neuropathy and initiators of semaglutide in US veterans with type 2 diabetes. JAMA Ophthalmol. Published online February 12, 2026. doi:10.1001/jamaophthalmol.2025.6262