Absolute Incidence Is Low, but Risk Is Significant
Click to Enlarge: Bar Graph of the Risk of New-Onset Nonarteritic Ischemic Optic Neuropathy (NAION) in the Unweighted Cohort and the Overlap Weighted CohortThe middle portion shows the number of patients at risk, number of NAION events, and number of censored events at 6-month intervals for the unweighted cohort. The incidence of NAION is significantly higher in the semaglutide group compared with the sodium-glucose cotransport protein 2 inhibitors (SGLT2i) group before and after weighting. With overlap weighting, compared with without overlap weighting, the estimated risk of new-onset NAION is elevated in the semaglutide initiators group and reduced in the SLGT2i initiators group. Significance in risk between the 2 groups was assessed using robust estimates from the log-rank test. Source: JAMA Network
PALO ALTO, CA — The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs), considered and effective medications for Type 2 diabetes (T2D) and weight loss, has exploded worldwide. But that doesn’t mean the drug class is completely without downsides.
Researchers from the VA Palo Alto, CA, Healthcare System found in a study of U.S. veterans with Type 2 diabetes (T2D) that initiation of semaglutide was associated with a twofold higher risk of incident new-onset nonarteritic anterior ischemic optic neuropathy (NAION) compared with initiation of an SGLT2i, with overlap weighted cumulative risks of 0.29% vs. 0.13% over a median follow-up of 2.1 years. NAION is a leading cause of sudden, painless and usually unilateral vision loss. Known as “eye stroke,” it is caused by interrupted blood flow to the optic nerve and often occurs upon waking. Most at risk are adults 50 and older.
“While absolute incidence of NAION is low in patients initiating semaglutide, medical counseling about this potential complication, which can result in substantial loss of vision, may be warranted,” wrote the study team in JAMA Ophthalmology.1
Also participating in the study were researchers from the VA Salt Lake City, UT, Healthcare System and from the University of Utah and Stanford University.
The study was conducted nationwide using data from the VHA between March 1, 2018, and March 1, 2025. This active-comparator, new-user, target trial emulation used cause-specific hazard ratios (HRs) that were estimated using overlap weighting to account for confounding. Participants included US veterans with T2D, current metformin use and no prior GLP-1RA or SGLT2i use. Data analysis was conducted from July 2025 through September 2025.
Overall, 102,361 U.S. veterans met inclusion criteria, including 11,478 initiators of semaglutide and 90,883 initiators of an SGLT2i as second-line T2D therapies. Participants had a mean age of 60, body mass index of 37.8 and hemoglobin A1c, of 7.0%. Most, 85.5% were male, with 61.9% non-Hispanic white, 20.7% Black and 8.1% Hispanic.
The authors reported that, over a maximum follow-up of 7.5 years, 173 total incident NAION events occurred. The incidence rate of NAION was 123 per 100,000 person-years among semaglutide initiators and 67 per 100,000 person-years among SGLT2i. “In 2.1 years of median follow-up, semaglutide initiators had a 2.33-fold higher risk than SGLT2i initiators (hazard ratio, 2.33; 95% CI, 1.54-3.54; P < .001),” they explained. “The overlap weighted incidence rate of NAION was 0.29% for semaglutide initiators and 0.13% for SGLT2i initiators, with a corresponding average treatment effect of 0.16 percentage points.”
The researchers concluded, “In this nationwide cohort of U.S. veterans with T2D, semaglutide initiators had a 2-fold NAION risk than SGLT2i initiators, while the absolute risk was low. Clinicians and patients should be counseled on the rare but evident increased risk of NAION after semaglutide initiation.”
Semaglutide, a GLP-1RA is used by an estimated 15 million U.S. adults taking it. “Although effective for glycemic control, weight loss, and cardiovascular risk reduction, nonarteritic anterior ischemic optic neuropathy (NAION) has emerged as a serious rare adverse event,” according to the study team. “Studies show conflicting associations. To address limitations of heterogeneous data sources, design quality, low NAION event rate, and short follow-up, we emulated a target trial within the Veterans Health Administration, U.S.’s largest integrated health care system from 2018 through 2025.”
Background information in the article advised that, from 2018 through 2025, semaglutide initiators among VHA patients with T2D taking metformin had a 2-fold higher NAION risk than SGLT2i in 2.1 years of median follow-up after extensive covariate adjustment, adding, “Findings align with growing evidence linking GLP-1RAs, particularly semaglutide, to NAION. Large observational analyses reported similar 2- to 3-fold risks,whereas others observed attenuated or null associations. Absolute incidence remains low (approximately 1 additional case per several thousand treated patients).”
The researchers recommended that, while clinicians should inform patients on semaglutide’s meaningful cardiometabolic benefits, they also should counsel on NAION as a rare, serious vision-loss event. “Consistent with recent commentaries, clinicians should encourage prompt evaluation of visual symptoms and consider ocular risk factors (eg, optic-nerve disease, prior NAION),” they emphasized. “Ophthalmologists should identify semaglutide use in patients with NAION, who should inform their prescribing clinicians.”
The authors called for future per-protocol effect studies should characterize dose or duration response relationships. They also pointed out that the biological mechanism linking GLP-1RAs to NAION remains unclear, including hypotension, volume depletion from gastrointestinal adverse effects, rapid glycemic improvement with transient microvascular dysregulation, and impaired vascular autoregulation at the optic nerve head.
- 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
