FDA requires NAION warning across the GLP-1 receptor agonist class

The US Food and Drug Administration (FDA) issued a Drug Safety Communication requiring safety labeling changes for the entire class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), citing a potential increased risk of non-arteritic anterior ischemic optic neuropathy (NAION).¹

Under the new requirement, every GLP-1 RA application holder must add NAION risk information to the Warnings and Precautions section of its labeling.¹ The action is notable for its breadth. Although most of the scientific and public attention has centered on semaglutide (Ozempic, Rybelsus, Wegovy; Novo Nordisk), the FDA applied the change classwide, from liraglutide (Victoza, Saxenda), dulaglutide (Trulicity) and exenatide to the dual GIP/GLP-1 agonist tirzepatide (Mounjaro, Zepbound; Eli Lilly) and the oral small-molecule agent orforglipron (Foundayo), approved earlier this year. The agency noted that NAION cases have been reported in postmarketing surveillance for every currently marketed GLP-1 RA.¹

Weighing a complex evidence base

The FDA was candid that no single data source settled the matter. Instead, the agency described a totality-of-evidence review across 6 streams of data.¹

The largest was a meta-analysis of 126 randomized controlled trials enrolling 134,253 patients and accounting for 288,879 person-years of exposure. Investigators identified 15 probable NAION events: 10 in GLP-1 RA-treated patients, 5 in placebo-treated patients and none in patients receiving other glucose-lowering drugs. That translated to an incidence of 6.4 per 100,000 person-years with GLP-1 RAs vs 3.8 per 100,000 person-years with comparators.¹

The FDA also analyzed data from its Sentinel system in adults with type 2 diabetes who started a GLP-1 RA, an SGLT-2 inhibitor or a DPP-4 inhibitor between 2019 and 2024. Crude NAION incidence was similar across the 3 groups, at roughly 26 to 32 per 100,000 person-years. Compared with DPP-4 inhibitors, GLP-1 RA initiation was associated with a significantly increased risk (HR, 1.43; 95% CI, 1.02-2.01). Compared with SGLT-2 inhibitors, the hazard ratio was 1.19 (95% CI, 0.91-1.54), which did not reach statistical significance.¹

The agency added that methodologically rigorous published observational studies have consistently shown elevated NAION risk in patients with type 2 diabetes who start GLP-1 RAs compared with those who start DPP-4 or SGLT-2 inhibitors. At the same time, it acknowledged the limits of its own adverse event reporting data, in which NAION risk factors overlap heavily with the conditions GLP-1 RAs are prescribed to treat, and noted that animal studies have not identified a mechanism by which these drugs might raise NAION risk.¹

The path to this decision

The signal first drew wide attention in July 2024, when Jimena Tatiana Hathaway, MD, MPH, and colleagues at Massachusetts Eye and Ear reported in JAMA Ophthalmology that semaglutide was associated with a higher risk of NAION in a neuro-ophthalmology cohort, with a hazard ratio of 4.28 among patients with type 2 diabetes and 7.64 among patients who were overweight or obese.²,³ The FDA cited that study in its communication, noting that it had limitations but warranted further assessment.¹

European regulators moved first. In December 2024, the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) agreed to review Danish and Norwegian registry studies at the request of the Danish Medicines Agency,⁴ and in June 2025 it concluded that NAION is a very rare side effect of semaglutide, affecting up to 1 in 10,000 users, and recommended that product information be updated accordingly.⁵ The FDA's action goes further in one respect: the European review was limited to semaglutide, while the US labeling change covers the whole class.

A 2025 Ophthalmology Times feature applied the Bradford Hill criteria to the semaglutide signal and concluded that, despite a plausible mechanism, key pieces of evidence for causation were still missing.⁶ At COPHy 2026 in March, Andrew G. Lee, MD, argued the "no" side of whether GLP-1 agonists cause NAION, stressing that retrospective cohort data show association rather than proven causation and that confounding by indication remains a central challenge.⁷ The FDA's language reflects that tension: the agency describes a potential increased risk of rare events, rather than a confirmed causal relationship.

What it means in the clinic

For ophthalmologists, the practical implications are concentrated in recognition and referral. The FDA advises prescribers to tell patients to report immediately any sudden, painless loss of vision, visual field deficit, or other visual disturbance in one eye and to refer patients with suspected NAION promptly to an ophthalmologist.¹ Patients are being told to watch for vision loss that is often noticed on waking, blurred or missing areas of vision, color distortion, and reduced central sharpness.¹

If NAION is confirmed, the agency recommends that prescribers consider discontinuing the GLP-1 RA unless the benefits clearly outweigh the risks. It also notes that patients with a prior history of NAION have an increased risk of recurrence and that an event in one eye raises the risk in the fellow eye.¹ Those points make the ophthalmologist's role in co-management with primary care physicians, endocrinologists, and obesity specialists more central, particularly for patients whose cardiometabolic, renal, or sleep apnea indications make stopping therapy a difficult trade-off.

Context on absolute risk will be essential in those conversations. The FDA put background NAION incidence at 2.3 to 10.2 cases per 100,000 persons per year in adults older than 50 years,¹ and the absolute differences seen in both the trial meta-analysis and the Sentinel cohort were small. With prescriptions for GLP-1 RAs continuing to climb, however, even a modest relative increase may translate into more NAION cases presenting to eye clinics.

Looking ahead

The labeling change resolves the regulatory question for now but leaves the mechanistic one open. With no animal model or biological pathway yet identified, and with confounding still difficult to untangle in observational data, prospective studies and larger pooled analyses will be needed to determine whether the risk is truly drug-related and whether it differs among agents, doses or patient populations. In the meantime, the FDA is encouraging clinicians to report NAION cases associated with GLP-1 RAs through MedWatch.¹

References

1. US Food and Drug Administration. FDA requires safety labeling changes for glucagon-like peptide-1 receptor agonists (GLP-1 RAs) due to potential risk of non-arteritic anterior ischemic optic neuropathy (NAION). Drug Safety Communication. November 9, 2026. Accessed November 9, 2026. https://www.fda.gov/drugs/drug-safety-communications/fda-requires-safety-labeling-changes-glucagon-peptide-1-receptor-agonists-glp-1-ras-due-potential

2. Hathaway JT, Shah MP, Hathaway DB, et al. Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmol. Published online July 3, 2024. doi:10.1001/jamaophthalmol.2024.2296

3. Charters L. Semaglutide may be associated with non-arteritic ischemic optic neuropathy (NAION). Ophthalmology Times. July 9, 2024. Accessed November 9, 2026. https://www.ophthalmologytimes.com/view/semaglutide-may-be-associated-with-non-arteritic-ischemic-optic-neuropathy-naion-

4. Hayes H. European Medicines Agency will assess semaglutide for link to NAION. Ophthalmology Times. December 20, 2024. Accessed November 9, 2026. https://www.ophthalmologytimes.com/view/european-medicines-agency-will-assess-semaglutide-for-link-to-naion

5. European Medicines Agency. PRAC concludes eye condition NAION is a very rare side effect of semaglutide medicines Ozempic, Rybelsus and Wegovy. News release. June 6, 2025. Accessed November 9, 2026. https://www.ema.europa.eu/en/news/prac-concludes-eye-condition-naion-very-rare-side-effect-semaglutide-medicines-ozempic-rybelsus-wegovy

6. Song T. Piecing it together: Does semaglutide fit the NAION puzzle? Ophthalmology Times. 2025;50(2). Accessed November 9, 2026. https://www.ophthalmologytimes.com/view/piecing-it-together-does-semaglutide-fit-the-naion-puzzle-

7. COPHy 2026: Weighing in on the evidence on GLP-1 agonists and NAION. Ophthalmology Times. March 20, 2026. Accessed November 9, 2026. https://www.ophthalmologytimes.com/view/cophy-2026-weighing-in-on-the-evidence-on-glp-1-agonists-and-naion