FDA requires all GLP-1 receptor agonists to carry a NAION warning after reviewing 126 clinical trials, identifying 15 probable cases and mixed real-world safety findings.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
On November 9, 2026, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication requiring application holders of all glucagon-like peptide-1 receptor agonist (GLP-1 RA) medicines to include information about a potential increased risk of non-arteritic anterior ischemic optic neuropathy (NAION) in the Warnings and Precautions section of product labeling. NAION is a rare eye condition caused by reduced blood flow to the optic nerve that can result in sudden, painless vision loss in one eye, including permanent impairment.
The FDA described the risk as potential rather than established, following an evaluation of randomized clinical trials, observational studies, postmarketing reports and animal data.
From a Semaglutide Signal to a Class-Wide Labeling Requirement
The safety concern gained attention in July 2024, when Hathaway and colleagues reported an association between semaglutide use and NAION in JAMA Ophthalmology. Although the FDA identified limitations in the study, it considered further investigation necessary.
In June 2025, the European Medicines Agency (EMA) concluded that NAION should be classified as a very rare adverse effect of semaglutide-containing medicines, including Ozempic, Rybelsus and Wegovy. The latest FDA action extends the labeling requirement beyond semaglutide to all marketed GLP-1 RA products.
The FDA-listed medicines include exenatide, liraglutide, dulaglutide, lixisenatide-containing combinations, semaglutide, tirzepatide and orforglipron. Tirzepatide acts on both GIP and GLP-1 receptors, while orforglipron represents an oral, non-peptide GLP-1 receptor agonist. FDA also reported NAION cases across all currently marketed products in the class.
Clinical Evidence: Findings From 126 Randomized Trials
Because individual clinical trials recorded few or no NAION cases, the FDA conducted a meta-analysis of 126 randomized controlled trials involving 134,253 participants. The analysis included 78,217 patients receiving GLP-1 RAs and 56,036 receiving placebo or other glucose-lowering comparators, contributing 288,879 person-years of exposure.
The analysis identified 15 probable NAION events: 10 among GLP-1 RA recipients and five among comparator recipients. No events were identified among patients receiving other non-GLP-1 RA glucose-lowering medicines.
The incidence was 6.4 cases per 100,000 person-years with GLP-1 RAs compared with 3.8 per 100,000 person-years among comparators. Although the absolute incidence was low, the numerical difference contributed to the FDA’s overall safety assessment. The agency did not report a confidence interval for this pooled comparison.
Sentinel Study Shows Different Results Across Comparators
The FDA also evaluated real-world safety data through its Sentinel programme, examining adults with type 2 diabetes who initiated GLP-1 RAs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors between 2019 and 2024.
NAION incidence ranged from 26 to 32 cases per 100,000 person-years. The incidence was 30–32 with GLP-1 RAs, 31 with SGLT-2 inhibitors and 26 with DPP-4 inhibitors.
Compared with SGLT-2 inhibitors, GLP-1 RAs were not associated with a statistically significant increase in NAION risk (HR 1.19; 95% CI 0.91–1.54). However, comparison with DPP-4 inhibitors showed a statistically significant increase (HR 1.43; 95% CI 1.02–2.01).
The differing results indicate that the observed association depends partly on the comparator used and should not be interpreted as uniform evidence of increased risk across all treatment comparisons.
Guidance for Patients and Healthcare Professionals
Patients should seek immediate medical attention if they experience sudden, painless vision loss in one eye, blind spots, tunnel vision, colour distortion or blurred central vision. Symptoms may become noticeable upon waking.
The FDA identifies smoking, diabetes, hypertension, sleep apnea, anemia and kidney disease as potential risk factors. Patients who have experienced NAION in one eye also face an increased risk of involvement in the other eye.
Healthcare professionals should promptly refer suspected cases to an ophthalmologist. The FDA recommends considering discontinuation of GLP-1 RA treatment in patients who develop NAION unless the benefits clearly outweigh the risks. Patients with a history of NAION should discuss treatment continuation with their healthcare professional.
Clinical Interpretation: A Broader Warning Despite Low Absolute Incidence
The FDA’s decision marks an important regulatory shift from an initial semaglutide-associated safety signal to a class-wide labeling requirement. However, the evidence remains imperfect. The randomized trial analysis identified only 15 probable events, while the Sentinel study showed a statistically significant association against DPP-4 inhibitors but not SGLT-2 inhibitors. Animal studies also did not identify a mechanism explaining the potential risk.
The findings support greater clinical awareness and updated safety information, but do not establish a causal relationship, quantify risk for individual drugs or doses, or justify routine discontinuation in patients without NAION. The regulatory challenge will be to strengthen recognition of this rare event while preserving appropriate access to GLP-1-based treatments.
Reference
FDA. Drug Safety Communication: GLP-1 RA labeling changes due to potential NAION risk.
Hathaway JT, et al. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. JAMA Ophthalmology. 2024;142(8):732–739. doi:10.1001/jamaophthalmol.2024.2296.
EMA. PRAC concludes NAION is a very rare side effect of semaglutide medicines.
About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.
