FDA Requires Class-Wide GLP-1 RA Labeling Changes for Potential NAION Risk

The FDA is requiring application holders for all glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications to add information about a potential increased risk of non-arteritic anterior ischemic optic neuropathy (NAION) to the Warnings and Precautions section of labeling, according to a Drug Safety Communication issued Monday.¹ NAION is a rare condition that can cause acute, painless, decreased vision in one eye, including permanent vision loss.

The agency described the risk as potential, and the underlying evidence has limits. The clinical trial analysis that informed the decision included only 15 probable NAION events, a review of animal data did not identify a mechanism by which GLP-1 RA use could increase risk, and results from an FDA real-world study varied by comparator.¹

Medications Affected by the Requirement

The labeling requirement applies to the following products listed by the FDA: exenatide; liraglutide (Victoza, Saxenda); liraglutide plus insulin degludec (Xultophy); dulaglutide (Trulicity); lixisenatide plus insulin glargine (Soliqua); semaglutide (Ozempic, Rybelsus, Wegovy); tirzepatide (Mounjaro, Zepbound), which also acts on the glucose-dependent insulinotropic polypeptide receptor; and orforglipron (Foundayo), which was approved in 2026.¹

The Byetta new drug application was voluntarily withdrawn for reasons unrelated to safety or effectiveness, and only generic exenatide products are currently marketed.¹ NAION cases have been reported for all currently marketed GLP-1 RA products.¹

What the FDA Reviewed

The FDA began its evaluation after a retrospective cohort study published in July 2024 in JAMA Ophthalmology reported an association between semaglutide and NAION.^1,2 Among patients seen by neuro-ophthalmologists at 1 academic institution, the investigators reported a higher risk of NAION with semaglutide vs non-GLP-1 RA medications in patients with type 2 diabetes (HR, 4.28; 95% CI, 1.62-11.29) and in patients who were overweight or obese (HR, 7.64; 95% CI, 2.21-26.36).² The FDA identified several limitations of that study but determined that further assessment was warranted, prompting a review of clinical trial, animal, and postmarketing data.¹

Because individual trials had few or no NAION cases, the FDA conducted a meta-analysis of 126 randomized controlled trials across GLP-1 RA development programs. The analysis included 134,253 patients, of whom 78,217 received a GLP-1 RA and 56,036 received a comparator, with 288,879 person-years (PY) of exposure.¹ Of the 15 probable NAION events identified, 10 occurred in patients treated with GLP-1 RAs, 5 occurred in patients receiving placebo, and none occurred in patients receiving other glucose-lowering medications. The incidence rate was 6.4 events per 100,000 PY with GLP-1 RAs vs 3.8 events per 100,000 PY with comparators.¹

The FDA also conducted a retrospective cohort study in its Sentinel Real-World Evidence Data Enterprise Commercial Network, assessing adults with type 2 diabetes who started a GLP-1 RA, a sodium glucose co-transporter-2 (SGLT-2) inhibitor, or a dipeptidyl peptidase-4 (DPP-4) inhibitor between 2019 and 2024.¹ NAION incidence rates were 30 to 32 events per 100,000 PY with GLP-1 RAs, 31 events per 100,000 PY with SGLT-2 inhibitors, and 26 events per 100,000 PY with DPP-4 inhibitors. The risk with GLP-1 RAs was not significantly increased vs SGLT-2 inhibitors (HR, 1.19; 95% CI, 0.91-1.54) but was increased vs DPP-4 inhibitors (HR, 1.43; 95% CI, 1.02-2.01).¹

According to the FDA, methodologically rigorous published observational studies consistently reported an increased risk of NAION in patients with type 2 diabetes who initiated GLP-1 RAs compared with those who initiated DPP-4 or SGLT-2 inhibitors.¹ Adverse event reports were challenging to interpret because NAION risk factors often overlap with conditions common in patients treated with GLP-1 RAs.¹ Those risk factors may include smoking, diabetes, high blood pressure, sleep apnea, anemia, and kidney disease.¹ In adults older than 50 years, the incidence of NAION in the general population is 2.3 to 10.2 cases per 100,000 persons per year, based on published literature.¹

Recommendations for Health Care Professionals

The FDA advises health care professionals to instruct patients to immediately report sudden onset of acute, painless, decreased vision; visual field deficits; or other visual disturbances in one eye. Patients with suspected NAION should be promptly referred to an ophthalmologist for evaluation.¹ The agency also recommends considering discontinuation of the GLP-1 RA in patients who develop NAION, unless the benefits of treatment clearly outweigh the risk, and notes that patients with a history of NAION are at increased risk of recurrence.¹

Although the FDA’s recommendations are directed to health care professionals broadly, they translate directly to pharmacist counseling for patients initiating or continuing any GLP-1 RA. Pharmacists can counsel patients to immediately report sudden, painless vision loss in 1 eye, which may be noticed upon waking, as well as blind spots, tunnel vision, color distortion, or blurry or hazy central vision. When a patient describes these symptoms, pharmacists can direct the patient for prompt ophthalmologic evaluation and alert the prescriber, who can weigh whether to discontinue therapy.

Asking about a history of NAION may also help identify patients at increased risk of recurrence, and patients with risk factors such as smoking, diabetes, high blood pressure, sleep apnea, anemia, or kidney disease may benefit from additional attention to these warning signs. Because NAION cases have been reported with all currently marketed GLP-1 RA products, this counseling applies across the class, including when a patient switches agents.

Patients may notice sudden, painless vision loss in one eye upon waking, blind spots or tunnel vision, distortion of colors, or blurry or hazy central vision, and the FDA advises them to contact a health care professional right away if these symptoms occur.¹ Patients who have had a NAION event should discuss with a health care professional whether to continue or stop the GLP-1 RA.¹ Adverse events can be reported to the FDA MedWatch program online or by calling 1-800-332-1088.¹

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 increased risk of rare but serious eye condition. Published 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. 2024;142(8):732-739. doi:10.1001/jamaophthalmol.2024.2296