Semaglutide Associated With Optic Neuropathy That Can Lead to Blindness, Mass Eye and Ear Researchers Report

Semaglutide, the active ingredient in Ozempic and Wegovy, is associated with much higher risk of an optic nerve condition that can lead to business, according to findings reported today in JAMA Ophthalmology.

The risk was fourfold higher for people prescribed semaglutide for type 2 diabetes and more than sevenfold among those prescribed the drug for overweight and obesity.

The investigators at Harvard-affiliated Massachusetts Eye and Ear in Boston cautioned that their observational study can’t prove a causal connection between semaglutide and the optic nerve condition. An accompanying editorial said that even if the findings are supported by further research, the absolute risk is probably low.

Jimena Tatiana Hathaway, M.D., M.P.H., and colleagues said in the JAMA Ophthalmology study they started investigating the association between semaglutide and optic nerve condition, called nonarteritic anterior ischemic optic neuropathy (NAION), after anecdotal clinical experience. The FDA-approved labels for Ozempic or Wegovy mention that diabetic retinopathy complications were more common among people randomly assigned to semaglutide in clinical trials, but there is no mention of NAION and the researchers say to the best of their knowledge, there is the first report about a possible association.

NAION is nerve damage to the part of the optic nerve nearest eye caused by lack of blood flow. It is labeled nonarteritic because the blood vessels are not inflamed as they are in arteritis, and there is a condition called arteritic anterior ischemic optic neuropathy. About 6,000 new cases of NAION occur in the U.S. each year, according to the American Academy of Opthalmology, and the academy says it is the most common cause of acute (sudden) optic neuropathy among people older than 50 in the United States.

Identifying the reasons for an association between semaglutide and NAION was beyond the scope of this study, but Hathaway and colleagues noted that the optic nerve has the glucagon-like peptide 1 (GLP-1) receptors so semaglutide and the other GLP-1 drugs might have an unintended effect on the nerve and nearby blood vessels.

In her editorial, Susan P. Mollan, M.Bc.H.B., a neuro-ophthalmologist at University Hospitals Birmingham, floated the notion that the rapid normalization of the cardiometabolic system semaglutide might be the cause of the NAION side effect rather than semaglutide itself. She noted that research has shown that tight glycemic control can have the short-term effect of worsening diabetic retinopathy.

Hathaway and colleagues conducted their study by sifting through the records of 17,298 patients seen at Massachusetts Eye and Ear’s neuro-ophthalmology clinic from Dec. 1, 2017, through Nov. 30, 2023. They winnowed that group down to 710 who had type 2 diabetes and 979 who were overweight and obese. Then within those groups, they compared those who had been prescribed semaglutide and with group who had not. To create an accurate comparison, they used some commons statistical matching techniques in their analysis,

Among the patients with type 2 diabetes, they found that 17 patients among the 169 in semaglutide group with NAION compared with 6 among the 234 in the nonsemaglutide group. A Kaplan-Meier analysis showed the cumulative incidence of NAION of 8.9% at 36 months in the semaglutide group versus 1.8% for the nonsemaglutide group. A Cox proportional hazard model analysis showed a 4.28 higher risk of NAION in the semaglutide group than in the nonsemaglutide group.

The results for the people who were overweight and obese were not dissimilar. The researchers identified 20 patients among the 254 in the semaglutide group with NAION compared with just three among the 359 in the matched, nonsemaglutide. A Kaplan-Meier analysis showed the cumulative incidence of NAION of 6.7% at 36 months compared with 0.8% in the nonsemaglutide group. The Co proportional hazard model analysis showed a 7.64 greater risk of NAION among the people in the semaglutide group compared with those in the nonsemglutide group.

As Hathaway and colleauges note in the limitations section of the study as published JAMA Ophthalmology, findings such as these come with a number of provisos. Patients seen at a specialized neuro-ophthalmology are not typical patients so the findings may not be generalizable. A retrospective study such as this, even with all the statistical adjustments made in the analysis of the data, may not eliminate the biases that go into deciding which patients are prescribed semaglutide (or any drug. They also note that relatively small proportion of Black patients in the study may limit the generalizability.

Still, in their conclusion, they say their study is the first to report an association between semaglutide and NAION.

“The best approaches to confirm, refute or refine our findings would be to conduct a much larger, retrospective multicenter population-based cohort study; a prospective, randomized clinical study; or a postmarket analysis of all GLP-1 RA drugs,” Hathaway and colleagues wrote.

This isn't the first time that a commonly prescribed drug has been linked to NAION. Several studies found an association between sildenafil, the active ingredient in Viagra. But there have also been some studies that have refuted those findings, and whether there is truly a connection between sildenafil and a higher risk of NAION is controversial.