Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have rapidly become central to the treatment of type 2 diabetes and obesity. However, research also suggests that one of the most widely used agents in this class – semaglutide – may be associated with a signal for ischaemic optic neuropathy (ION), raising important questions for ophthalmologists and prescribing clinicians.
In a new observational analysis published in the British Journal of Ophthalmology, researchers examined more than 30 million adverse event reports from the FDA’s Adverse Event Reporting System (FAERS) between 2017 and 2024. The aim was to evaluate whether reports of ION differed across different GLP-1RA drugs, formulations, and patient sex.
While recent case reports have suggested a possible link with GLP-1RA therapy and ION risk (particularly non-arteritic anterior ischaemic optic neuropathy), large-scale analyses examining formulation-specific risk have been lacking.
To address this gap, the Canada-based investigators identified 31,774 reports involving semaglutide, finding that that semaglutide overall was the only drug in the study associated with a significant signal for ION.
The strength of the signal was also found to differ markedly between formulations. Wegovy – the higher-dose injectable semaglutide approved for obesity – showed the strongest association, while Ozempic – the formulation used for diabetes – showed a lower but still significant signal. Meanwhile, no ION cases were reported with the oral semaglutide formulation used for type 2 diabetes, Rybelsus. Importantly, the odds of ION risk in patients was shown to be nearly five times higher with Wegovy than it was with Ozempic.
The analysis also revealed sex-specific differences. Stratified analyses showed particularly high reporting odds among men receiving Wegovy, while Ozempic-associated cases were more commonly reported in women. In multivariable models adjusting for age and sex, the odds of ION remained significantly higher with Wegovy compared with Ozempic, with ION risk being three times greater in men than in women.
Notably, no signal for ION was detected with tirzepatide, a dual GLP-1/GIP receptor agonist used for diabetes and obesity, and comparator drugs such as metformin and insulin also showed no significant associations.
While no direct clinical link has yet been established, the report authors propose several mechanisms that could explain a potential link between high-dose semaglutide and optic nerve ischaemia. Because Wegovy (when approved at its highest dose) produces rapid weight loss and sharper metabolic shifts, this could drive the “stronger association by predisposing to optic nerve hypoperfusion through intravascular volume contraction, hypotension with nocturnal dips and autonomic instability.”
For ophthalmologists, the findings highlight a potential safety signal that warrants further investigation but should be interpreted cautiously. Prospective studies will be needed to determine whether semaglutide truly increases the risk of NAION, and whether certain formulations, doses, or patient groups are particularly vulnerable.
As GLP-1RAs continue to reshape the management of metabolic disease, understanding their potential ocular effects will be essential for both clinicians and regulators.
