Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) prescribed to assist with weight management in patients with type 2 diabetes (T2D) or those who are overweight/obese, and there have been anecdotal reports of nonarteritic anterior ischemic optic neuropathy (NAION) in patients taking this medication. This single-center, observational study compared patients prescribed semaglutide to matched patients prescribed other medications for diabetes and found a greater risk of NAION in the semaglutide cohort, though additional studies are needed to verify this relationship and causality cannot be inferred.
Study Design
This retrospective, single-center, matched cohort study investigated the potential association between semaglutide prescription and NAION in patients with T2D or who were overweight/obese. The study patients were identified among those evaluated by the neuro-ophthalmology service at Massachusetts Eye and Ear, Boston, between December 1, 2017, and November 30, 2023; patients with a prior history of NAION were excluded. The study population included 710 patients with T2D (194 prescribed semaglutide; 516 prescribed non–GLP-1 RA antidiabetic medications) and 979 who were overweight/obese (361 prescribed semaglutide; 618 prescribed non–GLP-1 RA weight-loss medications).
Patients were propensity matched for age, sex, hypertension, hyperlipidemia, T2D, obstructive sleep apnea, and coronary artery disease. Kaplan-Meier and Cox proportional hazard regression models adjusted for potential confounding comorbidities were used to determine the cumulative incidence and hazard ratio of NAION in each group.
Outcomes
Semaglutide prescription was associated with an increased risk of developing NAION in both the diabetic cohort and the overweight/obese cohort (HR 4.28 and 7.64, respectively), with an NAION event most likely to occur within the first year of semaglutide prescription (cumulative incidence 6.5% and 5.5%). The 36-month cumulative incidences of NAION among patients with diabetes in the semaglutide and non–GLP-1 RA cohorts were 8.9% and 1.8%, respectively, and 6.7% and 0.8% among patients who were overweight/obese.
Limitations
This is an observational retrospective analysis of patients at a single quaternary institution in Boston, MA, and there may be selection biases. Additionally, this retrospective study did not indicate the severity of T2D or degree of overweightness/obesity, and it is likely that patients with more severe disease were prescribed semaglutide as opposed to other drugs.
Clinical Significance
Although this study reveals a possible relationship between semaglutide use and NAION in patients with T2D and those who are overweight/obese, future study is required to assess causality. If such an association is confirmed, it will be important to determine whether this is a drug-class effect or related to one particular GLP-1 RA agent.
Such an association is unexpected, and there is currently no logical pathophysiologic hypothesis to explain this finding, although previous reports have mentioned a paradoxical risk of temporary worsening of diabetic retinopathy in patients with diabetes receiving certain treatment, including semaglutide. Given the large number of participants who were included in semaglutide clinical trials and the very large number of people who use this drug globally, it is important to highlight that the absolute risk of developing NAION in direct relation to taking semaglutide is likely quite low. The potential risk of NAION should not outweigh the definite benefits semaglutide can otherwise provide for most patients prescribed this medication.
Until prospective studies clarify this potential association, ophthalmologists should remain cautious and use a similar approach for semaglutide as with other drugs reported to have a possible association with increased NAION risk (e.g., amiodarone and phosphodiesterase type 5 inhibitors). We should be ready to reassure our patients and discuss risks and benefits, emphasizing what is known vs what is unknown.
Financial Disclosures: Dr. Valerie Biousse discloses financial relationships with GenSight Biologics and Neurophoenix (Consultant/Advisor).