Use of semaglutide and risk of non-arteritic anterior ischemic optic neuropathy: A Danish–Norwegian cohort study
Authors: Simonsen Emma , Lund Lars Christian , Ernst Martin Thomsen , Hjellvik Vidar , Hegedüs Laszlo , Hamann Steffen , Jørstad Øystein Kalsnes , Gulseth Hanne Løvdal , Karlstad Øystein , Pottegård Anton 
Published: December 2024

Importance

Recent findings have raised concerns about an association between semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), and non-arteritic anterior ischemic optic neuropathy (NAION).

Objective

To further investigate the putative association between semaglutide use and NAION.

Design

Bi-national active comparator new-user cohort study with propensity score weighing to adjust for confounding, fixed-effect meta-analysis, and a supplementary self-controlled analysis (symmetry analysis).

Setting

Data were obtained from national health registries in Denmark and Norway, including prescription registries, patient registries, and civil registration systems.

Participants

New users of semaglutide and sodium-glucose co-transporter 2 inhibitors (SGLT-2is) during 2018-2022 (Norway) and 2018-2024 (Denmark).

Exposures

Initiation of semaglutide and SGLT-2is for the management of type 2 diabetes was assessed in the main analysis. In the self-controlled design, exposure to semaglutide, regardless of indication, was investigated.

Main Outcomes and Measures

Incidence rates of NAION among semaglutide and SGLT-2is users, along with hazard ratios (HRs) and incidence rate differences (IRDs) with robust 95% confidence intervals. Estimates from Denmark and Norway were pooled using a fixed-effects model (inverse variance weighting). The supplementary self-controlled study returned sequence symmetry ratios (SRs).

Results

We identified 44,517 eligible users of semaglutide for the management of type 2 diabetes in Denmark and 16,860 in Norway. In total, we observed 32 NAION events among semaglutide users (24 in Denmark and 8 in Norway). This yielded an unadjusted incidence rate of NAION of 2.19/10,000 person-years among Danish semaglutide initiators, compared to 1.18 among SGLT-2i initiators. The corresponding unadjusted incidence rates in Norway were 2.90 and 0.92. After adjustment, we obtained a pooled HR of 2.81 (95% CI 1.67 to 4.75) and IRD of +1.41 (95% CI +0.53 to +2.29). Estimates were compatible in the individual countries, although with higher and less precise estimates in Norway (HR 7.25; 95% CI 2.34 to 22.4) compared to Denmark (HR 2.17; 95% CI 1.20 to 3.92). Results were consistent across sensitivity and supplementary analysis, with a notably stronger association observed in a post hoc per-protocol analysis (HR 6.35; 95% CI 2.88 to 14.0). In the supplementary self-controlled study, SRs for NAION were 1.14 (95% CI 0.55 to 2.36) in Denmark and 2.67 (95% CI 0.91 to 8.99) in Norway.

Conclusions and Relevance

Our findings show an association between use of semaglutide for type 2 diabetes and risk of NAION. However, the absolute risk remains low.

Key Points

Question

Is there an association between semaglutide use and risk of non-arteritic anterior ischemic optic neuropathy (NAION)?

Findings

In this cohort study conducted in Denmark and Norway, use of semaglutide was associated with an increased risk of NAION; the pooled hazard ratio was 2.81 (95% confidence interval (CI) 1.67 to 4.75) and the incidence rate difference (absolute risk increase) was +1.41 (95% CI +0.53 to +2.29) NAION events per 10,000 person-years. The finding was consistent across sensitivity and supplementary analysis.

Meaning

Our study confirms that use of semaglutide is associated to an increased risk of NAION, but also that the excess absolute risk is low.