Semaglutide was the most prescribed drug in the United States in 2023 [1], with few serious side effects initially reported. Glucagon-like peptide-1 (GLP-1) receptor agonists are licensed to treat type 2 diabetes mellitus (T2DM) by improving glycaemic control and reducing adverse cardiovascular events in high-risk individuals. It is also approved for weight management [2]. However, a potential association between use of Semaglutide and non-arteritic anterior ischaemic optic neuropathy (NAION) has been identified [3]. NAION, is a common optic neuropathy with an incidence between 2 and 10/100,000 for those over 50 years. It’s major risk factors include hypertension and T2DM. It typically presents with painless loss of vision, and there are currently no effective treatments to recover sight loss [4].

The seminal study reviewed 16,827 patients who were prescribed Semaglutide, oral or subcutaneous, for any cause. Propensity scores based on demographics and known codable risk factors were used. Forty six cases of incident NAION were identified and verified by Neuro-ophthalmologist review [3]. A fourfold increase in the incidence of NAION in the Semaglutide group (8.9%) compared to the non-GLP-1 group (1.8%) was found; the majority of NAION occurring within 12 months following prescription [3]. While Cox proportional hazards regression model and Kaplan-Meier survival analysis were presented, the small incident figure and the moderate width of the Semaglutide group’s confidence interval (4.5–13.1%) suggested that while the results may be statistically significant, there should be some caution in interpretating the data [5].

Returning to the original randomised controlled trials (RCT) evaluating GLP-1 RA in T2DM and obesity where adverse events would be clearly documented, Silverii et al. [6] found that the cumulative experience was 144,226 and 132,922 patient-years of GLP1-RA and placebo use, respectively. Eight NAION were reported in the GLP1-RA group and four cases in control group. GLP1-RA treatment was not associated with a significantly increased risk for ischaemic optic neuropathy in the fixed-effects analysis with low heterogeneity [6].

Following Hathaway and colleagues’ publication [3], evidence has been examined with some studies supporting a potential association [7, 8], and others refuting it [6,7,8,9,10]. Using longitudinal data from the Danish National Patient Registry and National Prescription Registry once-weekly Semaglutide was found to more than double the risk of NAION in T2DM [7]. Here, the relationship between the prescription to ischaemic event was evenly distributed over the 5 years of observation [7], with no bias towards the first 12 months as originally found [3]. A yet-to-be peer reviewed study utilised the aforementioned Danish registries and the Norwegian Prescribed Drug Registry and Patient Registry. Using the prescription of a sodium-glucose co-transporter 2 inhibitors (SGLT-2is) as a suitable control, they primarily evaluated the incidence of Semaglutide associated NAION in T2DM. They found NAION was more common with Semaglutide users versus SGLT-2is users, but no more common than the known incidence of NAION [8].

Studying a large pharmacoepidemiology dataset (66 million patients), Klonoff et al. [9] primary analysis evaluated adults who initiated GLP-1RA for weight loss. A Cox proportional-hazards model to evaluate time to developing NAION demonstrated an increased risk in the GLP-1RA arm, however following adjustment for codable comorbidities this difference was eliminated. They performed various sensitivity analyses evaluating use in T2DM; those with an ophthalmology examination; and any GLP-1 RAs. No significant increase in the risk of NAION from Semaglutide or any GLP-1 RA was found. Chou et al. [10] evaluated Semaglutide use using 160 health care organizations electronic records across 21 countries. They concluded that use of Semaglutide may not be associated with an increased risk of NAION over and above what is found in the general population. This study may have been at risk of nondifferential exposure misclassification whereby the observed association between exposure and disease is underestimated [11].

Through the North American Neuro-ophthalmology Society membership communication platform, Katz et al. [12] have retrospectively collected seven cases of ischaemic optic neuropathy associated with Semaglutide or Tirzepatide use. This is the first report of Tirzepatide being associated with ischaemic optic neuropathy, and widens the debate over synthetic incretin use. While Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist it actually engages both the GIP receptor and the GLP-1 receptor [13]. Large metabolic shifts were observed with either moderate tightening of the HBa1C or major weight loss. All the patients had a recordable cup to disc ratio, suggesting that the “disc at risk” may be less influential. In one case, where the Semaglutide was reintroduced, the second eye became involved within 24 hours which may disrupt the theory of a dose-dependent mechanism [12].

While the discussion continues it is important to note that synthetic incretin use provides significant metabolic and cardiovascular benefits for both T2DM and obesity management, with an overall low risk profile. With one in four adults living with obesity in England [14], the potential benefits of these medicines cannot be overstated for the individual but also the health care economy. Future prospective research needs to determine the synthetic incretin associated ischaemic optic neuropathy (SIION) clinical phenotype; identify potential subgroups that may be higher risk of SIION; establish whether there is a dose dependant effect; or whether significant modification of the underlying systemic metabolic disease is a factor of SIION.

Until more evidence is provided, is seems suitable to inform patients of the controversy in the literature regarding a possible association: no definite causation has been established [15]. An ophthalmological evaluation to detect an optic “disc-at-risk” prior to synthetic incretin treatment would be unfeasible, and may be less relevant [12]. It may be only those with a prior history of NAION or those with known visual loss, from previous optic nerve injury or optic disc drusen, that a shared decision-making approach may air on the side of caution of considering alternative endocrine therapies such as dipeptidyl peptidase-4 inhibitors or SGLT-2is as indicated for T2DM, or bariatric surgery for those living with obesity.