Non-arteritic anterior ischemic optic neuropathy (NA-AION) is one of the most common causes of optic neuropathy and vision loss in persons over the age of 50 years, with an annual incidence of 10.2 cases per 100,000.¹ It accounts for approximately 85% of ischemic optic neuropathy compared to the less prevalent arteritic variant.² The optic disc configuration has a significant impact on the contribution of NA-AION in which a small and crowded optic disc carries the highest risk.³ Additionally, systemic vasculopathy pathologies interfering with disc perfusion, such as diabetes and dyslipidemia, have been linked to NA-AION development.³

Semaglutide (Ozempic, Novo Nordisk), a glucagon-like peptide-1 receptor agonist (GLP-1 RA), was recently approved to treat diabetes and obesity.⁴ However, emerging reports have linked the probable association between semaglutide and increased risk of ischemic optic neuropathy in the form of NA-AION.^5,6 Herin, we report a young patient with no medical comorbidities who presented with bilateral NA-AION associated with unilateral branch retinal artery occlusion (BRAO) on semaglutide.

A 37-year-old obese male, who is not diabetic, not hypertensive or dyslipidemic, presented with a sudden drop of vision in the right eye and blurred vision in the left eye. He gave a history of using semaglutide for 11 months for the purpose of losing weight, starting with 0.5 mg weekly for two months, and was escalated to 1 mg weekly for nine months.

On examination, his best-corrected visual acuity (BCVA) was 6/200 in the right eye and 20/25 in the left eye. A relative afferent pupillary defect (rAPD) of 0.9 log units was observed in the right eye. Ishihara color-vision testing yielded 0/15 and 10/15 results in the right and left eyes, respectively. Goldmann visual field testing demonstrated a band-shaped scotoma bisecting the visual axis, affecting the superior field in the right eye and was unremarkable in the left eye. Anterior segment examination, including intraocular pressure was unremarkable bilaterally. Dilated fundus examination showed bilateral optic disc swelling, more significantly in the right eye (Fig. 1A and B), along with an inferior macular ischemia indicating branch retinal artery occlusion (BRAO). Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) at the optic disced showed optic disc thickening in the right more than the left eye (Fig. 1C).

Further work-up, including contrasted magnetic resonance imaging of the brain and orbits, arteriography and venography magnetic resonance was unremarkable. The diagnosis of semaglutide-induced bilateral NA-AION and right BRAO was made and the discontinuation of the semaglutide was suggested. One month later, he presented with BCVA of 20/30 in the right eye and 20/20 in the left eye. Color-vision results were 12/15 and 15/15 in the right and left eye, respectively. Dilated fundus examination showed small optic nerve heads in both eyes with marked resolution of discs swelling in both eyes (Fig. 2A and B). OCT of the RNFL at the optic disc showed marked reduction of swelling in both eyes (Fig. 2C).

NA-AION is a major cause of severe visual impairment in adults, representing the most common cause of acute optic neuropathy in patients over 50 years of age, and the second most frequent etiology of all optic neuropathies after glaucoma.^1,2 Patients with systemic risk factors such as diabetes, hypertension, hyperlipidemia, and sleep apnea are more likely to develop NA-AION, particularly when combined with local factors in the form of small and crowded optic nerve heads.³

Semaglutide is a GLP-1 RA that has recently been approved and is widely used to treat type 2 diabetes and, more recently, obesity.⁴ Semaglutide has gained popularity due to its remarkable glucose control and cardiovascular benefits demonstrated in major trials, such as STEP and SUSTAIN trials.^4,7 However, semaglutide has recently raised concerns regarding potential side effects, including NA-AION, especially in individuals who are prone to ischemic episodes.^5,6,8–11 The pathogenic mechanism is not fully defined and poorly understood. Three possible causes were hypothesized, including firstly, medication-induced GLP-1 RA-enhanced autonomic tone on GLP-1 receptors in the optic nerve, which may interfere with optic disc perfusion.^7,12 Another argument was related to the known lowering effect of blood pressure by semaglutide, which may induce postural hypotension, and hence compromise the perfusion of the optic nerve.⁸ The final theory proposed that optic nerve enlargement, presumably produced by fast hyperglycemia correction in diabetic patients, might result in successive NA-AION secondary to the optic disc crowding.⁹ Although some authors were unable to determine whether the development of NA-AION was caused by the medication or by the culprit of vascular risk factors, Grausland et al. discovered a persistently higher risk of NA-AION in diabetic individuals even after glycemic control.^5,6 This indeed can be substantiated, as noted in our patient, who is medically free except for being overweight, and his unremarkable investigations, including the glycosylated hemoglobin and lipid profile.

The usual presentation of NA-AION is unilateral involvement with acute painless visual loss associated with an altitudinal field defect. However, the visual loss can range from mild to severe, and the visual field defects can be variable as well to include altitudinal, arcuate, or diffuse depression.¹³ This might explain our case results of high visual acuity and inferonasal depression in the visual field of the left eye. However, it is uncertain whether the altitudinal field defect in the right eye is attributed to the NA-AION, BRAO, or a combination of both diseases. Two studies reported bilateral NA-AION.^8,9 One case of semaglutide-induced bilateral sequential NA-AION was described in a patient with diabetes and hyperlipidemia, with the second eye becoming affected three weeks after the first. Nocturnal hypotension was assumed to be the mechanism behind NA-AION formation.⁸ Katz et al. documented two further cases in which the optic nerves were swollen at presentation, and both patients were diabetics. They hypothesized that fast glycemic management would cause optic nerve enlargement and crowding, predisposing the optic nerves to ischemia.⁹ Aside from being overweight, the reported patient in this paper was medically free. In 979 subjects with overweight or obesity, semaglutide exposure was associated with a hazard ratio of 7.64 (95% confidence interval 2.21–26.36) of developing NA-AION within three years.⁵ Nevertheless, in all of those cases, the manifestation was unilateral, as opposed to our patient's involvement in both eyes.

There have been multiple reports of BRAO associated with NA-AION. The primary relationship was hemodynamic dysfunction due to cavernous sinus thrombosis, hemodialysis, and blood loss following a surgical intervention.^14,15 For such a relationship, two theories have been proposed. The first is that the retinal and ciliary arterial trees were simultaneously affected. The second hypothesis is that the enlarged ischemic optic nerve compresses the retinal arteries leading to sequential rather than simultaneous BRAO. Since our patient had both findings at the first evaluation, we are unable to determine if this connection is sequential or simultaneous. However, the incidence of BRAO in the eye with more severely swollen optic disc increases the likelihood of the compression effect on retinal arteries. Shabto et al. reported the incidence of central retinal artery occlusion after semaglutide injection.¹⁰ The suspected mechanisms were either an inadvertent intravenous infusion of semaglutide or an increase in blood viscosity due to medication.¹⁰ However, the patient described in their research did not suffer an ischemia that impacted the optic nerve. On the other hand, one of the cases reported by Katz and colleagues indeed had a combined NA-AION with paracentral acute middle maculopathy, which was hypothesized to be related to GLP-1 receptor expression in the ganglion cell layer.⁹ To our knowledge, no study has reported the incidence of BRAO as an isolated finding or in association with NA-AION following semaglutide injection.

In conclusion, semaglutide is increasingly associated with an elevated risk of NA-AION. The absence of systemic risk factors, along with the presence of predisposing risk factors of the optic disc indicate that optic nerve assessments and retinal examinations are recommended before the initiation of GLP-1 RA treatment, even in the absence of systemic risk factors. Patients with crowded optic discs need to be counseled about the potential risks of developing NA-AION after using GLP-1 RA treatments.