What are the risks of semaglutide (glucagon-like peptide-1 receptor agonist) on the optic nerve?

Semaglutide and Optic Nerve Risk

Semaglutide increases the risk of nonarteritic anterior ischemic optic neuropathy (NAION) and other optic nerve disorders, with the most recent large-scale evidence showing a doubling of risk in patients with type 2 diabetes, though the absolute risk remains low at approximately 0.2 per 1000 person-years.

Primary Optic Nerve Risks

NAION (Nonarteritic Anterior Ischemic Optic Neuropathy)

• Semaglutide independently doubles the five-year risk of NAION (HR 2.19,95% CI 1.54-3.12) based on a Danish national cohort of 424,152 persons with type 2 diabetes followed prospectively 1

• The incidence rate increases from 0.093 to 0.228 per 1000 person-years with semaglutide exposure, with median time to event of 22.2 months after first prescription 1

• A US neuro-ophthalmology registry found even higher risk estimates: HR 4.28 (95% CI 1.62-11.29) in diabetic patients and HR 7.64 (95% CI 2.21-26.36) in overweight/obese patients, with cumulative 36-month incidence of 8.9% and 6.7% respectively 2

• A broader US population study confirmed increased NAION risk (HR 1.76,95% CI 1.01-3.07) among 159,398 matched patients with type 2 diabetes 3

Other Optic Nerve Disorders

• Semaglutide increases risk of other optic nerve disorders beyond NAION (HR 1.65,95% CI 1.18-2.31), though no association was found with other visual pathway disorders 3

• Case reports document progression from diabetic papillopathy to NAION in patients on semaglutide, with partial visual recovery only after corticosteroid treatment and drug discontinuation 4

Diabetic Retinopathy Complications

Established Risk with Rapid Glycemic Control

• The American College of Cardiology guidelines explicitly state that semaglutide has been associated with diabetic retinopathy complications, predominantly in patients with prior history of proliferative retinopathy 5

• This increased risk is hypothesized to be due to the rapid and sustained reductions in blood glucose observed with semaglutide, not a direct drug effect 5

• The American Diabetes Association confirms that GLP-1 receptor agonists including semaglutide have been shown to be associated with increased risk of rapidly worsening diabetic retinopathy in randomized trials 5

Clinical Implications

• Retinopathy status must be assessed when initiating semaglutide, since rapid reductions in A1C can be associated with initial worsening of retinopathy 5

• Patients should have a recent eye examination prior to semaglutide initiation, as recommended by current guidelines 5

• The risks and benefits of semaglutide therapy should be considered carefully in patients with prior history of proliferative retinopathy 5

Critical Clinical Algorithm

Pre-Treatment Assessment

1. Obtain comprehensive ophthalmologic examination before initiating semaglutide, particularly assessing for:

   • Pre-existing diabetic retinopathy (especially proliferative) 5
   • Optic disc appearance and cup-to-disc ratio (NAION risk factors) 2
   • Baseline visual fields 2

2. Identify high-risk patients who warrant extra caution:

   • History of proliferative diabetic retinopathy 5
   • Small optic disc with crowded appearance 2
   • Vascular risk factors (hypertension, hyperlipidemia, sleep apnea) 2, 1

During Treatment Monitoring

• Instruct patients to report immediately: sudden vision loss, blurred vision, visual field defects, or optic disc changes 4, 6

• If visual symptoms develop: discontinue semaglutide immediately and obtain urgent ophthalmologic evaluation, as continued use may worsen outcomes 6

• Consider more frequent ophthalmologic monitoring (every 6 months rather than annually) in high-risk patients 5

Dose Titration Considerations

• Start at the lowest dose (0.25 mg weekly) and titrate slowly every 4 weeks to minimize rapid glycemic changes that may precipitate retinopathy worsening 7

• Avoid aggressive A1C reduction in patients with established retinopathy, as the mechanism appears related to rapidity of glucose lowering rather than the drug itself 5

Important Caveats and Pitfalls

Absolute vs. Relative Risk

• While relative risk doubles, absolute risk remains low (approximately 0.2-0.9% over 2-3 years depending on population), so this should not automatically preclude use in appropriate patients 3, 2, 1

• The cardiovascular benefits of semaglutide (13% reduction in major adverse cardiovascular events) may outweigh optic nerve risks in many patients with established cardiovascular disease 5

Causality Considerations

• These are observational studies and case reports; causality has not been definitively established through randomized controlled trials 4, 2, 1

• The temporal relationship (median 22 months to NAION) and dose-response relationship support but do not prove causation 1

• NAION is untreatable and causes irreversible vision loss, making even a potential association clinically significant 1

Documentation Requirements

• Document pre-treatment ophthalmologic assessment and informed consent discussion about optic nerve risks, particularly NAION and retinopathy worsening 5

• This is especially critical given the increasing off-label use for weight loss in patients without diabetes who may have lower baseline risk but still face these complications 2, 6