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From the Journals

Could Wegovy Raise Optic Nerve Risk?

A pharmacovigilance analysis of FDA adverse event reports finds the strongest ischemic optic neuropathy reporting signal with high-dose semaglutide formulations, with higher adjusted odds reported in men.

Conexiant

Semaglutide—particularly the higher-dose 2.4-mg weekly formulation used for obesity—is associated with a substantially stronger reporting signal for ischemic optic neuropathy (ION) than lower-dose semaglutide formulations, according to a global pharmacovigilance analysis of more than 30 million reports in the FDA Adverse Event Reporting System (FAERS).

In adjusted analyses, the 2.4-mg semaglutide formulation (Wegovy) was associated with about 4.7 times the odds of ION reports vs the lower-dose formulation (Ozempic), and men had more than three times the odds of reported ION vs women, researchers reported in the British Journal of Ophthalmology.

ION is a rare but vision-threatening condition that can cause permanent visual field loss and, in some cases, blindness.

The study—led by Moiz Lakhani, of the Faculty of Medicine at the University of Ottawa—analyzed FAERS reports submitted between December 2017 and December 2024 to evaluate formulation- and sex-specific reporting patterns for semaglutide-associated ION.

Methods

Investigators deduplicated FAERS reports and identified cases in which a glucagon-like peptide-1 receptor agonist (GLP-1 RA) was listed as the primary suspect drug for ION.

Semaglutide products were analyzed both collectively and by formulation:

  • Ozempic (weekly injectable semaglutide for type 2 diabetes; FDA approval 2017)

  • Wegovy (weekly injectable semaglutide for obesity; FDA approval 2021)

  • Rybelsus (daily oral semaglutide for type 2 diabetes; FDA approval 2019)

The dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide was analyzed overall and by formulation:

  • Mounjaro (type 2 diabetes; FDA approval 2022)

  • Zepbound (obesity; FDA approval 2023)

Comparator drugs included metformin, insulin, and tirzepatide.

Researchers assessed disproportionality using reporting odds ratios (RORs). Signals were required to meet adapted Evans criteria with Bonferroni correction and Bayesian confirmation. Multivariable logistic regression adjusted for age and sex to estimate adjusted odds ratios (AORs).

Results

Among the millions of FAERS reports, investigators identified 31,774 reports involving semaglutide (mean age 56 years; 54% female).

Of those:

  • 3,070 reports involved Wegovy (mean age 55 years)

  • 20,608 involved Ozempic (mean age 58 years)

Semaglutide was the only agent in the analysis with a statistically significant ION reporting signal.

The strongest signal was observed with the higher-dose semaglutide formulation:

  • Wegovy: 28 ION reports; ROR 74.89

  • Ozempic: 47 ION reports; ROR 18.81

No ION reports were identified with oral semaglutide (Rybelsus).

Comparator drugs showed no meaningful signal:

  • Tirzepatide: ROR 0.56

  • Mounjaro: ROR 1.02

  • Zepbound: no reports

  • Metformin: ROR 1.35

  • Insulin: ROR 1.61

In sex-stratified analyses, the strongest signal occurred in men receiving Wegovy (ROR 116). Women showed a strong signal with Ozempic (ROR 26.86)

After adjusting for age and sex:

  • Wegovy was associated with 4.7-fold higher odds of ION reports vs Ozempic

  • Men had 3.3-fold higher odds of reported ION vs women

All signals met the study’s Bayesian confirmation criteria.

Discussion

Researchers suggested that the stronger reporting signal with higher-dose semaglutide formulations may reflect dose-dependent effects on optic nerve perfusion, potentially related to intravascular volume contraction, hypotension with nocturnal dips, or autonomic instability. However, these mechanisms remain hypothetical, and the study did not evaluate causality.

The absence of an ION signal with oral semaglutide may reflect its low oral bioavailability (approximately 1%), which produces lower systemic drug levels than injectable formulations.

Tirzepatide showed no detectable ION reporting signal in this analysis. Investigators noted that its combined GLP-1 and GIP activity could theoretically mitigate vascular effects associated with GLP-1–mediated fluid shifts, although this hypothesis requires further study.

The authors also emphasized that prescribing volume differs substantially across products. Ozempic has accounted for the majority of semaglutide prescriptions since its 2017 approval, whereas uptake of Wegovy has been more limited due to supply constraints and insurance coverage. As a result, the stronger signal observed with Wegovy likely reflects higher reporting intensity relative to exposure, not necessarily higher absolute case counts.

Limitations

Because FAERS is a spontaneous reporting database, the analysis cannot establish incidence or causality.

Key limitations include:

  • Lack of denominator data to calculate true event rates

  • Potential reporting bias following regulatory or media attention

  • Limited clinical information, including comorbidities, disease severity, and laterality

  • Shorter market availability for tirzepatide vs semaglutide

The authors called for longitudinal pharmacoepidemiologic studies with exposure denominators and prospective risk stratification to clarify whether a causal relationship exists.

“The reproducible semaglutide signal, supported by mechanistic plausibility and Bayesian evidence, highlights the need for individualised GLP-1 therapy and prospective risk stratification,” the researchers wrote.

The authors reported no specific funding for the study. Disclosures are detailed in the original report.

Source: British Journal of Ophthalmology