PMID-38958939 — Hathaway NAION Cohort (JAMA Ophthalmol 2024)

[DRAFT — authored 2026-04-18. Requires Medical Director review.]

Citation

Hathaway JT, Shah MP, Hathaway DB, Zekavat SM, Krasniqi D, Gittinger JW Jr, Cestari D, Mallery R, Abbasi B, Bouffard M, Chwalisz BK, Estrela T, Rizzo JF 3rd. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. JAMA Ophthalmol. 2024;142(8):732-739. doi: 10.1001/jamaophthalmol.2024.2296. PMID: 38958939.

Study Design

Design: Retrospective matched cohort study, single-center (Massachusetts Eye and Ear)
Cohort period: December 2017 – November 2023
Matching: Propensity-matched to similar non-semaglutide-exposed patients on age, sex, race, and systemic comorbidities
N: 16,827 patients (semaglutide + non-semaglutide cohorts combined across T2D and overweight/obese strata)
Primary comparison: NAION incidence in semaglutide-exposed vs. non-exposed patients

Population

Adults receiving care at Massachusetts Eye and Ear neuro-ophthalmology service
Two parallel strata:
- Type 2 diabetes stratum: semaglutide-exposed vs non-GLP-1 standard-of-care
- Overweight/obesity stratum: semaglutide-exposed vs non-GLP-1 anti-obesity treatment

Intervention / Exposure

Exposure: Active prescription for semaglutide (Ozempic or Wegovy) identified from medical record
Comparator: Propensity-matched patients without GLP-1 agonist exposure

Outcomes

Primary — Cumulative incidence of NAION over 3-year follow-up

Type 2 diabetes stratum (n=710 pairs):

Semaglutide-exposed: 17 NAION events
Non-exposed: 6 NAION events
Hazard ratio: 4.28 (95% CI 1.62–11.29)

Overweight/obesity stratum (n=979 pairs):

Semaglutide-exposed: 20 NAION events
Non-exposed: 3 NAION events
Hazard ratio: 7.64 (95% CI 2.21–26.36)

Both strata: statistically significant increased risk of NAION among semaglutide-prescribed patients.

Key Findings

Hathaway is the seminal single-center cohort study that first raised the NAION safety signal for semaglutide in the peer-reviewed literature. The 4-fold (T2D) to 7-fold (obesity) increased hazard prompted:

Subsequent large-cohort replications (Danish/Norwegian PMID-39696569 – Danish Norwegian NAION Cohort; other national-registry analyses)
Pharmacovigilance-database analyses (Lakhani 180-country PMID-40383360 – Lakhani 180 Countries GLP-1 Ocular Events)
EMA PRAC formal evaluation and June 2025 "very rare" classification (REG-EMA-PRAC-Semaglutide-NAION-2025 – EMA NAION Very Rare)

Mechanistic hypothesis (speculative): Rapid glycemic improvement or rapid weight loss may transiently alter optic nerve head perfusion pressure in predisposed individuals (crowded optic disc, "disc at risk"). The association is not established to be causal; confounding by indication (patients prescribed semaglutide have higher baseline metabolic/vascular risk) remains a consideration.

Limitations (Author-acknowledged)

Single-center, tertiary neuro-ophthalmology referral population — NAION is over-represented in the denominator, inflating apparent risk relative to general-population incidence.
Retrospective design — residual confounding cannot be excluded despite propensity matching.
Semaglutide exposure duration and cumulative dose not characterized.
No information on semaglutide indication-specific dosing regimen (Ozempic vs Wegovy).
Generalizability to community populations unclear.

Clinical Relevance

Triggers clinician awareness; counseling on NAION is advisable regardless of US label status.
NAION remains rare in absolute terms — EMA quantifies risk as up to 1 in 10,000 person-years exposed, with ~1 additional case per 10,000 person-years attributable to semaglutide.
Patient-level ophthalmic risk factors (crowded optic disc, history of NAION in fellow eye, hypertension, sleep apnea, dyslipidemia) should inform shared decision-making.
If NAION occurs during semaglutide therapy, discontinue semaglutide (EMA PRAC guidance).

Evidence Level

Level III (Oxford CEBM) — retrospective matched cohort, single-center. Supported by subsequent Level II population-scale evidence.

Linked Peptides

Semaglutide

Related Studies

PMID-39696569 – Danish Norwegian NAION Cohort — population-scale replication
PMID-40383360 – Lakhani 180 Countries GLP-1 Ocular Events — pharmacovigilance with tirzepatide class-differentiation
PMID-29217386 – Feldman-Billard Retinopathy Rapid Glycemic Correction — prior rapid-glycemic-correction retinopathy literature
REG-EMA-PRAC-Semaglutide-NAION-2025 – EMA NAION Very Rare — regulatory downstream

Orchestrator Notes

Primary citation that launched the NAION safety conversation.
Lesson 5.2 Section 6 cites this with HR values; keep synchronized with any clinical-guideline updates.
Semaglutide profile safety section cites this as first-in-sequence evidence; full triangulation: Hathaway → Danish → Lakhani → EMA.

PMID-38958939 – Hathaway NAION Cohort