New-Onset Nonarteritic Anterior Ischemic Optic Neuropathy and Initiators of Semaglutide in US Veterans With Type 2 Diabetes
- Design
- Retrospective cohort · 102361 participants · Hard outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: every participant had type 2 diabetes and was taking metformin; weighted mean BMI was 37.8 and mean age 60.1, and 85.5% were men. Age fits the target range, but the diabetes and weight profile does not.
- Could weight loss explain it?
- PossiblyNo weight or HbA1c change after starting treatment and no mediation analysis are reported. Overlap weighting balanced baseline BMI and HbA1c, which addresses confounding, not mediation; the authors list rapid glycaemic improvement among possible mechanisms, alongside hypotension and volume depletion.
- Study tier
- Study tier 3LOW: a single observational study (a target-trial emulation in VA health records) with an active comparator, new-user design, overlap weighting and 173 events. It is well designed, but an individual observational study is capped at LOW, and the outcome is a coded diagnosis.
- Assessment
- Version 3 · Two independent AI reviews agreed · Nov 11, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
This study used US veterans' health records to compare 11 478 people with type 2 diabetes, all already taking metformin, who started semaglutide with 90 883 who started an SGLT2 inhibitor, over a median of 2.1 years. Starting semaglutide was linked to about twice the risk of NAION, a sudden loss of blood supply to the optic nerve (hazard ratio 2.33; 123 against 67 cases per 100 000 person-years), but the absolute risk stayed low (0.29% against 0.13%). Because this is an observational study, it shows an association, not proof that semaglutide caused the cases, and the people studied had diabetes with an average BMI of 37.8 and were mostly men.
01Findings
What the study reported
- Drugs
- Semaglutide
- Comparator
- SGLT2 inhibitors (almost all empagliflozin)
- Primary outcome
- Incident NAION, identified by ICD-10 and SNOMED codes
- Effect
- Semaglutide against SGLT2i initiators: overlap-weighted HR 2.33 for NAION (unweighted HR 1.84); incidence 123 vs 67 per 100 000 person-years; overlap-weighted incidence 0.29% vs 0.13% (average treatment effect 0.16 percentage points)
- 95% confidence interval
- 95% CI, 1.54-3.54 (abstract); the full-text Results print 95% CI, 1.53-3.54
- P value
- P < .001
- Follow-up
- median 2.1 years; maximum 7.5 years
- Adverse events
- NAION, the study's safety outcome: 30 events on semaglutide vs 143 on SGLT2i; overlap-weighted HR 2.33; absolute risk low (0.29% vs 0.13%)
- Limitations
- Observational target-trial emulation with possible residual unmeasured confounding (for example optic nerve head anatomy, sleep apnea severity, nocturnal hypotension, diabetes duration, non-VA care) and outcome misclassification from coded diagnoses; mostly older men with high cardiometabolic risk, and exposure was initiation only, so dose and duration effects were not studied.
Who was studied
- Mean age
- 60.1 (SD 11.7) years, after overlap weighting
- Age min
- 18
- Sex distribution
- 85.5% male, 14.5% female (after overlap weighting)
- Bmi mean
- 37.8
- Obesity status
- not reported (not an entry criterion; weighted mean BMI 37.8)
- Diabetes status
- type 2 diabetes required
- Cvd status
- mixed (not an entry criterion; congestive heart failure 7.7% and myocardial infarction 2.9% after weighting)
- Ckd status
- mixed (not an entry criterion; kidney disease 8.0% after weighting)
- Baseline condition
- type 2 diabetes on metformin, starting second-line therapy
- Sample size
- 102361
- Inclusion exclusion
- Veterans aged 18 or older with T2D on metformin, new initiators of semaglutide or SGLT2i; excluded type 1 or secondary diabetes, other antidiabetic drugs, 30 or more days of insulin, prior NAION, giant cell arteritis or traumatic optic nerve injury
Study quality details
- Study design
- Retrospective cohort
- Sample size
- 102361
- Randomization
- no
- Blinding
- n/a
- Comparator
- SGLT2 inhibitors (almost all empagliflozin)
- Follow up duration
- median 2.1 years; maximum 7.5 years
- Outcome type
- hard
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% CI, 1.54-3.54 (abstract); the full-text Results print 95% CI, 1.53-3.54
- Risk of bias
- not assessed
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- VA Cooperative Studies Program (CSP#2012); one author partly funded by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases
- Industry funded
- No
- Manufacturer
- not stated in source
- Sponsor role
- The VA Cooperative Studies Program was involved in the design and conduct of the study, data collection, management, analysis and interpretation, manuscript preparation, review and approval, and the decision to submit
- Author conflicts
- One author reported personal fees from TeCure Consulting and two reported grants from companies (Novartis, Alnylam, AstraZeneca, Biodesix, Celgene, Janssen), all outside the submitted work; one also reported VA grants during the study; no other disclosures.
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
03Claims
Claims this study bears on
- Semaglutide increases the risk of non-arteritic anterior ischaemic optic neuropathy (NAION).Supports
Target trial emulation in US veterans with type 2 diabetes taking metformin (11 478 semaglutide vs 90 883 SGLT2 inhibitor initiators): semaglutide initiation was associated with a higher NAION risk (hazard ratio, 2.33; 95% CI, 1.54-3.54), with incidence rates of 123 vs 67 per 100 000 person-years and overlap weighted incidence of 0.29% vs 0.13% (average treatment effect 0.16 percentage points); observational, coded diagnoses, absolute risk low.
04Source
The source, as retrieved
Abstract
[IMPORTANCE] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are considered safe, effective medications for type 2 diabetes (T2D) and weight loss, used by millions worldwide. While their cardiometabolic benefits are well established, emerging observations suggest a potential association between GLP-1RA use and new-onset nonarteritic anterior ischemic optic neuropathy (NAION). [OBJECTIVE] To emulate a target trial evaluating the risk of NAION associated with initiation of semaglutide (GLP-1RA), compared with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as second-line therapy for T2D in a nationwide cohort of US veterans. [DESIGN, SETTING, AND PARTICIPANTS] This study was conducted nationwide using data from the Veterans Health Administration health care system between March 1, 2018, and March 1, 2025. This active-comparator, new-user, target trial emulation used cause-specific hazard ratios (HRs) that were estimated using overlap weighting to account for confounding. Participants included US veterans with T2D, current metformin use, and no prior GLP-1RA or SGLT2i use. Data analysis was conducted from July 2025 through September 2025. [EXPOSURE] Initiation of semaglutide or any SGLT2i. [MAIN OUTCOME AND MEASURE] Incident NAION, identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision and Systematized Nomenclature of Medicine codes. [RESULTS] A total of 102 361 US veterans met inclusion criteria, including 11 478 initiators of semaglutide and 90 883 initiators of an SGLT2i. Baseline characteristics were well balanced between treatment groups after overlap weighting (mean [SD] age, 60.1 [11.7] years; body mass index, 37.8 [6.7]; hemoglobin A1c, 7.0% [1.4]; 85.5% male and 14.5% female; 20.7% Black, 8.1% Hispanic, and 61.9% non-Hispanic White). Over a maximum follow-up of 7.5 years, 173 total incident NAION events occurred. The incidence rate of NAION was 123 per 100 000 person-years among semaglutide initiators and 67 per 100 000 person-years among SGLT2i. In 2.1 years of median follow-up, semaglutide initiators had a 2.33-fold higher risk than SGLT2i initiators (hazard ratio, 2.33; 95% CI, 1.54-3.54; P < .001). The overlap weighted incidence rate of NAION was 0.29% for semaglutide initiators and 0.13% for SGLT2i initiators, with a corresponding average treatment effect of 0.16 percentage points. [CONCLUSIONS AND RELEVANCE] In this nationwide cohort of US veterans with T2D, semaglutide initiators had a 2-fold NAION risk than SGLT2i initiators, while the absolute risk was low. Clinicians and patients should be counseled on the rare but evident increased risk of NAION after semaglutide initiation.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Nov 11, 2026 | 41678180 first ingestion |