Cohort studyindependent cross-checkabstract checked★ key study I-ODD-118 in-depth review
Danish-Norwegian data: semaglutide linked to a rare optic nerve stroke
Use of semaglutide and risk of non-arteritic anterior ischemic optic neuropathy: A Danish-Norwegian cohort study.
Overview
Simonsen E et al.. Diabetes Obes Metab 2025 · PMID 40098249 · DOI 10.1111/dom.16316
HR 2.81, but only about 1 extra case per 7,000 patient-years.
Does the study support the specific claim? Partly · Methodological quality: moderate
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Test semaglutide-NAION association in national data.
- How was the study done?
Register cohort vs SGLT2i users.
- How many people, animals or samples were studied?
61,377 semaglutide users.
- What was actually found?
About 3-fold relative risk; very low absolute risk.
- How large was the observed effect?
HR 2.81 (1.67-4.75); IRD +1.41/10,000 PY.
- What do the results mean in everyday life?
A real but very rare risk; sudden vision loss needs urgent care.
- What are the study's limitations?
32 events.
- What does it say about Elawady's specific claim?
Supports the association, not the 'markedly higher' size from the referral study.
- Do the results apply to Germany and Europe?
High.
- What can explicitly not be concluded from this study?
Causality.
Scientific in-depth review
1. Full reference
- Authors
- Simonsen E et al.
- Journal
- Diabetes Obes Metab
- Year
- 2025
- Identifier
- PMID 40098249 DOI 10.1111/dom.16316
- Verification
- verified – PubMed efetch 2026-10-26; Crossref works API 2026-10-26
- Retracted
- no
- Corrections
- none
- Extent checked
- abstract only
- Conflicts of interest and funding
Danmarks Frie Forskningsfond (PubMed record); individual disclosures not reviewed.
2. Research question
Is semaglutide associated with NAION compared with SGLT2 inhibitors in type 2 diabetes?
3. Study design and population
- Study design
- Cohort study – Nationwide register-based active-comparator new-user cohort (Denmark, Norway) with self-controlled supplementary analysis
- Population
People with type 2 diabetes initiating semaglutide or SGLT2i
- Country
Denmark, Norway
- Period
Denmark 2018-2024; Norway 2018-2022
- Sample size
44,517 (Denmark) and 16,860 (Norway) semaglutide users; 32 NAION events
- Inclusion and exclusion criteria
New users with type 2 diabetes
4. Methods and endpoints
- Exposure / intervention
Semaglutide
- Comparator
SGLT2 inhibitors
- Endpoints
NAION
- Statistical methods
Adjusted Cox models pooled by fixed effects; incidence rate difference; symmetry analysis
5. Actual results
- Results
Unadjusted NAION rate 2.19 vs 1.18 per 10,000 PY (Denmark) and 2.90 vs 0.92 (Norway). Pooled adjusted HR 2.81 (1.67-4.75); IRD +1.41 (0.53-2.29) per 10,000 PY. Per-protocol HR 6.35 (2.88-14.0). Self-controlled symmetry ratios 1.14 (0.55-2.36) Denmark and 2.67 (0.91-8.99) Norway.
- Absolute risks
+1.41 per 10,000 person-years (about 1 extra case per 7,100 person-years).
- Authors' conclusion
Semaglutide use for type 2 diabetes is associated with increased NAION risk vs SGLT2 inhibitors; absolute risk remains low.
6. Strengths
- Population-based national registries
- Active comparator
- Two countries
7. Weaknesses
- Only 32 events
- NAION coding validity
- Self-controlled analyses not significant
8. Risk of bias
- Orienting tool
- ROBINS-E
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
Residual confounding and outcome misclassification possible.
9. Assessment of the statistical interpretation
HR CI log-symmetric (stats/C-ODD-10.py). Relative risk roughly doubled to tripled; absolute excess about 1 per 7,000 person-years, consistent with EMA's estimate.
10. Relevance to the specific claim
Population-based support for a semaglutide-NAION association, with far lower absolute risk than the referral-centre study cited by the archive (A-ODD-16).
11. Independent contrary findings
RCT meta-analysis (I-ODD-119) found no significant increase; I-ODD-14 found no consistent increase.
12. Transferability to Germany and Europe
High (EU data).
13. Overall methodological judgement
Supports a real but very rare association.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | moderate |
| Risk of bias | some concerns |
| Precision of results | low |
| Directness | direct |
| Reproducibility | partly replicated |
| Consistency with the overall evidence | mixed |
| Regional transferability | high |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
Causality and mechanism.