Observational Study

. 2025 Apr 1;143(4):304-314.

doi: 10.1001/jamaophthalmol.2024.6555.

Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy

Cindy X Cai^{1

2}, Michelle Hribar^{3

4}, Sally Baxter^{5

6}, Kerry Goetz³, Swarup S Swaminathan⁷, Alexis Flowers^{8

9}, Eric N Brown⁹, Brian Toy¹⁰, Benjamin Xu¹⁰, John Chen^{11

12}, Aiyin Chen⁴, Sophia Wang¹³, Cecilia Lee^{14

15}, Theodore Leng¹⁶, Joshua R Ehrlich^{17

18}, Andrew Barkmeier¹¹, Karen R Armbrust¹⁹, Michael V Boland²⁰, David Dorr²¹, Danielle Boyce^{22

23}, Thamir Alshammari^{24

25}, Joel Swerdel²⁶, Marc A Suchard^{27

28}, Martijn Schuemie^{26

27}, Fan Bu²⁹, Anthony G Sena^{26

30}, George Hripcsak³¹, Akihiko Nishimura³², Paul Nagy³³, Thomas Falconer³¹, Scott L DuVall^{28

34}, Michael Matheny³⁵, Benjamin Viernes²⁸, William O'Brien²⁸, Linying Zhang³⁶, Benjamin Martin², Erik Westlund³², Nestoras Mathioudakis³⁷, Ruochong Fan³⁶, Adam Wilcox³⁸, Albert Lai³⁸, Jacqueline C Stocking³⁹, Sahar Takkouche⁴⁰, Lok Hin Lee⁴¹, Yangyiran Xie⁴¹, Izabelle Humes⁴², David B McCoy⁴², Mohammad Adibuzzaman⁴², Raymond G Areaux Jr¹⁹, William Rojas-Carabali⁴³, James Brash⁴⁴, David A Lee⁴⁵, Nicole G Weiskopf⁴⁶, Louise Mawn⁴⁷, Rupesh Agrawal⁴⁸, Hannah Morgan-Cooper⁴⁹, Priya Desai⁴⁹, Patrick B Ryan^{50

51}

Affiliations

¹ Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
² Biomedical Informatics and Data Science, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
³ National Eye Institute, National Institutes of Health, Bethesda, Maryland.
⁴ Casey Eye Institute, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland.
⁵ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla.
⁶ Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla.
⁷ Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.
⁸ Vanderbilt Eye Institute, Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.
⁹ Vanderbilt Eye Institute, Department of Ophthalmology, Vanderbilt University Medical Center, Nashville, Tennessee.
¹⁰ Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California.
¹¹ Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.
¹² Department of Neurology, Mayo Clinic, Rochester, Minnesota.
¹³ Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California.
¹⁴ Department of Ophthalmology, University of Washington, Seattle.
¹⁵ Karalis Johnson Retina Center, Seattle, Washington.
¹⁶ Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, California.
¹⁷ Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor.
¹⁸ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor.
¹⁹ Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota.
²⁰ Department of Ophthalmology, Mass Eye and Ear and Harvard Medical School, Boston, Massachusetts.
²¹ Department of Medical Informatics & Clinical Epidemiology, Portland, Oregon.
²² Johns Hopkins University School of Medicine, Baltimore, Maryland.
²³ Tufts University School of Medicine, Boston, Massachusetts.
²⁴ Department of Clinical Practice, Faculty of Pharmacy, Jazan University, Jazan, Saudi Arabia.
²⁵ Pharmacy Practice Research Unit, Faculty of Pharmacy, Jazan University, Jazan, Saudi Arabia.
²⁶ Janssen Research and Development, Titusville, New Jersey.
²⁷ Department of Biostatistics, UCLA School of Public Health, University of California, Los Angeles, Los Angeles.
²⁸ VA Informatics and Computing Infrastructure, US Department of Veterans Affairs, Salt Lake City, Utah.
²⁹ Department of Biostatistics, University of Michigan, Ann Arbor.
³⁰ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, the Netherlands.
³¹ Department of Biomedical Informatics, Columbia University, New York, New York.
³² Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
³³ Department of Biomedical Informatics and Data Science, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland.
³⁴ Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.
³⁵ VA Informatics and Computing Infrastructure, US Department of Veterans Affairs, Nashville, Tennessee.
³⁶ Institute for Informatics, Data Science and Biostatistics, Department of Medicine, Washington University in St Louis, St Louis, Missouri.
³⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
³⁸ Department of Medicine, Washington University in St Louis, St Louis, Missouri.
³⁹ Department of Internal Medicine, University of California Davis, Sacramento.
⁴⁰ Department of Medicine, Division of Diabetes and Endocrinology, Vanderbilt University, Nashville, Tennessee.
⁴¹ Vanderbilt University School of Medicine, Nashville, Tennessee.
⁴² Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland.
⁴³ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁴⁴ IQVIA, Real World Solutions, Brighton, United Kingdom.
⁴⁵ Ruiz Department of Ophthalmology and Visual Science, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston.
⁴⁶ Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland.
⁴⁷ Vanderbilt University Medical Center, Nashville, Tennessee.
⁴⁸ Tan Tock Seng Hospital, Singapore.
⁴⁹ Stanford School of Medicine and Stanford Health Care, Palo Alto, California.
⁵⁰ Columbia University Irving Medical Center, New York, New York.
⁵¹ Johnson & Johnson, Horsham, Pennsylvania.

PMID: 39976940
PMCID: PMC11843465
DOI: 10.1001/jamaophthalmol.2024.6555

Observational Study

Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy

Cindy X Cai et al. JAMA Ophthalmol. 2025.

. 2025 Apr 1;143(4):304-314.

doi: 10.1001/jamaophthalmol.2024.6555.

Authors

Affiliations

¹ Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
² Biomedical Informatics and Data Science, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
³ National Eye Institute, National Institutes of Health, Bethesda, Maryland.
⁴ Casey Eye Institute, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland.
⁵ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla.
⁶ Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla.
⁷ Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.
⁸ Vanderbilt Eye Institute, Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.
⁹ Vanderbilt Eye Institute, Department of Ophthalmology, Vanderbilt University Medical Center, Nashville, Tennessee.
¹⁰ Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California.
¹¹ Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.
¹² Department of Neurology, Mayo Clinic, Rochester, Minnesota.
¹³ Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California.
¹⁴ Department of Ophthalmology, University of Washington, Seattle.
¹⁵ Karalis Johnson Retina Center, Seattle, Washington.
¹⁶ Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, California.
¹⁷ Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor.
¹⁸ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor.
¹⁹ Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota.
²⁰ Department of Ophthalmology, Mass Eye and Ear and Harvard Medical School, Boston, Massachusetts.
²¹ Department of Medical Informatics & Clinical Epidemiology, Portland, Oregon.
²² Johns Hopkins University School of Medicine, Baltimore, Maryland.
²³ Tufts University School of Medicine, Boston, Massachusetts.
²⁴ Department of Clinical Practice, Faculty of Pharmacy, Jazan University, Jazan, Saudi Arabia.
²⁵ Pharmacy Practice Research Unit, Faculty of Pharmacy, Jazan University, Jazan, Saudi Arabia.
²⁶ Janssen Research and Development, Titusville, New Jersey.
²⁷ Department of Biostatistics, UCLA School of Public Health, University of California, Los Angeles, Los Angeles.
²⁸ VA Informatics and Computing Infrastructure, US Department of Veterans Affairs, Salt Lake City, Utah.
²⁹ Department of Biostatistics, University of Michigan, Ann Arbor.
³⁰ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, the Netherlands.
³¹ Department of Biomedical Informatics, Columbia University, New York, New York.
³² Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
³³ Department of Biomedical Informatics and Data Science, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland.
³⁴ Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.
³⁵ VA Informatics and Computing Infrastructure, US Department of Veterans Affairs, Nashville, Tennessee.
³⁶ Institute for Informatics, Data Science and Biostatistics, Department of Medicine, Washington University in St Louis, St Louis, Missouri.
³⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
³⁸ Department of Medicine, Washington University in St Louis, St Louis, Missouri.
³⁹ Department of Internal Medicine, University of California Davis, Sacramento.
⁴⁰ Department of Medicine, Division of Diabetes and Endocrinology, Vanderbilt University, Nashville, Tennessee.
⁴¹ Vanderbilt University School of Medicine, Nashville, Tennessee.
⁴² Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland.
⁴³ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁴⁴ IQVIA, Real World Solutions, Brighton, United Kingdom.
⁴⁵ Ruiz Department of Ophthalmology and Visual Science, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston.
⁴⁶ Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland.
⁴⁷ Vanderbilt University Medical Center, Nashville, Tennessee.
⁴⁸ Tan Tock Seng Hospital, Singapore.
⁴⁹ Stanford School of Medicine and Stanford Health Care, Palo Alto, California.
⁵⁰ Columbia University Irving Medical Center, New York, New York.
⁵¹ Johnson & Johnson, Horsham, Pennsylvania.

PMID: 39976940
PMCID: PMC11843465
DOI: 10.1001/jamaophthalmol.2024.6555

Abstract

Importance: Semaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns in the treatment of type 2 diabetes (T2D).

Objective: To investigate the potential association between semaglutide and NAION in the Observational Health Data Sciences and Informatics (OHDSI) network.

Design, setting, and participants: This was a retrospective study across 14 databases (6 administrative claims and 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to December 31, 2023. The incidence proportion and rate of NAION were calculated. Association between semaglutide and NAION was assessed using 2 approaches: an active-comparator cohort design comparing new users of semaglutide with those taking other GLP-1RAs and non-GLP-1RA drugs, and a self-controlled case-series (SCCS) analysis to compare individuals' risks during exposure and nonexposure periods for each drug. The cohort design used propensity score-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). Network-wide HR and IRR estimates were generated using a random-effects meta-analysis model.

Exposures: GLP-1RA and non-GLP-1RAs.

Main outcomes and measures: NAION under 2 alternative definitions based on diagnosis codes: one more inclusive and sensitive, the other more restrictive and specific.

Results: The study included 37.1 million individuals with T2D, including 810 390 new semaglutide users. Of the 43 620 new users of semaglutide in the Optum's deidentified Clinformatics Data Mart Database, 24 473 (56%) were aged 50 to 69 years, and 26 699 (61%) were female. The incidence rate of NAION was 14.5 per 100 000 person-years among semaglutide users. The HR for NAION among new users of semaglutide was not different compared with that of the non-GLP-1RAs using the sensitive NAION definition-empagliflozin (HR, 1.44; 95% CI, 0.78-2.68; P = .12), sitagliptin (HR, 1.30; 95% CI, 0.56-3.01; P = .27), and glipizide (HR, 1.23; 95% CI, 0.66-2.28; P = .25). The risk was higher only compared with patients taking empagliflozin (HR, 2.27; 95% CI, 1.16-4.46; P = .02) using the specific definition. SCCS analysis of semaglutide exposure showed an increased risk of NAION (meta-analysis IRR, 1.32; 95% CI, 1.14-1.54; P < .001).

Conclusions and relevance: Results of this study suggest a modest increase in the risk of NAION among individuals with T2D associated with semaglutide use, smaller than that previously reported, and warranting further investigation into the clinical implications of this association.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cai reported receiving grants from Regeneron Pharmaceuticals outside the submitted work. Dr Baxter reported receiving grants from National Institutes of Health (NIH) and Research to Prevent Blindess, personal fees from Topcon, and nonfinancial support from Optomed outside the submitted work. Dr Swaminathan reported receiving personal fees from AbbVie, Elios Vision, and Lumata Health and grants from Heidelberg Engineering outside the submitted work. Dr Toy reported receiving advisory board fees from Alimera Sciences, Bausch & Lomb, and Regeneron outside the submitted work. Dr C. Lee reported receiving grants from NIH, Centers for Disease Control and Prevention, and the Alzheimer’s Disease Drug Foundation outside the submitted work. Dr Leng reported receiving grants from Astellas and personal fees from Topcon, Astellas, Alcon, Boehringer Ingelheim, Iridex, Nanoscope, Regeneron, Genentech/Roche, Virtual Field, Aptitude Medical, Protagonist Therapeutics, Apellis, and Graybug outside the submitted work. Dr Boland reported receiving personal fees from Carl Zeiss Meditec, Topcon Healthcare, Allergan, and Janssen during the conduct of the study. Dr Swerdel reported being an employee and shareholder of Johnson & Johnson outside the submitted work. Dr Suchard reported receiving grants from NIH, US Department of Veterans Affairs, and the US Food and Drug Administration and personal fees from Johnson & Johnson outside the submitted work. Drs Schuemie and Sena reported being and employee and shareholder of Johnson & Johnson outside the submitted work. Dr DuVall reported receiving grants from Alnylam Pharmaceuticals, Astellas Pharma, AstraZeneca, Biodesix, Celgene Corp, Cerner Enviza, GSK, IQVIA, Janssen Pharmaceuticals, Moderna, Novartis International AG, and Parexel International Corp outside the submitted work. Dr Lai reported being a shareholder of Johnson & Johnson outside the submitted work. Dr Brash reported being employed by IQVIA outside the submitted work. Dr Mawn reported receiving grants from Research to Prevent Blindness and consultant fees from Amgen and Genentech. Dr Ryan reported being an employee and shareholder of Johnson & Johnson. No other disclosures were reported.

Figures

**Figure 1.. Incidence of Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) Among Patients With Type 2 Diabetes**

**Figure 2.. Forest Plot for the Active-Comparator New-User Cohort Analysis**
Hazard ratio (HR) and 95% CI estimates for the risk of nonarteritic anterior ischemic optic neuropathy (NAION) while receiving treatment with a second-line medication for type 2 diabetes comparing between semaglutide and other glucagonlike peptide-1 receptor agonists (GLP-1RAs), ie, dulaglutide and exenatide, and non–GLP-1RA medications, ie, empagliflozin, sitagliptin, and glipizide. Only results from databases and comparisons that passed study diagnostics are provided, as well as the meta-analytic estimates.^a The total number of patients in each comparison is shown. A, Results using the sensitive NAION definition. B, Results using the specific NAION definition.^bCCAE indicates Merative MarketScan Commercial Claims and Encounters Database; Clinformatics, Optum’s deidentified Clinformatics Data Mart Database; IQVIA, IQVIA Open Claims; PharMetrics, PharMetrics Plus. ^aDatabases that have 0 cases of NAION are unable to produce HR estimates but still contribute to the meta-analytic estimate. ^bThe sensitive NAION definition only required 1 diagnosis of ischemic optic neuropathy, and the specific NAION definition required 2 diagnoses. All other criteria were the same between the 2 definitions.

**Figure 3.. Forest Plot for the Self-Controlled Case Series Analysis, Sensitive Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) Definition^a**
Incidence rate ratio (IRR) and 95% CI estimate for the risk of NAION (using the sensitive definition)^a while receiving treatment with one of the medications for type 2 diabetes compared with control time, not taking treatment with the medication of interest. Results are shown for semaglutide, other glucagonlike peptide-1 receptor agonists (GLP-1 RAs), ie, dulaglutide and exenatide, and non–GLP-1 RA medications, ie, empagliflozin, sitagliptin, and glipizide. Results from databases that passed study diagnostics are provided, as well as the meta-analytic estimates.^b The total number of patients included is shown. CCAE indicates Merative MarketScan Commercial Claims and Encounters Database; Clinformatics, Optum’s deidentified Clinformatics Data Mart; IQVIA, IQVIA Open Claims; JHME, Johns Hopkins Medical Enterprise; MDCD, Merative MarketScan Multi-State Medicaid Database; MDCR, Merative MarketScan Medicare Supplemental and Coordination of Benefits Database; PharMetrics, PharMetrics Plus; VA, Department of Veterans Affairs; WashU, Washington University in St Louis. ^aThe sensitive NAION definition only required 1 diagnosis of ischemic optic neuropathy. All other criteria were the same between the 2 definitions. ^bDue to data privacy issues, databases that have counts less than 5 are unable to produce IRR estimates but still contribute to the meta-analytic estimate.

**Figure 4.. Forest Plot for the Self-Controlled Case Series Analysis, Specific Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) Definition^a**
Incidence rate ratio (IRR) and 95% CI estimate for the risk of NAION (using the specific definition)^a while receiving treatment with one of the medications for type 2 diabetes compared with control time, not taking treatment with the medication of interest. Results are shown for semaglutide, other glucagonlike peptide-1 receptor agonists (GLP-1 RAs), ie, dulaglutide and exenatide, and non–GLP-1 RA medications, ie, empagliflozin, sitagliptin, and glipizide. Results from databases that passed study diagnostics are provided, as well as the meta-analytic estimates.^b The total number of patients included is shown. CCAE indicates Merative MarketScan Commercial Claims and Encounters Database; Clinformatics, Optum’s deidentified Clinformatics Data Mart; IQVIA, IQVIA Open Claims; JHME, Johns Hopkins Medical Enterprise; MDCD, Merative MarketScan Multi-State Medicaid Database; MDCR, Merative MarketScan Medicare Supplemental and Coordination of Benefits Database; PharMetrics, PharMetrics Plus; VA, Department of Veterans Affairs; WashU, Washington University in St Louis. ^aThe specific NAION definition required 2 diagnoses. All other criteria were the same between the 2 definitions. ^bDue to data privacy issues, databases that have counts less than 5 are unable to produce IRR estimates but still contribute to the meta-analytic estimate.

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Comment on

Semaglutide and Risk of NAION-Additional Insights.
Rizzo JF 3rd, Hathaway JT. Rizzo JF 3rd, et al. JAMA Ophthalmol. 2025 Apr 1;143(4):315-316. doi: 10.1001/jamaophthalmol.2025.0005. JAMA Ophthalmol. 2025. PMID: 39976950 No abstract available.

References

1. Hayreh SS. Ischemic optic neuropathy. Prog Retin Eye Res. 2009;28(1):34-62. doi:10.1016/j.preteyeres.2008.11.002 - DOI - PubMed
1. Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: natural history of visual outcome. Ophthalmology. 2008;115(2):298-305.e2. doi:10.1016/j.ophtha.2007.05.027 - DOI - PMC - PubMed
1. The Ischemic Optic Neuropathy Decompression Trial Research Group . Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA. 1995;273(8):625-632. doi:10.1001/jama.1995.03520320035038 - DOI - PubMed
1. Hathaway JT, Shah MP, Hathaway DB, et al. . Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmol. 2024;142(8):732-739. doi:10.1001/jamaophthalmol.2024.2296 - DOI - PMC - PubMed
1. Klonoff DC, Hui G, Gombar S. Real-world evidence assessment of the risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. J Diabetes Sci Technol. 2024;18(6):1517-1518. doi:10.1177/19322968241268050 - DOI - PMC - PubMed

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Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy

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Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy

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Conflict of interest statement

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