Semaglutide and diabetic retinopathy: an OHDSI network study

Cindy Xinji Cai; Akihiko Nishimura; Sally Baxter; Kerry Goetz; Michelle Hribar; Brian Toy; Andrew Barkmeier; Sophia Wang; Swarup Swaminathan; Alexis Flowers; Eric Brown; Benjamin Xu; John Chen; Aiyin Chen; Theodore Leng; Michael Boland; Thamir Alshammari; Fan Bu; Thomas Falconer; Benjamin Martin; Erik Westlund; Nestoras Mathioudakis; Linying Zhang; Ruochong Fan; Adam Wilcox; Albert Lai; Jacqueline C Stocking; Yangyiran Xie; Lok Hin Lee; David Dorr; Izabelle Humes; David McCoy; Mohammad Adibuzzaman; Raymond Areaux Jr; James Brash; Nicole Weiskopf; Hannah Morgan-Cooper; Priya Desai; Diep Tran; Zainab Rustam; Gina Zhu; Joel Swerdel; Anthony Sena; Paul Nagy; Marc Suchard; Martijn Schuemie; George Hripcsak; Patrick Ryan

doi:10.1136/bmjdrc-2025-005424

Semaglutide and diabetic retinopathy: an OHDSI network study

BMJ Open Diabetes Res Care. 2025 Nov 4;13(6):e005424. doi: 10.1136/bmjdrc-2025-005424.

Authors

Cindy Xinji Cai^{1

2}, Akihiko Nishimura³, Sally Baxter^{4

5}, Kerry Goetz⁶, Michelle Hribar^{6

7

8}, Brian Toy⁹, Andrew Barkmeier¹⁰, Sophia Wang¹¹, Swarup Swaminathan¹², Alexis Flowers¹³, Eric Brown¹³, Benjamin Xu⁹, John Chen¹⁰, Aiyin Chen^{7

8}, Theodore Leng¹¹, Michael Boland¹⁴, Thamir Alshammari^{15

16}, Fan Bu¹⁷, Thomas Falconer¹⁸, Benjamin Martin², Erik Westlund³, Nestoras Mathioudakis¹⁹, Linying Zhang²⁰, Ruochong Fan²⁰, Adam Wilcox²⁰, Albert Lai²⁰, Jacqueline C Stocking²¹, Yangyiran Xie¹³, Lok Hin Lee¹³, David Dorr⁸, Izabelle Humes²², David McCoy²², Mohammad Adibuzzaman²², Raymond Areaux Jr²³, James Brash²⁴, Nicole Weiskopf⁸, Hannah Morgan-Cooper²⁵, Priya Desai²⁵, Diep Tran²⁶, Zainab Rustam²⁶, Gina Zhu²⁶, Joel Swerdel²⁷, Anthony Sena^{27

28}, Paul Nagy², Marc Suchard^{29

30}, Martijn Schuemie^{29

31}, George Hripcsak¹⁸, Patrick Ryan^{18

31}

Affiliations

¹ Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA ccai6@jhmi.edu.
² Biomedical Informatics and Data Science, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁴ Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, California, USA.
⁵ Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁶ National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA.
⁸ Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA.
⁹ Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁰ Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California, USA.
¹² Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
¹³ Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁴ Department of Ophthalmology, Mass Eye and Ear, Boston, Massachusetts, USA.
¹⁵ Department of Clinical Practice, Jazan University, Jazan, Jazan, Saudi Arabia.
¹⁶ Pharmacy Practice Research Unit, Jazan University, Jazan, Saudi Arabia.
¹⁷ Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
¹⁸ Department of Biomedical Informatics, Columbia University, New York, New York, USA.
¹⁹ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁰ Institute for Informatics, Data Science and Biostatistics,Department of Medicine, Washington University in St Louis, St. Louis, Missouri, USA.
²¹ Department of Internal Medicine, University of California Davis, Davis, California, USA.
²² Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA.
²³ Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA.
²⁴ IQVIA, Real World Solutions, Brighton, England, UK.
²⁵ Stanford School of Medicine and Stanford Health Care, Stanford, California, USA.
²⁶ Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
²⁷ Janssen Research & Development, Titusville, New Jersey, USA.
²⁸ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands.
²⁹ Department of Biostatistics, University of California Los Angeles School of Public Health, Los Angeles, California, USA.
³⁰ VA Informatics and Computing Infrastructure, US Department of Veterans Affairs, Salt Lake City, UT, USA.
³¹ Johnson and Johnson, Horsham, PA, USA.

Abstract

Introduction: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes mellitus (T2D), has potential associations with higher rates of diabetic retinopathy (DR) complications including proliferative DR (PDR) and diabetic macular edema (DME). The purpose of this study was to determine whether an association exists between semaglutide and PDR and treatment-requiring DR/DME.

Research design and methods: This was a retrospective cohort study of 14 databases (six administrative claims and eight electronic health records) in the Observational Health Data Sciences and Informatics Evidence Network. Adults with T2D on semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from 1 December 2017 to 31 December 2023 were included. The association between semaglutide and PDR or treatment-requiring DR/DME was assessed using an active-comparator cohort design comparing new users of semaglutide as second-line T2D treatment to those on other GLP-1RAs and non-GLP-1RAs. Propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs). Network-wide HR estimates were generated using a random-effects meta-analysis.

Results: The study included 810 390 new semaglutide users for T2D. PDR risk for semaglutide was similar to dulaglutide (HR 0.81, 95% CI 0.42 to 1.54, p=0.51), empagliflozin (HR 0.83, 95% CI 0.53 to 1.30, p=0.41) and sitagliptin (HR 0.83, 95% CI 0.45 to 1.55, p=0.57) but was lower than glipizide (HR 0.59, 95% CI 0.39 to 0.88, p=0.01). The risk for treatment-requiring DR/DME for semaglutide was similar to empagliflozin (HR 0.66, 95% CI 0.43 to 1.02, p=0.06) but lower than dulaglutide (HR 0.53, 95% CI 0.31 to 0.91, p=0.02), sitagliptin (HR 0.46, 95% CI 0.26 to 0.81, p=0.008) and glipizide (HR 0.55, 95% CI 0.33 to 0.91, p=0.02).

Conclusions and relevance: We did not identify increased risk for either PDR or treatment-requiring DR/DME comparing semaglutide with other GLP-1RAs or non-GLP-1RAs. Patients with T2D should still undergo close eye care follow-up, particularly when initiating new antihyperglycemic medications.

Keywords: Diabetes Complications; Diabetic Retinopathy.

Publication types

Multicenter Study
Observational Study

MeSH terms

Aged
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Diabetic Retinopathy* / chemically induced
Diabetic Retinopathy* / epidemiology
Female
Follow-Up Studies
Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor Agonists
Glucagon-Like Peptides* / adverse effects
Glucagon-Like Peptides* / analogs & derivatives
Glucagon-Like Peptides* / therapeutic use
Humans
Hypoglycemic Agents* / adverse effects
Hypoglycemic Agents* / therapeutic use
Male
Middle Aged
Retrospective Studies
Semaglutide

Substances

Glucagon-Like Peptide-1 Receptor Agonists
Glucagon-Like Peptides
Hypoglycemic Agents
Glucagon-Like Peptide 1
Semaglutide