Diabetic Retinal Disease Onset and Progression During Established Semaglutide or Tirzepatide Treatment: A Retrospective Comparative Cohort Study With a Descriptive Regional Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) Review

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Abstract

[OBJECTIVES] This study aims to compare diabetic retinal disease onset or progression between established semaglutide or tirzepatide users and patients without documented exposure to either drug. Secondary exploratory objectives included medication-specific comparisons, adjusted analyses, and visual acuity assessment. Regional nonarteritic anterior ischemic optic neuropathy (NAION) case ascertainment was evaluated separately and descriptively. [METHODS] This retrospective cohort reviewed retinal records covering January 1, 2025, through March 31, 2026. Of 342 patients screened, 221 were excluded, leaving 121 records with two bilateral retinal assessments approximately one year apart. Analysis was at the patient-record level. Thirty patients received the same study drug before baseline and throughout follow-up; 91 had no documented exposure to either drug. Incident diabetic retinopathy (DR) and/or diabetic macular edema (DME) was evaluated among records without baseline disease, and progression was evaluated separately among records with baseline disease. Risk ratios (RRs), 95% confidence intervals (CIs), exact tests, and exploratory adjusted models were calculated. A separate regional NAION search covered January 1, 2022, through December 31, 2025, followed by investigator review of identified cases and medication histories. [RESULTS] The combined retinal endpoint occurred in 12/30 exposed and 46/91 unexposed records (40.0% versus 50.5%; RR: 0.79, 95% CI: 0.49-1.28; p = 0.400). Incident disease occurred in 7/14 versus 32/43 records (RR: 0.67; 95% CI: 0.39-1.17), and progression occurred in 5/16 versus 14/48 records (RR: 1.07; 95% CI: 0.46-2.51). Combined event proportions differed across semaglutide, tirzepatide, and unexposed categories (2/14, 10/16, and 46/91; global p = 0.017). No NAION was recorded in the retinal cohort. None of the seven separately identified regional NAION cases had documented study-drug use after investigator review. [CONCLUSIONS] No statistically significant association was detected for the combined retinal endpoint, but estimates were imprecise. Medication-specific findings were exploratory and do not establish comparative safety. Regional NAION findings were descriptive and could not quantify or exclude an association.

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