Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene, characterized by early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration. The condition selectively affects pancreatic β cells and neurons via chronic endoplasmic reticulum (ER) stress, and no proven disease-modifying therapy currently exists. Diabetes mellitus is typically the first manifestation, presenting at a mean age of 6 years as an insulin-dependent phenotype with preserved C-peptide and negative diabetes-related autoantibodies.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established agents in the management of type 2 diabetes, augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Preclinical evidence further suggests that GLP-1 RAs preserve β-cell mass, attenuate ER stress, and confer neuroprotective effects, properties of particular therapeutic relevance to Wolfram syndrome.

We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study. Clinical data were extracted from medical records; for participants concurrently enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study, longitudinal data were obtained from that source as well. Thirty-five percent of eligible participants had received a GLP-1 RA at some point during follow-up. We characterize the prevalence of GLP-1 RA use, documented rationale for initiation, observed effects on glycemic control and visual outcomes, adverse effects, and reasons for discontinuation. No statistically significant changes in hemoglobin A1c (HbA1c) or body mass index (BMI) were observed. Visual acuity declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common and contributed to frequent discontinuation.

These observational data provide important clinical context and a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.

FU had a sponsored research agreement and has received material support from Prilenia Therapeutics. He is the current principal investigator of the Phase 2 clinical trial of AMX0035 in patients with Wolfram syndrome, sponsored by Amylyx Pharmaceuticals. He has received grants from the National Institutes of Health (NIH) and royalties from Novus Biologicals and Sana Biotechnology. He has also received licensing and/or consulting fees from Opris Biotechnologies and Emerald Biotherapeutics, and travel support from Wolfram France, Wolfram UK, and the Snow Foundation. He serves in unpaid advisory roles for the Snow Foundation and the Be A Tiger Foundation. He holds U.S. patents (9,891,231; 10,441,574; 10,695,324) and was previously President and a shareholder of the now-dissolved CURE4WOLFRAM.

This work was partly supported by the grants from the National Institutes of Health (NIH) DK132090, DK020579 to F. Urano and HD070855 to T. Hershey. Research reported in this publication was also partly supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.

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The studies involving humans were approved by the Washington University in St. Louis Human Research Protection Office. The studies were conducted in accordance with the local legislation and institutional requirements. Children under age 18 gave informed assent, and parents/guardians gave informed, written consent. Participants 18 or older gave informed, written consent for participation in this study.

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The deidentified data supporting the findings of this study will be made available from the corresponding author, Fumihiko Urano, MD, PhD (uranowustl.edu), upon reasonable request and subject to institutional review and execution of an appropriate data use agreement.