Evaluating the use of GLP-1 receptor agonists in Wolfram syndrome patients

Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene and characterized by early-onset, insulin-dependent diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration driven by chronic endoplasmic reticulum (ER) stress; no proven disease-modifying therapy currently exists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) augment glucose-dependent insulin secretion and, in preclinical models, preserve β-cell mass, attenuate ER stress, and confer neuroprotection - 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, with additional longitudinal data for participants co-enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study. We characterized the prevalence of GLP-1 RA use and the documented rationale for initiation, and evaluated within-participant pre-post changes in glycemic (HbA1c, body mass index) and visual (LogMAR best-corrected visual acuity, retinal nerve fiber layer thickness) parameters, along with adverse effects and reasons for discontinuation.

Thirty of the 84 participants (35.7%) had received a GLP-1 RA in addition to insulin. No statistically significant changes in HbA1c or body mass index were observed at one or two years. Best-corrected visual acuity (LogMAR) declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common (56.7% of users) and were the leading cause of discontinuation.

In this largest reported evaluation of GLP-1 RA use in Wolfram syndrome, these agents were already integrated into clinical care and were generally tolerated, but showed no glycemic or visual benefit over one to two years. Given the retrospective, uncontrolled design, the small number of participants with paired pre-post measurements, and the absence of a longitudinally followed comparator group, these findings are preliminary and hypothesis-generating rather than definitive, and provide a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.