Association of GLP-1 Receptor Agonist Use with Hypersomnolence: A Real-world Cohort Analysis

Our study sought to evaluate the association between Glucagon-like peptide-1 receptor agonist use and the development of hypersomnolence at 1 and 5-year timepoints. A retrospective cohort study was done using TriNetX's research network. Patients aged 18-50 with type-2 diabetes mellitus or obesity who underwent polysomnography were included. Patients were excluded if they had any prior use of antidepressants. Patients who used Glucagon-like peptide-1 receptor agonists were 1:1 propensity matched to patients without Glucagon-like peptide-1 receptor agonist exposure. The primary outcome was new onset hypersomnolence with secondary outcomes including parasomnia, narcolepsy/cataplexy, disturbed sleep, restless legs syndrome, iron deficiency, and Parkinsonism. Hazard ratios and risk ratios were calculated at 1- and 5-years. Kaplan-Meier analyses and log-rank tests were performed for time to event comparisons. After matching, there were two equal cohorts of 118,993 patients. The Glucagon-like peptide-1 receptor agonist cohort was associated with increased hypersomnolence at 1-year (HR 1.21, 95% CI 1.10-1.32; p < 0.001) and 5-years (HR 1.23, 95% CI 1.14-1.32; p < 0.001). The absolute risk increase was approximately 0.4% at 1 year and 0.7% at 5 years. Iron deficiency was significantly increased at 5-years (HR 1.11, 95% CI 1.06-1.16; p < 0.001). A decreased hazard of Parkinsonism was observed at 5-years (HR 0.26, 95% CI 0.08-0.80; p = 0.012), although event counts were low. Time to event analyses did not demonstrate statistically significant associations for parasomnia, disturbed sleep, restless legs syndrome, or narcolepsy/cataplexy. These findings highlight the need for further studies to evaluate the effects of Glucagon-like peptide-1 receptor agonists on sleep regulation and the neurophysiological consequences of these agents.

The online version contains supplementary material available at 10.1007/s40200-026-01929-0.