Abstract Background Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder linked to cardiovascular and metabolic morbidity. While continuous positive airway pressure (CPAP) remains the standard of care, poor adherence has prompted exploration of pharmacologic alternatives targeting the underlying pathophysiology. Two emerging strategies include glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which reduce upper airway collapsibility primarily through weight loss and metabolic modulation, and the combination of atomoxetine with antimuscarinic agents—initially oxybutynin, and more recently its R-enantiomer aroxybutynin—which enhance upper airway dilator muscle tone during sleep. Objective This scoping review aims to map and compare current evidence on the efficacy, safety, and mechanistic profiles of GLP-1 RAs versus atomoxetine-antimuscarinic combinations (oxybutynin or aroxybutynin) in improving OSA severity and related outcomes. Methods A comprehensive search of PubMed, Embase, Scopus, and Cochrane Library was performed from inception to October 2025. Eligible studies included randomized controlled trials, cohort studies, and mechanistic investigations evaluating GLP-1 RAs (liraglutide, semaglutide, tirzepatide) or atomoxetine-oxybutynin/aroxybutynin combinations in adults with OSA. Data were extracted on apnea-hypopnea index (AHI), body weight, daytime sleepiness, cardiometabolic parameters, and adverse effects. Results GLP-1 RAs consistently reduced AHI, primarily mediated by weight loss and improved metabolic control, with additional evidence suggesting direct effects on ventilatory control. Atomoxetine-oxybutynin and the newer atomoxetine-aroxybutynin (AD109) combinations demonstrated rapid, weight-independent reductions in AHI by enhancing upper airway muscle tone and reducing pharyngeal collapsibility. However, long-term efficacy, safety, and adherence data remain limited for these agents. GLP-1 RAs offer broader cardiometabolic benefits and established safety, whereas atomoxetine-aroxybutynin represents a promising adjunct or alternative, particularly in non-obese patients or those intolerant to CPAP. Conclusion GLP-1 RAs and atomoxetine-antimuscarinic combinations target distinct yet complementary mechanisms in OSA pathogenesis—metabolic versus neuromuscular. Integrating these approaches, or selecting therapy based on phenotype, may personalize OSA management. Further head-to-head and combination trials are warranted to define long-term outcomes and optimal patient selection. This abstract is funded by: None
Siddenthi et al. (Fri,) studied this question.