GLP-1 Receptor Agonists in Obstructive Sleep Apnea: A Translational Perspective on Mechanisms and Clinical...

Obstructive sleep apnea (OSA) affects nearly one billion adults worldwide and involves mechanical upper-airway obstruction alongside metabolic dysfunction, systemic inflammation, and gut-brain axis disruption. Despite the efficacy of continuous positive airway pressure (CPAP), suboptimal long-term adherence highlights the need for complementary pharmacological strategies. This narrative review synthesizes preclinical and clinical evidence on GLP-1-based therapies, encompassing selective GLP-1 receptor agonists and tirzepatide, a dual GIP/GLP-1 receptor agonist, in obesity-associated OSA. Preclinical studies show that GLP-1 receptor activation can reduce visceral adiposity, attenuate pro-inflammatory signaling, improve glucose and lipid metabolism, and modulate hypothalamic appetite circuits. However, the only identified murine study evaluating liraglutide during intermittent hypoxia-an experimental model of one component of OSA rather than the complete disorder-did not reverse hypoxia-induced insulin resistance, indicating that persistent intermittent hypoxia may limit metabolic improvement in that model. Clinically, liraglutide and tirzepatide have reduced the apnea-hypopnea index (AHI) and improved several cardiometabolic outcomes. Numerically larger AHI reductions were reported in the tirzepatide trials, although no head-to-head comparison with selective GLP-1 receptor agonists is available. Tirzepatide is approved by the U.S. Food and Drug Administration for moderate-to-severe OSA in adults with obesity, together with a reduced-calorie diet and increased physical activity, and may be used without concomitant positive airway pressure in eligible patients or as an adjunct to ongoing therapy. The observed respiratory benefits appear to be mediated predominantly by weight loss and related reductions in mechanical and metabolic burden. Evidence supporting additional weight-independent mechanisms remains insufficient, and longer-term mechanistic studies in broader populations are required.