Mechanism-Targeted Therapy in Adult Obstructive Sleep Apnea: Aligning New Treatment Modalities with Pathophysiological Endotypes

Abstract

Advances in Positive Airway Pressure (PAP) technology, including novel pressure algorithms such as Kairos PAP, aim to improve comfort without compromising efficacy. Pharmacologic therapies have emerged as viable options, with tirzepatide demonstrating substantial reductions in apnea–hypopnea index (AHI), hypoxic burden, and cardiometabolic risk in obese individuals, and the atomoxetine–aroxybutynin combination (AD109) showing efficacy across a broader patient population independent of obesity. Device-based therapies have also evolved, including transoral daytime neuromuscular electrical stimulation for mild OSA and expanding hypoglossal nerve stimulation (HNS) platforms that improve upper airway patency in patients intolerant to PAP. Newer HNS systems, including bilateral and proximal stimulation approaches, broaden eligibility by addressing prior anatomical and procedural limitations. Despite these advances, important gaps remain, including limited long-term outcome data, lack of comparative effectiveness studies, uncertainty regarding cardiovascular benefit, and incomplete integration of pathophysiological endotyping into clinical decision-making. Emerging evidence underscores the heterogeneity of OSA, suggesting that treatment should be individualized based on underlying mechanisms, disease severity, comorbidities, and patient preferences.