Pharmacotherapy for obstructive sleep apnea: a critical review of randomized placebo-controlled trials

Abstract

Positive airway pressure therapy remains the gold standard treatment for obstructive sleep apnea (OSA), but challenges with adherence, acceptability, and side effects persist. Interest in pharmacological therapies has grown, culminating in the recent U.S. Food and Drug Administration approval of tirzepatide as the first pharmacotherapy for OSA. Our review critically examines the efficacy of pharmacologic treatments for OSA and highlights current limitations and future research directions. We conducted a search of Medline and Embase for randomized controlled trials published from January 2005 to February 2025, identifying 41 studies investigating 37 different drugs or drug combinations. Weight-loss therapies showed the most consistent and substantial improvements in OSA severity. Tirzepatide produced the largest reduction in apnea-hypopnea index and improved patient-reported outcomes and cardiometabolic risk factors. Other pharmacotherapies demonstrated modest and inconsistent effects on OSA severity, sometimes with side-effects that contradict the treatment goal to reduce daytime sleepiness. Weight-loss agents, particularly tirzepatide, represent a promising and now clinically viable treatment option. While endotype-targeted approaches are conceptually attractive, many agents were too early in their testing/re-purposing phase to demonstrate improvements in sleepiness, quality of life or sustained reductions of OSA severity; or were insufficiently targeted at the endotype they might best treat.

Keywords: Atomoxetine-oxybutynin; Atomoxetine-trazodone; Eszopiclone; Liraglutide; Obstructive sleep apnea; Placebo; Randomized controlled trials; Sulthiame; Zolpidem; Zopiclone.