Orforglipron for Obstructive Sleep Apnea

Importance: Obstructive sleep apnea (OSA) is a common disorder characterized by repeated upper airway collapse during sleep that is associated with reduced quality of life and increased incidence of cardiometabolic disease. Objective: To assess the effects of orforglipron on moderate to severe OSA in adults with obesity or overweight, compared with placebo. Design, Setting, and Participants: Two 52-week, phase 3, multicenter, double-blind, placebo-controlled randomized clinical trials were conducted at 66 sites in the US, Argentina, Brazil, China, Czech Republic, Germany, Japan, Mexico, and Taiwan. Adults with moderate to severe OSA and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 27 or higher were enrolled between November 11, 2024, and July 23, 2025. Final follow-up occurred on July 30, 2026. Trial 1 included patients not receiving positive airway pressure treatment and trial 2 included patients receiving positive airway pressure treatment. Intervention: Patients were randomized (1:1) to receive either once-daily orforglipron (maximum tolerated dose: equivalent to 9-, 14.5-, or 17.2-mg tablet dose) or placebo. Main Outcomes and Measures: The primary end point was change in apnea-hypopnea index (AHI, events/h) from baseline to week 52. Seven key multiplicity-controlled secondary end points included change in sleep apnea-specific hypoxic burden, the Patient-Reported Outcomes Measurement Information System Short Form Sleep-Related Impairment T-score, and high-sensitivity C-reactive protein. Results: A total of 363 patients were randomized in trial 1 (mean age, 48.4 years; BMI, 37.4; AHI, 50.7 events/h; 31.4% female) and 349 patients were randomized in trial 2 (mean age, 51.1 years; BMI, 38.6; AHI, 57.6 events/h; 26.9% female). For the treatment regimen estimand, in trial 1, the mean AHI change was -17.8 for orforglipron compared with -4.5 for placebo (difference, -13.2 [95% CI, -17.7 to -8.7]; P < .001) at 52 weeks. In trial 2, the mean AHI change was -17.3 for orforglipron and -5.3 for placebo (difference, -12.0 [95% CI, -17.1 to -6.9]; P < .001) at 52 weeks. Of 7 key secondary end points, 6 were statistically significant, favoring orforglipron. Gastrointestinal events were the most commonly reported adverse events, occurring in 123 (68.0%) participants randomized to receive orforglipron vs 68 (37.4%) randomized to receive placebo in trial 1 and in 125 (70.6%) participants randomized to receive orforglipron vs 63 (36.6%) randomized to receive placebo in trial 2. Conclusions and Relevance: These results provide evidence for the potential use of oral orforglipron to improve sleep-disordered breathing in adults with moderate to severe OSA and obesity or overweight. Trial Registration: ClinicalTrials.gov Identifier: NCT06649045.