Authors: Atul Malhotra, M.D., Ronald R. Grunstein, M.D., Ph.D., Ingo Fietze, M.D., Terri E. Weaver, Ph.D., Susan Redline, M.D., M.P.H., Ali Azarbarzin, Ph.D., Scott A. Sands, Ph.D., +5 , Richard J. Schwab, M.D., Julia P. Dunn, M.D., Sujatro Chakladar, Ph.D., Mathijs C. Bunck, M.D., Ph.D., and Josef Bednarik, M.D., for the SURMOUNT-OSA Investigators*
Published June 21, 2024
N Engl J Med 2024;391:1193-1205
DOI: 10.1056/NEJMoa2404881
Abstract
Background
Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment.
Methods
We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea–hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure.
Results
At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was −25.3 events per hour (95% confidence interval [CI], −29.3 to −21.2) with tirzepatide and −5.3 events per hour (95% CI, −9.4 to −1.1) with placebo, for an estimated treatment difference of −20.0 events per hour (95% CI, −25.8 to −14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was −29.3 events per hour (95% CI, −33.2 to −25.4) with tirzepatide and −5.5 events per hour (95% CI, −9.9 to −1.2) with placebo, for an estimated treatment difference of −23.8 events per hour (95% CI, −29.6 to −17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity.
Conclusions
Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.)
Notes
This article was published on June 21, 2024, and last updated on July 1, 2024, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Presented in part at the 84th Scientific Sessions of the American Diabetes Association, Orlando, FL, June 21–24, 2024.
Supported by Eli Lilly.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the participants and caregivers involved in the trial, as well as Eli Lilly employees Casey J. Mast, Pharm.D., for medical writing and editorial assistance; Bram Brouwers, Ph.D., and Meri Kay Scott, Ph.D., for trial design advice; and Angel Rodriguez, M.D., Ph.D., for a critical review of an earlier version of the manuscript.