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).
Statistically-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.)
The change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) (Panels A & B) and body weight (Panels C & D) from baseline to week 52 for trial 1 and trial 2 are shown according to the weeks since randomization, derived from a mixed-model-for-repeated-measures analysis for the efficacy estimand, and no explicit imputations were performed for missing data. Week 52 estimates for the treatment-regimen estimand are also shown.
For the treatment-regimen estimand, missing data at week 52 due to coronavirus disease 2019, missing data at week 52 from participants in the tirzepatide and placebo groups who completed the study period, missing data at week 52 after trial discontinuation due to the participant having undergone randomization in error, or missing data at baseline were assumed to be missing at random and were imputed with the use of multiple imputation from the same trial group. All other missing data at week 52 were considered to be not missing at random, and a placebo-based multiple imputation method was implemented. Least-squares means are shown unless otherwise noted. 𝙸 bars indicate 95% confidence intervals.