SURMOUNT-OSA deep dive: tirzepatide for obstructive sleep apnea (Malhotra 2024 NEJM)
Last verified 2026-05-28 · Phase 3 · Completed; primary results published June 2024 · NCT05412004 ↗
SURMOUNT-OSA (NCT05412004) is the pair of phase-3 trials that made obstructive sleep apnea the third FDA-approved indication for tirzepatide. Eli Lilly ran two cohorts under one master protocol: SURMOUNT-OSA-1 randomized 234 adults with moderate-to-severe OSA and obesity not using positive airway pressure (PAP) therapy; SURMOUNT-OSA-2 randomized 235 adults with the same diagnosis already established on PAP. Both cohorts received weekly subcutaneous tirzepatide at maximum tolerated dose (10 or 15 mg) or matching placebo for 52 weeks. The primary endpoint was change from baseline in the apnea-hypopnea index (AHI, events per hour) by overnight polysomnography. Results published by Malhotra and colleagues in the New England Journal of Medicine on June 21, 2024 supported the December 20, 2024 FDA label expansion of Zepbound to moderate-to-severe OSA in adults with obesity.
- Enrollment
- 469
- Duration
- 52 weeks of randomized treatment under a 24-week dose-escalation schedule, plus a 4-week safety follow-up
- Drug
- Tirzepatide (Zepbound)
- Population
- Adults aged 18 or older with a body-mass index of at least 30 kg/m² and a diagnosis of moderate-to-severe obstructive sleep apnea (apnea-hypopnea index ≥15 events/hour on screening polysomnography). Type 2 diabetes was an exclusion. SURMOUNT-OSA-1 enrolled adults unable or unwilling to use positive airway pressure therapy; SURMOUNT-OSA-2 enrolled adults established on PAP therapy for at least 3 months at screening. Across both cohorts the mean baseline AHI was approximately 51 events/hour, mean body weight approximately 116 kg, mean BMI approximately 39 kg/m², and roughly 70% of participants were male — the reverse of the female-skewed obesity trial populations.
Primary endpoint
Change from baseline in apnea-hypopnea index (AHI, events/hour) at week 52 — measured by overnight polysomnography
Treatment arm
Cohort 1 (without PAP): −25.3 events/hour; Cohort 2 (with PAP): −29.3 events/hour
Comparator
Cohort 1: −5.3 events/hour; Cohort 2: −5.5 events/hour
Treatment difference: Estimated treatment difference vs placebo: cohort 1 −20.0 events/hour (95% CI −25.8 to −14.2); cohort 2 −23.8 events/hour (95% CI −29.6 to −17.9); P<0.001 for both
Baseline AHI of approximately 51 events/hour fell by roughly 25-29 events/hour on tirzepatide vs roughly 5 events/hour on placebo — a magnitude that moved most participants from severe OSA (≥30 events/hour) toward mild or remission (<15 events/hour).
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Proportion achieving AHI reduction ≥50% from baseline at week 52 More than half of cohort-1 participants and nearly two-thirds of cohort-2 participants achieved a halving of their AHI — the clinical threshold for meaningful OSA response. | Cohort 1: 51.5%; Cohort 2: 65.2% | Cohort 1: 13.6%; Cohort 2: 17.2% | Cohort 1 odds ratio favoring tirzepatide; cohort 2 similar; P<0.001 for both |
| Proportion achieving disease resolution (AHI <5 events/hour or AHI 5-14 with no daytime sleepiness) at week 52 Roughly half of tirzepatide participants met the prespecified definition of OSA disease resolution — a regulatory anchor for the FDA approval. No prior drug has produced this outcome in a randomized trial. | Cohort 1: 43.0%; Cohort 2: 51.5% | Cohort 1: 14.9%; Cohort 2: 13.6% | P<0.001 for both cohorts |
| Percent change in body weight from baseline at week 52 Weight loss in SURMOUNT-OSA was similar in magnitude to SURMOUNT-1 (−20.9% at 72 weeks in adults with obesity without diabetes), confirming that the AHI benefit was layered on top of substantial weight reduction. | Cohort 1: −18.1%; Cohort 2: −20.1% | Cohort 1: −1.3%; Cohort 2: −2.3% | Cohort 1: estimated treatment difference −16.8 percentage points (95% CI −19.3 to −14.4); cohort 2: −17.8 percentage points (95% CI −20.3 to −15.3); P<0.001 for both |
| Change in hypoxic burden at week 52 (% min/hour, area-under-curve of oxygen desaturation) Hypoxic burden integrates the depth and duration of overnight oxygen desaturations and is a stronger predictor of OSA-related cardiovascular mortality than AHI alone. | Cohort 1: −79.3%; Cohort 2: −78.4% (relative reductions) | Cohort 1: −19.0%; Cohort 2: −15.6% | Treatment-difference ratios favored tirzepatide in both cohorts; P<0.001 |
| Change in PROMIS Sleep-Related Impairment T-score at week 52 (patient-reported daytime sleepiness) Patient-reported daytime functional impairment improved on the validated PROMIS Sleep-Related Impairment instrument; the magnitude exceeds the minimal clinically important difference of approximately 2 points. | Cohort 1: −5.0 points; Cohort 2: −5.0 points (improvement) | Cohort 1: −2.3 points; Cohort 2: −1.4 points | Estimated treatment differences −2.6 points (cohort 1) and −3.5 points (cohort 2); P<0.001 for both |
| Change in high-sensitivity C-reactive protein (hsCRP) at week 52 (ratio to baseline) Systemic inflammation, elevated in OSA and obesity, fell substantially on tirzepatide. Consistent with hsCRP reductions seen in STEP-1, SURMOUNT-1, and SELECT. | Cohort 1: 0.63 (37% reduction); Cohort 2: 0.59 (41% reduction) | Cohort 1: 0.97; Cohort 2: 0.96 | Cohort 1: estimated treatment ratio 0.65; cohort 2: 0.61; nominal P<0.001 in both |
| Change in systolic blood pressure at week 52 (mmHg, measured by 24-hour ambulatory monitoring) Magnitude comparable to a low-to-moderate-dose antihypertensive added to standard care. OSA-related sympathetic activation is a major driver of resistant hypertension; the drop here is clinically meaningful. | Cohort 1: −9.7 mmHg; Cohort 2: −7.6 mmHg | Cohort 1: −2.5 mmHg; Cohort 2: −1.0 mmHg | Estimated treatment differences −7.2 mmHg (cohort 1) and −6.6 mmHg (cohort 2); P<0.001 for both |
| Change in HbA1c at week 52 (percentage points) Participants were non-diabetic at entry; HbA1c shifted from upper-normal toward mid-normal range, consistent with the prediabetes-prevention pattern seen across SURMOUNT-1. | Cohort 1: −0.32; Cohort 2: −0.35 | Cohort 1: −0.05; Cohort 2: −0.10 | Estimated treatment differences approximately −0.27 (cohort 1) and −0.25 (cohort 2) percentage points; P<0.001 |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Diarrhea Most common gastrointestinal AE in both cohorts; clustered during the 24-week dose-escalation phase and generally mild-to-moderate. | Cohort 1: 21.6%; Cohort 2: 21.9% | Cohort 1: 5.9%; Cohort 2: 5.9% |
| Nausea Second-most-common AE; typically transient and concentrated during titration. | Cohort 1: 25.4%; Cohort 2: 18.6% | Cohort 1: 6.8%; Cohort 2: 9.3% |
| Vomiting | Cohort 1: 11.0%; Cohort 2: 7.6% | Cohort 1: 2.5%; Cohort 2: 4.2% |
| Constipation | Cohort 1: 11.9%; Cohort 2: 12.7% | Cohort 1: 2.5%; Cohort 2: 6.8% |
| Injection-site reaction | Cohort 1: 4.2%; Cohort 2: 4.2% | Cohort 1: 0.8%; Cohort 2: 0.0% |
| COVID-19 (any) Background COVID-19 incidence; rates were broadly similar between arms and not attributable to treatment. | Cohort 1: 15.3%; Cohort 2: 16.1% | Cohort 1: 16.1%; Cohort 2: 18.6% |
| Serious adverse events (any) Rates similar between arms; no concentration in any single organ system. | Cohort 1: 6.8%; Cohort 2: 5.1% | Cohort 1: 4.2%; Cohort 2: 5.9% |
| Permanent discontinuation due to adverse events Gastrointestinal events were the leading reason in both cohorts; absolute rates were comparable to other tirzepatide phase-3 trials. | Cohort 1: 5.9%; Cohort 2: 5.1% | Cohort 1: 1.7%; Cohort 2: 1.7% |
Clinical significance
SURMOUNT-OSA is the trial that turned obstructive sleep apnea into a pharmacologically treatable disease for the first time. Tirzepatide cut AHI by 25-29 events/hour across both cohorts — moving most participants from severe OSA toward mild or full resolution — with a 17-18 percentage-point placebo-subtracted weight loss, a 7-9 mmHg drop in systolic blood pressure, a 35-40% reduction in hsCRP, and improvements in patient-reported daytime sleepiness on the PROMIS instrument. The benefit appeared whether or not participants were using PAP therapy, which matters clinically because PAP adherence rates are estimated at roughly 50% in real-world cohorts. The December 20, 2024 FDA approval of Zepbound for moderate-to-severe OSA in adults with obesity made tirzepatide the first drug ever approved for OSA and reframed the condition as part of the cardiometabolic disease spectrum rather than as a standalone sleep disorder.
Frequently Asked Questions
References
- 1.Malhotra A, Grunstein RR, Fietze I, et al.; SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N Engl J Med. 2024. PMID: 38912654.
- 2.Eli Lilly and Company. Obstructive Sleep Apnea Master Protocol GPIF: A Study of Tirzepatide (LY3298176) in Participants With Obstructive Sleep Apnea (SURMOUNT-OSA, NCT05412004). ClinicalTrials.gov. 2024. https://clinicaltrials.gov/study/NCT05412004
- 3.U.S. Food and Drug Administration. FDA Approves First Medication for Obstructive Sleep Apnea (Zepbound, tirzepatide). FDA Press Announcement, December 20, 2024. 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-obstructive-sleep-apnea
- 4.Jastreboff AM, Aronne LJ, Ahmad NN, et al.; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022. PMID: 35658024.