SURMOUNT-OSA
Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity
Bottom Line
Tirzepatide significantly reduced sleep apnea severity, body weight, and cardiovascular risk factors in adults with moderate-to-severe OSA and obesity, both with and without concurrent PAP therapy
Major Points
- Two parallel phase 3 trials: Trial 1 (no PAP therapy) and Trial 2 (stable PAP therapy)
- Primary endpoint was change in AHI from baseline to 52 weeks
- Tirzepatide reduced AHI by 20.0-23.8 events/hour vs placebo (P<0.001 both trials)
- 61-72% of tirzepatide patients achieved ≥50% AHI reduction vs 19-23% with placebo
- Tirzepatide reduced body weight by 17-20% vs 1.6-2.3% with placebo
- Significant improvements in hypoxic burden, blood pressure, and inflammation markers
- Most adverse events were mild-moderate gastrointestinal symptoms
Design
Study Type: Phase 3, double-blind, randomized, placebo-controlled trial
Randomization: 1
Blinding: Participants, investigators, and sponsor were blinded to treatment assignment
Enrollment Period: June 21, 2022 to March 29, 2024
Follow-up Duration: 52 weeks
Centers: 60
Countries: United States, Canada, Australia, Germany, Belgium, Netherlands, Czech Republic, Poland, Japan
Sample Size: 469
Analysis: Intention-to-treat analysis using ANCOVA models with treatment-regimen and efficacy estimands. Missing data handled with multiple imputation approaches
Inclusion Criteria
- Adults with moderate-to-severe obstructive sleep apnea (AHI ≥15 events per hour)
- Obesity (BMI ≥30 or ≥27 in Japan)
- Trial 1: Unable or unwilling to use PAP therapy
- Trial 2: Using PAP therapy for at least 3 consecutive months at screening with plan to continue
Exclusion Criteria
- Type 1 or type 2 diabetes
- Participant-reported weight change >5 kg in 3 months before screening
- Planned surgery for sleep apnea or obesity
- Diagnosis of central or mixed sleep apnea
- Major craniofacial abnormalities
Arms
| Field | Control | Tirzepatide |
|---|---|---|
| Intervention | Subcutaneous placebo injection once weekly with lifestyle counseling (500 kcal deficit, 150 min/week physical activity) | Subcutaneous tirzepatide starting at 2.5 mg weekly, escalated by 2.5 mg every 4 weeks to maximum tolerated dose (10-15 mg) with lifestyle counseling |
| Duration | 52 weeks | 52 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change in apnea-hypopnea index (AHI) from baseline to week 52 | Primary | Trial 1: -5.3 events/hr (95% CI: -9.4 to -1.1); Trial 2: -5.5 events/hr (95% CI: -9.9 to -1.2) | Trial 1: -25.3 events/hr (95% CI: -29.3 to -21.2); Trial 2: -29.3 events/hr (95% CI: -33.2 to -25.4) | <0.001 for both trials | |
| Percent change in AHI | Secondary | Trial 1: -3.0% (95% CI: -16.9 to 10.9); Trial 2: -2.5% (95% CI: -16.2 to 11.2) | Trial 1: -50.7% (95% CI: -62.3 to -39.1); Trial 2: -58.7% (95% CI: -69.1 to -48.4) | <0.001 | |
| ≥50% reduction in AHI events | Secondary | Trial 1: 19.0%; Trial 2: 23.3% | Trial 1: 61.2%; Trial 2: 72.4% | RR 3.3 (2.1-5.1) Trial 1; RR 3.1 (2.1-4.5) Trial 2 | <0.001 |
| Percent change in body weight | Secondary | Trial 1: -1.6% (95% CI: -2.9 to -0.2); Trial 2: -2.3% (95% CI: -3.8 to -0.9) | Trial 1: -17.7% (95% CI: -19.0 to -16.3); Trial 2: -19.6% (95% CI: -21.0 to -18.2) | <0.001 | |
| Change in systolic blood pressure | Secondary | Trial 1: -1.8 mm Hg (95% CI: -3.9 to 0.2); Trial 2: -3.9 mm Hg (95% CI: -6.3 to -1.6) | Trial 1: -9.5 mm Hg (95% CI: -11.5 to -7.5); Trial 2: -7.6 mm Hg (95% CI: -9.7 to -5.6) | <0.001 Trial 1; P=0.02 Trial 2 | |
| Any adverse event | Adverse | Trial 1: 76.7%; Trial 2: 72.8% | Trial 1: 79.8%; Trial 2: 83.2% | ||
| Diarrhea | Adverse | Trial 1: 12.5%; Trial 2: 8.8% | Trial 1: 26.3%; Trial 2: 21.8% | ||
| Nausea | Adverse | Trial 1: 10.0%; Trial 2: 5.3% | Trial 1: 25.4%; Trial 2: 21.8% | ||
| Vomiting | Adverse | Trial 1: 4.2%; Trial 2: 0.9% | Trial 1: 17.5%; Trial 2: 9.2% | ||
| Serious adverse events | Adverse | Trial 1: 5.8%; Trial 2: 10.5% | Trial 1: 7.9%; Trial 2: 5.9% | ||
| Acute pancreatitis | Adverse | Trial 1: 0%; Trial 2: 0% | Trial 1: 0%; Trial 2: 1.7% |
Subgroup Analysis
Results were consistent across both trials regardless of concomitant PAP therapy use
Criticisms
- 52-week duration insufficient to assess long-term cardiovascular outcomes
- Excluded participants without obesity, limiting generalizability
- Trial 2 not designed to assess PAP adherence as endpoint
- Clinical importance thresholds for PROMIS sleep scores not established
- No assessment of treatment effects beyond 52 weeks
Funding
Eli Lilly
Based on: SURMOUNT-OSA (New England Journal of Medicine, 2024)
Authors: Atul Malhotra, Ronald R. Grunstein, Ingo Fietze, ..., Josef Bednarik
Citation: N Engl J Med 2024;391:1193-205
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