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SURMOUNT-OSA

Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity

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Year of Publication: 2024

Authors: Atul Malhotra, Ronald R. Grunstein, Ingo Fietze, ..., Josef Bednarik

Journal: New England Journal of Medicine

Citation: N Engl J Med 2024;391:1193-205

Clinical Question

Does tirzepatide improve obstructive sleep apnea severity and associated complications in adults with moderate-to-severe OSA 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

FieldControlTirzepatide
InterventionSubcutaneous 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
Duration52 weeks52 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in apnea-hypopnea index (AHI) from baseline to week 52PrimaryTrial 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 AHISecondaryTrial 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 eventsSecondaryTrial 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 weightSecondaryTrial 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 pressureSecondaryTrial 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 eventAdverseTrial 1: 76.7%; Trial 2: 72.8%Trial 1: 79.8%; Trial 2: 83.2%
DiarrheaAdverseTrial 1: 12.5%; Trial 2: 8.8%Trial 1: 26.3%; Trial 2: 21.8%
NauseaAdverseTrial 1: 10.0%; Trial 2: 5.3%Trial 1: 25.4%; Trial 2: 21.8%
VomitingAdverseTrial 1: 4.2%; Trial 2: 0.9%Trial 1: 17.5%; Trial 2: 9.2%
Serious adverse eventsAdverseTrial 1: 5.8%; Trial 2: 10.5%Trial 1: 7.9%; Trial 2: 5.9%
Acute pancreatitisAdverseTrial 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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