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SURMOUNT-OSA

Q: What were the key findings of the SURMOUNT-OSA trial?

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

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

Link: https://doi.org/10.1056/NEJMoa2404881

PDF: https://escholarship.org/content/qt5xf6509x/qt5xf6509x.pdf

Clinical Question

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

Study Overview

Objective

To evaluate the efficacy and safety of tirzepatide for the treatment of adults with moderate-to-severe obstructive sleep apnea and obesity

Study Summary

Tirzepatide significantly reduced AHI by 20-24 events per hour vs placebo (P<0.001)
61-72% of tirzepatide patients had ≥50% AHI reduction vs 19-23% with placebo
Tirzepatide also reduced body weight by 17-20%, improved sleep symptoms, and decreased cardiovascular risk factors

Intervention

Weekly subcutaneous tirzepatide (maximum tolerated dose 10-15 mg) vs placebo for 52 weeks with lifestyle counseling

Patients per Arm

234 in Trial 1 (114 tirzepatide, 120 placebo); 235 in Trial 2 (120 tirzepatide, 115 placebo)

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: Trials conducted June 21, 2022 to March 29, 2024

Follow-up Duration: 52 weeks with 4-week safety follow-up (blood pressure assessed at week 48 to avoid PAP washout confounding in Trial 2)

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

Baseline Characteristics

Characteristic	Control	Active
Age - years	Trial 1: 48.4±11.9, Trial 2: 52.7±11.3	Trial 1: 47.3±11.0, Trial 2: 50.8±10.7
Female sex	Trial 1: 34.2%, Trial 2: 27.8%	Trial 1: 31.6%, Trial 2: 27.5%
White race	Trial 1: 66.7%, Trial 2: 75.4%	Trial 1: 64.9%, Trial 2: 70.8%
BMI	Trial 1: 38.6±6.7, Trial 2: 38.7±6.0	Trial 1: 39.7±7.3, Trial 2: 38.6±6.1
Body weight - kg	Trial 1: 112.8±22.6, Trial 2: 115.1±22.7	Trial 1: 116.7±24.6, Trial 2: 115.8±21.5
AHI - events/hr	Trial 1: 50.1±31.5, Trial 2: 53.1±30.2	Trial 1: 52.9±30.5, Trial 2: 46.1±22.4
Severe OSA (AHI ≥30)	Trial 1: 61.3%, Trial 2: 65.8%	Trial 1: 64.9%, Trial 2: 70.6%
Systolic BP - mm Hg	Trial 1: 130.3±10.7, Trial 2: 130.5±12.8	Trial 1: 128.4±12.2, Trial 2: 130.5±14.3
Hypertension	Trial 1: 77.5%, Trial 2: 79.1%	Trial 1: 73.7%, Trial 2: 75.8%
Prediabetes	Trial 1: 65.0%, Trial 2: 55.7%	Trial 1: 64.9%, Trial 2: 57.5%

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 (treatment-regimen estimand)	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 at wk 52	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)	ETD Trial 1: -47.7 (-65.8 to -29.6); Trial 2: -56.2 (-73.7 to -38.7)	<0.001
≥50% reduction in AHI at wk 52	Secondary	Trial 1: 23 (19.0%); Trial 2: 27 (23.3%)	Trial 1: 70 (61.2%); Trial 2: 86 (72.4%)	RR Trial 1: 3.3 (2.1 to 5.1); Trial 2: 3.1 (2.1 to 4.5)	<0.001
AHI <5, or AHI 5-14 with ESS ≤10 at wk 52 (composite disease-control endpoint)	Secondary	Trial 1: 19 (15.9%); Trial 2: 16 (14.3%)	Trial 1: 48 (42.2%); Trial 2: 60 (50.2%)	RR Trial 1: 2.9 (1.8 to 4.8); Trial 2: 3.3 (2.0 to 5.4)	<0.001
Percent change in body weight at wk 52	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)	ETD Trial 1: -16.1 (-18.0 to -14.2); Trial 2: -17.3 (-19.3 to -15.3)	<0.001
Change in hsCRP concentration at wk 52 (mg/liter)	Secondary	Trial 1: -0.7 (-1.1 to -0.3); Trial 2: -0.3 (-0.8 to 0.1)	Trial 1: -1.4 (-1.7 to -1.1); Trial 2: -1.4 (-1.6 to -1.1)	ETD Trial 1: -0.7 (-1.2 to -0.2); Trial 2: -1.0 (-1.6 to -0.5)	Trial 1: P=0.004; Trial 2: P<0.001
Change in sleep apnea-specific hypoxic burden at wk 52 (% min/hr)	Secondary	Trial 1: -25.1 (-44.3 to -5.9); Trial 2: -41.7 (-63.9 to -19.5)	Trial 1: -95.2 (-103.2 to -87.2); Trial 2: -103.0 (-110.3 to -95.6)	ETD Trial 1: -70.1 (-90.9 to -49.3); Trial 2: -61.3 (-84.7 to -37.9)	<0.001
Change in systolic blood pressure at wk 48 (mm Hg)	Secondary	Trial 1: -1.8 (95% CI: -3.9 to 0.2); Trial 2: -3.9 (95% CI: -6.3 to -1.6)	Trial 1: -9.5 (95% CI: -11.5 to -7.5); Trial 2: -7.6 (95% CI: -9.7 to -5.6)	ETD Trial 1: -7.6 (-10.5 to -4.8); Trial 2: -3.7 (-6.8 to -0.7)	Trial 1: P<0.001; Trial 2: P=0.004
Change in PROMIS Sleep-Related Impairment T score at wk 52 (pooled trials)	Secondary	-3.6 (95% CI: -4.9 to -2.3), N=233	-7.5 (95% CI: -8.8 to -6.3), N=234	ETD -3.9 (-5.7 to -2.2)	<0.001
Change in PROMIS Sleep Disturbance T score at wk 52 (pooled trials)	Secondary	-2.7 (95% CI: -3.8 to -1.6), N=233	-5.7 (95% CI: -6.8 to -4.7), N=234	ETD -3.1 (-4.5 to -1.5)	<0.001
Safety population denominators	Adverse	Trial 1: N=120; Trial 2: N=114	Trial 1: N=114; Trial 2: N=119
Any adverse event	Adverse	Trial 1: 92 (76.7%); Trial 2: 83 (72.8%)	Trial 1: 91 (79.8%); Trial 2: 99 (83.2%)
Death	Adverse	Trial 1: 0 (0%); Trial 2: 0 (0%)	Trial 1: 0 (0%); Trial 2: 0 (0%)
Serious adverse events	Adverse	Trial 1: 7 (5.8%); Trial 2: 12 (10.5%)	Trial 1: 9 (7.9%); Trial 2: 7 (5.9%)
Adverse events leading to discontinuation	Adverse	Trial 1: 2 (1.7%); Trial 2: 8 (7.0%)	Trial 1: 5 (4.4%); Trial 2: 4 (3.4%)
Diarrhea	Adverse	Trial 1: 15 (12.5%); Trial 2: 10 (8.8%)	Trial 1: 30 (26.3%); Trial 2: 26 (21.8%)
Nausea	Adverse	Trial 1: 12 (10.0%); Trial 2: 6 (5.3%)	Trial 1: 29 (25.4%); Trial 2: 26 (21.8%)
Vomiting	Adverse	Trial 1: 5 (4.2%); Trial 2: 1 (0.9%)	Trial 1: 20 (17.5%); Trial 2: 11 (9.2%)
Adjudication-confirmed acute pancreatitis	Adverse	Trial 1: 0 (0%); Trial 2: 0 (0%)	Trial 1: 0 (0%); Trial 2: 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)