Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity - SURMOUNT-OSA

Contribution To Literature:

The SURMOUNT-OSA trial showed that in patients with obesity and moderate-to-severe OSA treated with or without PAP therapy, tirzepatide was associated with a significant reduction in AHI compared with placebo.

Description:

The goal of the trial was to determine the effect of tirzepatide, both alone and in the setting of positive airway pressure (PAP) therapy, on obstructive sleep apnea (OSA) burden in patients with obesity.

Study Design

  • Randomized
  • Double-blind
  • Multicenter international
  • Basket trial

Patients with obesity and moderate-to-severe OSA were enrolled in one of two simultaneous trials if they were unable or unwilling to use PAP therapy (trial 1) or had been using PAP therapy for ≥3 consecutive months and planned to continue (trial 2). Within each study population, participants were randomized in a 1:1 fashion to receive the maximum tolerated dose (10 or 15 mg) of once-weekly subcutaneous tirzepatide injection (trial 1: n = 114, trial 2: n = 120) or matching placebo (trial 1: n = 120, trial 2: n = 115). Tirzepatide was initiated at 2.5 mg weekly and up-titrated every 4 weeks until week 20, when baseline apnea–hypopnea index (AHI) was obtained. All participants also received regular dietary and lifestyle counseling.

  • Total number of enrollees: 469 (trial 1: 234, trial 2: 235)
  • Duration of follow-up: 52 weeks
  • Mean patient age: 50 years
  • Percentage female: 30%

Inclusion criteria:

  • Age ≥18 years
  • Body mass index (BMI) ≥30 kg/m2 (≥27 kg/m2 in Japan)
  • AHI ≥15 events/hour
  • ≥1 self-reported unsuccessful dietary attempt to lose weight

Exclusion criteria:

  • Type 1 or type 2 diabetes
  • Central or mixed sleep apnea
  • Prior or planned surgical or minimally invasive treatment for OSA or obesity
  • Significant renal, pulmonary, or liver disease
  • Other comorbidities or medications that may affect weight or daytime sleepiness
  • Prior acute or chronic pancreatitis
  • Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia, type 2

Other salient features/characteristics:

  • Mean BMI: 38.8 kg/m2
  • Mean baseline AHI: 50.1 events/hour
  • Severe OSA (AHI ≥30 events/hour): 65%

Principal Findings:

The primary outcome, mean change in AHI from baseline, for tirzepatide vs. placebo at 52 weeks:

  • Trial 1: -25.3 vs. -5.3 events/hour, estimated treatment difference -20.0 events/hour (95% confidence interval [CI] -25.8 to -14.2), p < 0.001
  • Trial 2: -29.3 vs. -5.5 events/hour, estimated treatment difference -23.8 events/hour (95% CI -29.6 to -17.9), p < 0.001

Multiplicity-adjusted secondary outcomes for tirzepatide vs. placebo at 52 weeks, presented as estimated treatment differences:

  • Percent change in AHI:
  • Trial 1: -47.7% (95% CI -65.8 to -29.6), p < 0.001
  • Trial 2: -56.2% (95% CI -73.7 to -38.7), p < 0.001 
  • Percent change in OSA-specific hypoxia burden:
  • Trial 1: -70.1% (95% CI -90.9 to -49.3), p < 0.001
  • Trial 2: -61.3% (95% CI -84.7 to -37.9), p < 0.001
  • Percent change in body weight:
  • Trial 1: -16.1% (95% CI -18.0 to -14.2), p < 0.001
  • Trial 2: -17.3% (95% CI -19.3 to -15.3), p < 0.001
  • Change in systolic blood pressure:
  • Trial 1: -7.6 mm Hg (95% CI -10.5 to -4.8), p < 0.001
  • Trial 2: -3.7 mm Hg (95% CI -6.8 to -0.7), p = 0.02

Pooled safety outcomes for tirzepatide vs. placebo:

  • Adverse events leading to study drug discontinuation: 3.9% vs. 4.3%
  • Diarrhea: 24.0% vs. 10.7%
  • Nausea: 23.6% vs. 7.7%
  • Acute pancreatitis: 0.9% vs. 0%

Interpretation:

At 1 year, tirzepatide was associated with significant reductions in AHI, OSA-related nocturnal hypoxia, and OSA severity compared with placebo. Similar effect sizes were observed in both trials, suggesting a role for tirzepatide in the treatment of OSA in the setting of obesity irrespective of whether PAP therapy is also pursued. Reduction in AHI burden was apparent by week 20, when the maximum tolerated tirzepatide dose was achieved, and AHI continued to decline before reassessment at week 52. Weight loss in the tirzepatide arm was consistent with prior data in comparison to lifestyle counseling alone.

Although statistically significant improvements in sleep-related symptoms were observed, clinically relevant cutoffs for these assessments are not well defined, and the trials were not limited to patients with daytime symptoms due to OSA. Additionally, the potential cardiovascular impact of tirzepatide’s effects on weight, AHI, and blood pressure are not yet known. Though not limited to patients with OSA, the ongoing SURMOUNT-MMO trial of tirzepatide in obesity may provide valuable insight regarding long-term clinical benefits. The current data nevertheless support tirzepatide as a novel pharmacologic option in the treatment of obesity-related OSA.

References:

Malhotra A, Grunstein RR, Fietze I, et al., on behalf of the SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N Engl J Med 2024;Jun 21:[Epub ahead of print].

Editorial: Patel SR. Entering a New Era in Sleep-Apnea Treatment. N Engl J Med 2024;Jun 21:[Epub ahead of print].

Presented at the 84th Scientific Sessions of the American Diabetes Association, Orlando, FL, June 21-24, 2024.

Clinical Topics: Diabetes and Cardiometabolic Disease, Sleep Apnea, Prevention

Keywords: Metabolic Syndrome, Obesity, Sleep Apnea, Obstructive


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