<scp>GLP</scp> ‐1 Receptor Agonists for Obstructive Sleep Apnea: An Otolaryngologist's Prescription?

Obstructive sleep apnea (OSA) is a prevalent, chronic condition characterized by recurrent upper airway collapse during sleep, resulting in intermittent hypoxia, cardiovascular morbidity, metabolic dysfunction, and diminished quality of life [1, 2]. Obesity is a well-established major modifiable risk factor, with excess adipose tissue contributing to pharyngeal narrowing and collapsibility as well as increased work of breathing [2]. Although many patients may be anatomically appropriate candidates for OSA surgery, excess adiposity can reduce treatment efficacy [1]. Sustained weight loss is associated with improvements in OSA severity; however, lifestyle-based interventions are frequently insufficient [2]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes and now widely used for weight management, have emerged as a promising adjunctive therapy for OSA, addressing the metabolic contributors to upper airway obstruction [1-3]. The recent FDA approval of tirzepatide (Zepbound), a dual GIP and GLP-1RA, for adults with moderate to severe OSA and obesity underscores a shift toward addressing metabolic drivers of the disease [1]. Traditionally, Otolaryngology—Head and Neck Surgeons have focused on anatomical management, but should they now take an active role in understanding and/or prescribing GLP-1RAs for OSA management? Altobaishat et al. [2] conducted a systematic review and meta-analysis of three randomized controlled trials (RCTs) involving 828 patients evaluating the efficacy and safety of GLP-1RAs, including tirzepatide and liraglutide, in adults with OSA [2]. Pooled results demonstrated a significant reduction in the Apnea–Hypopnea Index (AHI) by 16.57 events/h, with additional benefits including a 12.71% reduction in body weight and a decrease in systolic blood pressure [2]. Patients who used tirzepatide had a significant reduction of ≥ 50% in AHI at week 52 [2]. Tirzepatide specifically reduced high-sensitivity C-reactive protein (−0.89 mg/dL) and hypoxic burden (−66.21%/min), suggesting systemic anti-inflammatory effects [2]. Importantly, no serious adverse events were reported, although gastrointestinal side effects such as nausea and diarrhea were more frequent in the treatment group [2]. The SURMOUNT-OSA program [1] was comprised of two large, phase 3, double-blind, multicenter RCTs evaluating tirzepatide in adults with moderate-to-severe OSA and obesity. Trial 1 enrolled individuals not using CPAP, while Trial 2 included those on stable CPAP therapy. Across both trials (n = 469), tirzepatide led to significant reductions in the AHI: −25.3 events/h in Trial 1 and −29.3 in Trial 2, compared to −5.3 and −5.5 with placebo, respectively (p < 0.001) [1]. These changes corresponded to a 50.7% (Trial 1) and 58.7% (Trial 2) reduction in AHI, accompanied by a 17.7% and 19.6% reduction in body weight, respectively. Notably, these findings reinforce the relationship between obesity and OSA severity, suggesting that tirzepatide's greater AHI reduction is attributed to its robust effects on weight and BMI reduction. Up to 50.2% of patients achieved a ≥ 50% AHI reduction or reached mild OSA thresholds, a level at which CPAP therapy may not be routinely indicated [1]. Tirzepatide also led to consistent improvements in systolic blood pressure, inflammation markers, and patient-reported sleep-related outcomes, with effects independent of CPAP use [1]. The SCALE Sleep Apnea trial was a 32-week double-blind RCT assessing Liraglutide in patients with obesity and moderate-to-severe OSA who were unwilling or unable to use CPAP [2]. Liraglutide achieved a modest AHI reduction (−12.2 events/h), corresponding to an approximate 25% AHI reduction, and a mean weight loss of 5.7% [2]. Improvements in OSA severity were attributed to weight loss, and liraglutide also improved glycemic control and systolic blood pressure [2]. Complementing these findings, Li et al. [3] conducted a broader meta-analysis including six studies (n = 1067), which confirmed the overall efficacy of GLP-RAs. The analysis demonstrated a significant reduction in AHI (−9.48 events/h), along with notable improvements in weight, body mass index, and systolic blood pressure [3]. Notably, tirzepatide achieved a greater reduction in AHI compared to liraglutide. These benefits were more pronounced in patients with obesity and severe OSA and were observed regardless of CPAP use or treatment duration [3]. Interestingly, the findings suggest that GLP-1RAs may exert therapeutic effects beyond weight loss alone. Although heterogeneity was high, sensitivity analyses supported the overall consistency and reliability of the results [3]. Notably, semaglutide is the most widely recognized GLP-1RA for weight management but has not yet been evaluated in large RCTs for OSA. The recent studies suggest tirzepatide provides greater mean weight loss and BMI reduction, which may explain its stronger AHI improvement [1-3]. Refer to Table 1 for a comparative summary evaluating GLP-1RAs for OSA. In addition to demonstrating efficacy, these trials provide guidance for the clinical application of GLP-1RAs in the management of OSA. Ideal candidates include adults with moderate-to-severe OSA and obesity (BMI ≥ 30), particularly those with poor adherence to CPAP or persistent symptoms despite therapy [1]. The SURMOUNT-OSA trials identified appropriate candidates for tirzepatide as those with stable weight, without diabetes, central sleep apnea, or a personal or family history of medullary thyroid cancer (MTC) or MEN2 [1]. Similarly, Li et al. found the strongest treatment effects in patients with obesity and severe OSA, with or without concurrent CPAP use, suggesting its utility among patients with cardiometabolic comorbidities [3]. Altobaishat et al. [2] further suggested that GLP-1RAs may be particularly effective in patients with elevated baseline AHI and systemic inflammation. Table 2 outlines the clinical considerations in prescribing GLP-1RAs for OSA. GLP-1RAs, particularly tirzepatide, represent an evidence-based adjunctive for OSA management in patients with obesity, offering significant improvements in AHI, weight, blood pressure, and systemic inflammation regardless of CPAP use and without major side effects. While not intended to be curative as the sole therapeutic modality, GLP-1RAs should be used in conjunction with established medical and surgical therapies. For Otolaryngology—Head and Neck Surgeons, GLP-1RAs represent a valuable tool in optimizing patients for surgical intervention by reducing BMI and OSA severity and helping to improve criteria for surgical candidacy or enhance surgical outcomes. Surgeons can consider prescribing GLP-1RAs for patients with BMI ≥ 30 kg/m2, stable renal function, and no personal or family history of MTC or MEN2. While emerging data have noted a transient increase in MTC diagnoses within the first year of use, this is likely attributable to increased clinical surveillance rather than a causal relationship [4]. Clinicians should review history and counsel patients on common side effects prior to prescribing. Given that prescribing may require prior authorization and long-term monitoring, collaboration with endocrinology or primary care may help streamline care. Clinicians should be aware that insurance coverage and prior authorization requirements may vary and are evolving, which can impact patient access to GLP-1RAs. Further research is needed to evaluate long-term outcomes and the potential direct effects of GLP-1RAs on upper airway physiology. This review incorporates three studies: two classified as level 1 (a high-quality systematic review and a double-blind phase 3 RCT) and one as level 2 (meta-analysis of mixed study designs with high heterogeneity). Collectively, these represent strong evidence supporting the safety and efficacy of GLP-1RAs in OSA treatment. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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