The potential impact of GLP‐1 agonists on obstructive sleep apnoea

Obesity is the major risk factor for obstructive sleep apnoea (OSA).1 While weight loss (either via lifestyle or surgical interventions) is an established effective therapy for improving OSA severity and symptoms, OSA resolution is uncommon and the reduction in apnoea hypopnoea index (AHI) with weight loss is unpredictable.2, 3 Despite these known benefits, the biggest challenge for OSA patients, and in obesity in general, is the ability to maintain weight loss over time. The most effective way to achieve large and sustained weight loss is via bariatric surgery,3 however, this is either not available or acceptable to many patients and has the potential for morbidity and perioperative risk. Obesity management has been revolutionized in recent years by novel pharmacotherapies such as glucagon-like peptide 1 receptor (GLP-1) agonists. These medications stimulate insulin secretion, but also down regulate appetite via central mechanisms and via delay in gastric emptying. Drugs such as Semaglutide (Ozempic™) were initially developed to improve glycaemic control in type 2 diabetes. Their effectiveness was accompanied by significant weight loss, leading to subsequent studies in non-diabetics demonstrating similar degrees of weight loss. For example, with high dose Semaglutide (Wegovy™) at 2.4 mg once weekly via subcutaneous injection in non-diabetic obese patients, over 50% of patients achieved and sustained at least a 15% weight loss.4 The predominant side effects of GLP-1 agonists are gastrointestinal, but uncommonly lead to cessation of treatment, if the dose is gradually up-titrated. Semaglutide is now Food and Drug Administration (FDA) and Therapeutic Goods Administration (TGA) approved for both the treatment of Type 2 diabetes (Ozempic™) and for the management of obesity (or overweight with at least one obesity-related complication) [Wegovy™]. A similar alternative is Liraglutide (Victoza™ and Saxenda™), however, this needs to be given as a once-daily injection and may not be quite as effective as Semaglutide with respect to diabetes control and weight loss.5 GLP-1 agonists are so effective that they have become a worldwide phenomenon. Ozempic™ has been used off-label for the management of obesity, but also by celebrities and social media influencers as a means of losing weight. Such has been the demand, there has been a worldwide shortage of Semaglutide over the past couple of years, making the drug difficult to access even for type 2 diabetics. Given that weight loss is recommended for the majority of patients with OSA, GLP-1 agonists have the potential to play a major role in OSA treatment. Currently, there is limited direct evidence for their use in OSA, however, the SCALE Sleep Apnoea randomized controlled trial (RCT) demonstrated that Liraglutide improved AHI in OSA subjects unwilling or unable to use continuous positive airway pressure (CPAP).6 There are many other ongoing clinical trials assessing Liraglutide in OSA, including the effect on cardiometabolic outcomes. This is of particular interest given that GLP-1 agonists reduce cardiovascular risk and all-cause mortality in diabetic populations.7 Interestingly, an even more effective agent, tirzepatide, is shortly to become available. This is a combination GLP-1 agonist and glucose-dependent insulinotropic polypeptide (GIP) agonist. When used for the treatment of obesity, high dose (15 mg) achieved greater than 20% weight loss in 57% of subjects.8 This magnitude of weight loss is similar to that seen with bariatric surgery. There is currently a RCT underway exploring the efficacy of tirzepatide for the treatment of OSA (SURMOUNT-OSA NCT05412004). How could these medications be used in OSA? For some patients, particularly those with milder disease, weight loss with lifestyle measures and GLP-1 agonists may be the only treatment required. For other patients, their main role may be in those who do not tolerate device-based therapy, particularly CPAP—both to improve the OSA itself and the associated symptom benefit that comes with weight loss, independent of AHI improvement.3 GLP-1 agonists and the weight loss they induce could potentially be used as a method for directly improving cardiovascular risk in patients with OSA, independent of other treatment recommendations. Finally, OSA treatment is moving closer towards personalized medicine with the advent of novel therapies targeting the underlying causative pathophysiological endotypes.9 GLP-1 agonists can potentially play an adjunct role in this approach. For example, all of the novel pharmacological therapies targeting non-anatomical factors causing OSA have limited benefit in patients with severe upper airway collapsibility (most notably seen in patients with severe obesity).9 GLP-1 agonists could therefore be used to reduce weight and improve airway collapsibility, opening up the potential for additional endotype-based treatments to be effective in those with residual OSA. What are the potential downsides? Although these medications are generally well tolerated, a small proportion will experience limiting side-effects, particularly gastrointestinal. There are also contraindications, most notably those with a history (or family history) of medullary carcinoma of the thyroid, pancreatitis or during pregnancy. Further, their benefits in the elderly are less clear. More importantly, when patients stop these medications, most will have rebound weight gain. On average patients regain two-thirds of the weight initially lost over a 12-month period.10 This means that if these medications are commenced as a treatment for OSA with obesity, we are consigning them to long-term (potentially indefinite) therapy if they want to maintain the benefits. This plays into the final concern, which is how as a society do we afford these medications? Even if we only consider OSA, rather than obesity itself, it is estimated that just under 1 billion people around the world have OSA,11 the majority of whom will be overweight or obese. The high cost of the medications combined with the high prevalence of OSA means that there is no way that universal healthcare funding schemes can afford these medications, unless strict criteria are in place to prioritize those who can gain subsidized access and/or a duration of use limit is in place.12 This will no doubt exacerbate inequities in healthcare access and outcome between those from lower versus higher socioeconomic populations, as the attributable benefit from GLP-1 agonists is likely to be dependent on a patient's ability to afford them. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians. Garun S. Hamilton has received equipment to support research projects from Resmed and Air Liquide Healthcare. Garun S. Hamilton is a current Board member and President-elect of the Australasian Sleep Association. Bradley A. Edwards has received research support from the National Health and Medical Research Council (NHMRC) and Apnimed. He has received speaker fees from Philips Respironics and served as a consultant for Signifier Medical.