In December 2024, the US Food and Drug Administration (FDA) approved tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist previously approved for type 2 diabetes and obesity, as the first prescription medication for adults with moderate to severe OSA and obesity.1
The approval was based on the phase 3 SURMOUNT-OSA study, which compared tirzepatide with placebo for improving OSA outcomes in adults with moderate to severe OSA and obesity.2
“The approval [of tirzepatide for OSA] is exciting,” said Atul Malhotra, MD, FCCP, the global principal investigator on the SURMOUNT-OSA study. “We have a new treatment for sleep apnea. The standard of care first-line treatment is still nasal CPAP. If patients cannot or will not use CPAP therapy, then tirzepatide may be an option. For patients who are on CPAP for OSA who [have obesity], tirzepatide is better than placebo in terms of improving systolic blood pressure, high-sensitivity C-reactive protein levels, patient-reported outcomes, and other parameters assessed in the study.”
Participants received tirzepatide at the maximum tolerated dose (10 mg or 15 mg weekly, via subcutaneous injection) for 52 weeks or placebo.
Tirzepatide improved the apnea-hypopnea index (AHI) at week 52, with an estimated treatment difference of −23.8 and −20.0 events per hour in patients who were or were not receiving concomitant CPAP therapy, respectively. Notably, these improvements were accompanied by a significant decrease (17.7% to 19.6%) in body weight in patients who received tirzepatide, compared with placebo (1.6% to 2.3%).
The bidirectional obesity-OSA relationship
The prevalence of obesity is increasing globally, with more than 40% of adults and nearly 20% of children in the United States reported to have obesity.3–5 Clinicians are tasked with a truly Sisyphean endeavor—tackling this growing epidemic of obesity and associated complications. A significant comorbidity of obesity is OSA, with 60% to 70% of individuals with obesity developing the sleep disorder.
“Obesity and sleep problems and apnea are closely interrelated, and this relationship is bidirectional,” said Rizwana Sultana, MD, Pediatric Sleep Medicine Specialist, Division of Pulmonary Critical Care and Sleep Medicine at the University of Texas Medical Branch. “We do know that the initiating step is a physiological process driven by slowed metabolism, concomitant with lower activity, due to different factors, leading to weight gain, which then affects sleep.”
She added, “Once people develop sleep apnea, the resulting difficulty staying asleep and daytime sleepiness can trigger abnormalities in leptin and ghrelin—hormones that regulate hunger, energy balance, and food intake. Sleep deprivation is associated with higher levels of ghrelin, the hunger/appetite regulator, causing increased food intake, especially calorie-dense food, particularly at night. The increased food intake, coupled with other lifestyle factors, can in turn lead to further weight gain, which exacerbates sleep disturbances.”
Dr. Malhotra characterized the obesity-OSA relationship as complex, stating, “The interconnectedness between obesity and OSA is not fully understood, and although there certainly are mechanical effects, there are other effects, such as how the body controls breathing. In addition, the dilator muscles in the upper airway that are important for maintaining airway patency may be affected in people with sleep apnea plus obesity, compared [with] people with obesity alone.”
Tackling obesity to treat OSA
There has been a significant shift in the clinical approach to obesity, with clinicians considering multimodal and multidisciplinary management of this serious disease, Dr. Sultana said. There must be a similar shift in perception among patients, she added. The stigma associated with obesity and the multifactorial barriers to lifestyle modification-mediated weight loss are the biggest challenges in managing obesity and complications like obesity-related OSA.
“Until recently, we were focusing on asking the patient to change their lifestyle and eat healthier. In my opinion, we must treat obesity as a disease, akin to how we treat other conditions,” Dr. Sultana said. “For instance, while a low-salt diet is a key principle for managing hypertension, clinicians consider and use other components, including medication, to ensure that the patient meets their blood pressure goals.”
Significant reliance on the patient’s ability to implement and sustain a range of lifestyle modifications may set some patients up for failure, she noted, as systemic factors and circumstances beyond their control may impede or limit the patient’s progress on their weight-loss journey.
Practice implications for treating OSA
The approval of tirzepatide for OSA comes at a time when GLP-1 receptor agonists, especially semaglutide, have already captured significant public attention, resulting in intermittent shortages of this class of medications. The good news is that the FDA formally reported resolution of these shortages in late 2024, though many clinicians report that the drug is still difficult to obtain.6
“Obesity is the mother of all diseases,” Dr. Sultana said. “Once we start treating obesity, it is easier for people to lose weight, which can improve not just their OSA but allow for opportunities to improve their overall health. Using anti-obesity medications is a game changer, not only for diabetes and obesity but also for treating obesity-associated OSA and comorbidities. I am a big advocate of obesity-targeted treatments, including GLP-1 medications and bariatric surgery.”
Dr. Sultana acknowledged that clinicians and their patients need to be aware of the side effects. She added that GLP-1 medications may not be appropriate for every patient.
Dr. Malhotra framed the practice implications, stating, “The standard of care has not changed. The first-line treatment for sleep apnea is CPAP. The standard of care in OSA management has always been to address both obesity and sleep apnea, rather than either one alone; and, we now have more effective treatments for obesity, which could be coupled with treatment of sleep apnea to optimize results. While diet, exercise, and lifestyle modifications have been core components of OSA management in patients with obesity, these approaches are not always effective or sustained in the long term. This is an exciting time.”
The next phase
The story of novel obesity medications in OSA is still unfolding. The phase 3 SURMOUNT-MMO study is evaluating the impact of tirzepatide on long-term outcomes in adults with obesity.9 Additional randomized studies are needed to clarify the GLP-1 receptor agonist medications in the comanagement of obesity, OSA, and cardiovascular complications.
Dr. Sultana expressed confidence and optimism about the emerging role of medications in managing obesity and OSA, noting, “Sleep medicine is a multidisciplinary field. Physicians are now able to utilize this medication as part of their patient management.”
References
1. FDA Press Release. FDA Approves First Medication for Obstructive Sleep Apnea. FDA. December 27, 2024. Accessed December 30, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-obstructive-sleep-apnea
2. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391(13):1193-1205. doi:10.1056/NEJMoa2404881
3. CDC. New CDC Data Show Adult Obesity Prevalence Remains High. CDC Newsroom. November 1, 2024. Accessed December 30, 2024. https://www.cdc.gov/media/releases/2024/p0912-adult-obesity.html
4. WHO. Obesity and overweight. WHO Newsroom. March 1, 2024. Accessed December 30, 2024. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
5. CDC. Childhood Obesity Facts. Obesity. December 20, 2024. Accessed December 30, 2024.
6. Pagliarulo N. Zepbound, Mounjaro shortages are resolved, FDA confirms. BioPharma Dive. December 19, 2024. Accessed December 30, 2024. https://www.biopharmadive.com/news/fda-tirzepatide-shortage-resolved-lilly-zepbound-compounding/736020/
7. Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (Lond). 2016;40(8):1310-1319. doi:10.1038/ijo.2016.52
8. Li M, Lin H, Yang Q, et al. Glucagon-like peptide-1 receptor agonists for the treatment of obstructive sleep apnea: a meta-analysis. Sleep. Published online November 29, 2024. doi:10.1093/sleep/zsae280
9. Eli Lilly and Company. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Effect of Tirzepatide on the Reduction of Morbidity and Mortality in Adults With Obesity. clinicaltrials.gov. 2024. Accessed December 31, 2024. https://clinicaltrials.gov/study/NCT05556512