Tirzepatide and Emerging OSA Pharmacotherapy Expand the Treatment Toolkit, With Ashesha Mechineni, MD

The December 2024 US Food and Drug Adminstration (FDA) approval of tirzepatide (Zepbound; Eli Lilly) for moderate-to-severe obstructive sleep apnea (OSA) in adults with obesity marked the first time a pharmacological agent received regulatory clearance for this indication, fundamentally shifting how sleep specialists conceptualize OSA management.¹

The FDA based its decision on the phase 3 SURMOUNT-OSA clinical trials, which ere 2 randomized, placebo-controlled 52-week studies enrolling adults with moderate-to-severe OSA and obesity. Across both studies, tirzepatide produced significant reductions in the apnea-hypopnea index, hypoxic burden, systolic blood pressure, and high-sensitivity C-reactive protein compared with placebo.¹

Recognizing OSA as a heterogeneous disease has added nuance to how practitioners select among available tools. Phenotyping and endotyping now inform clinical decision-making: weight-driven pathophysiology is only one contributor to OSA, and the degree to which tirzepatide improves outcomes corresponds to how centrally obesity drives disease severity in individual patients.

Beyond tirzepatide and hypoglossal nerve stimulation, the pipeline is expanding further. AD109 (Apnimed), a fixed-dose once-nightly oral combination of aroxybutynin 2.5 mg and atomoxetine 75 mg, is under FDA review following positive primary endpoints in 2 pivotal phase 3 trials, SynAIRgy and LunAIRo, with its neuromuscular mechanism targeting upper airway muscle tone during sleep rather than weight reduction.²

Ashesha Mechineni, MD, FSCP, clinical assistant professor of medicine at the University of Illinois Chicago, spoke with Patient Care Online at SLEEP 2026 in Baltimore about how tirzepatide fits within a multidisciplinary OSA framework, how disease phenotyping shapes treatment selection, and what the emerging pharmacotherapy pipeline means for specialists managing this population.

Q&A:

PCO: What does an ideal multidisciplinary approach to managing obesity and OSA look like in 2026?

Ashesha Mechineni, MD: The FDA approval of tirzepatide for OSA — based on the SURMOUNT-OSA trials — has brought a lot of focus to sleep clinics over the past year. The trials showed significant weight loss in these patients, which ultimately reduced disease severity and improved outcomes and symptoms. So we started using tirzepatide as one of the tools to treat OSA patients. It serves a dual role, with expected benefit in both directions — weight management for obesity and symptom improvement from a sleep standpoint. When we have multiple tools for OSA, we have to recognize these patients are very varied. Their phenotyping and endotyping determines how much weight contributes to their problem. If weight is their biggest problem and we use this tool, they feel better — it's a success. But if weight is not the biggest problem, it still helps, though not to the point of complete treatment. Having an additional option has helped us move patients to a different health endpoint where subjectively they feel much better. If you are talking about multidisciplinary care more broadly, I think we need to approach patient care from a comprehensive 360-degree health standpoint. It is not just medications — we are also counseling patients about activity, mental health, and nutrition, and all of these things add up to improve whole health, not just sleep.

PCO: How has the emergence of effective obesity therapies changed the conversation around OSA management and CPAP's role?

Mechineni: Over the past few years there has been more focus among sleep clinicians, with new research helping us identify that not all sleep apnea patients are the same. Everyone has their own significant pathophysiology, which changes what their sleep apnea looks like. A clear example is how sleep apnea presents very differently in men and women. In men, it tends to be loud snoring and sleepiness. In women, it is more tiredness and not sleeping well. Identifying these different presentations has helped us realize CPAP is not the answer in every case. Different patients may respond to different treatments. We now have tirzepatide to offer some patients, hypoglossal nerve stimulation for others, and there is a new drug potentially coming in the upcoming months — so having more options helps us take care of patients in a more well-rounded way.

PCO: Can you speak more to that new treatment coming down the pipeline?

Mechineni: There is a new treatment still in the investigational stage — it has not been approved yet — but it is a medical treatment for sleep apnea taken in pill form as a once-daily formulation. The mechanism of action involves acting on receptors, changing muscle activation, holding the upper airway open, and reducing the collapsibility of the upper airway, which is what we see in OSA. We are all hoping it gets approved soon, so there will be another targeted pharmacological option available for our patients.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. Malhotra A, et al. Tirzepatide for obstructive sleep apnea and obesity. N Engl J Med. 2024. doi:10.1056/NEJMoa2404881

2. Apnimed, Inc. Apnimed reports positive topline results from second phase 3 trial of AD109, reinforcing potential of first oral pill for obstructive sleep apnea. Published July 23, 2025. Accessed June 25, 2026. https://apnimed.com/article/ad109toplinephase3results/