OSA Treatment Beyond CPAP: Tirzepatide, Phenotyping, and What's Next, With Ashesha Mechineni, MD

CPAP is no longer the only answer for obstructive sleep apnea (OSA), and for practicing clinicians, that shift is already reshaping patient conversations. Tirzepatide has an OSA indication, hypoglossal nerve stimulation is reaching more patients, and an investigational once-nightly oral pill targeting the neuromuscular root cause of airway collapse has an NDA under FDA review.

Ashesha Mechineni, MD, of the University of Illinois Chicago, took stock of where the field stands at SLEEP 2026 and what it means for clinicians managing OSA in patients with obesity. She framed the moment as one of meaningful clinical expansion, with individualized patient phenotyping now driving treatment selection in ways CPAP-era practice did not require. The shift toward a multidisciplinary, whole-health model reflects both the heterogeneity of OSA pathophysiology and the recognition that weight, cardiovascular risk, mental health, and sleep are intertwined targets that rarely respond to single-axis intervention.

For primary care physicians managing patients with obesity and OSA, the evolving toolkit creates both new options and new responsibilities: identifying which patients are most likely to benefit from each approach, and ensuring treatment is not siloed from the broader metabolic and behavioral picture.

Tirzepatide's Dual Role in OSA and Obesity: Phenotype-Driven Patient Selection

Tirzepatide (Zepbound) received US Food and Drug Administration (FDA) approval in 2024 for moderate-to-severe OSA in adults with obesity, becoming the first pharmacologic agent with a dedicated OSA indication.² For sleep physicians, Mechineni described the drug's value as both direct and indirect: in patients whose OSA is predominantly weight-driven, tirzepatide addresses the root cause of airway compromise and produces meaningful symptom relief. In patients with OSA driven by other anatomical or neuromuscular factors, weight reduction still contributes benefit without resolving the condition entirely.

"If weight is their biggest problem and we're using this tool, they feel better and it's a success," Mechineni said. "But if weight is not the biggest problem, it still helps, but not to the point they're completely treated."

The addition of tirzepatide has nonetheless expanded the available option set in ways Mechineni described as clinically significant, particularly for patients who had reached a therapeutic dead end with existing tools.

Patient phenotyping and endotyping now inform which intervention is most likely to succeed for a given individual. OSA presentation differs substantially by sex: men more commonly present with loud snoring and daytime sleepiness, while women more often report fatigue, poor sleep quality, and non-restorative sleep. These differences mean symptom-based clinical suspicion calibrated primarily to male presentation may miss a substantial proportion of affected women.¹

Mechineni emphasized true multidisciplinary management means addressing activity, nutrition, and mental health alongside pharmacotherapy, not treating pharmacology as a substitute for comprehensive care.

AD109 and the Expanding OSA Treatment Pipeline Beyond CPAP, Tirzepatide

Beyond tirzepatide, Mechineni pointed to an investigational oral agent advancing through the regulatory process as a next development in OSA pharmacotherapy. AD109 combines aroxybutynin (2.5 mg), an antimuscarinic, with atomoxetine (75 mg), a selective norepinephrine reuptake inhibitor, and is taken once nightly at bedtime. Its mechanism targets the root cause of OSA by increasing upper airway muscle tone during sleep, reducing the airway collapsibility that drives obstructive events.

In the phase 3 SynAIRgy trial, participants treated with AD109 achieved a mean reduction in AHI of 55.6% from baseline, meeting the primary endpoint with statistical significance (P = .001) at 26 weeks across patients with mild, moderate, and severe OSA. An NDA for AD109 was submitted to the FDA in May 2026.

The most common adverse events in SynAIRgy were dry mouth, nausea, insomnia, and urinary hesitation, with 21% of AD109-treated participants and 3% of placebo-treated participants discontinuing by week 26 due to adverse events. AD109 treatment was also associated with a 1.4 mmHg increase in blood pressure and a 3.6 beats per minute increase in heart rate compared with placebo.

Mechineni's broader message at SLEEP 2026 was that OSA is no longer a single-treatment condition, and the clinicians best positioned to serve patients with it are those approaching care from a 360-degree health standpoint — addressing sleep, weight, cardiovascular risk, and behavioral health as a unified problem rather than parallel ones.

References

1. Mechineni A. Integrated Management of Obesity in Obstructive Sleep Apnea: Case-Based Perspectives. Presented at: SLEEP 2026; June 2026.

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. Strollo PJ, Patel SR, Taranto-Montemurro L, et al. Aroxybutynin and atomoxetine (AD109) for obstructive sleep apnea: a randomized phase 3 trial. Am J Respir Crit Care Med. 2026. doi:10.1164/rccm.202502-0459OC