OSA is increasingly recognized as a heterogeneous syndrome driven by distinct underlying pathophysiologic mechanisms known as endotypes. Traditional frameworks have emphasized impaired upper airway anatomy; however, this approach fails to capture the diversity in pathophysiology and treatment response observed across patients.1 OSA is now understood to reflect varying contributions from anatomical vulnerability (upper airway collapsibility) and nonanatomical traits, including ventilatory control instability (high loop gain), low arousal threshold, and impaired pharyngeal dilator muscle responsiveness.2 As these mechanisms are increasingly being derived from polysomnography (PSG), there is growing interest in precision sleep medicine: selecting therapies based on an individual’s underlying pathophysiology rather than relying on a uniform approach.3
Endotypic traits frequently coexist in varying combinations, explaining why patients with similar apnea-hypopnea index (AHI) values may differ substantially in symptoms and treatment response. Importantly, advances in PSG signal processing now allow estimation of patient-specific pathophysiology, expanding therapeutic targets beyond upper airway anatomy.4 Emerging pharmacotherapies are therefore being developed to enhance pharyngeal dilator muscle activity, stabilize ventilatory control, and modulate arousal threshold.
Upper airway collapsibility remains the most prevalent contributor to OSA, influenced by obesity-related peripharyngeal fat deposition, craniofacial structure, soft tissue enlargement, and fluid shifts. Accordingly, pharmacologic strategies have targeted this endotype indirectly through weight reduction, fluid management, and improvement in nasal patency.5 The most notable recent advance is in antiobesity therapy. In the SURMOUNT-OSA trial, tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, reduced AHI by approximately 50% at 52 weeks in adults with moderate to severe OSA and obesity, alongside improvements in weight, hypoxic burden, BP, and patient-reported outcomes.6 This led to its regulatory approval as the first pharmacologic therapy indicated for OSA in this population, to be used adjunctively with lifestyle interventions.
A low arousal threshold contributes to OSA by promoting premature awakening before sufficient ventilatory drive accumulates to restore airway patency. Sleep-promoting agents, such as eszopiclone, zolpidem, trazodone, triazolam, and sodium oxybate, have been studied to raise the arousal threshold, stabilize sleep, and permit airway reopening before arousals occur. Results have been variable, with generally modest effects that must be balanced against potential risks, including worsened hypoxemia and residual sedation.7 Accordingly, hypnotics are not recommended as monotherapy, though they may have a role as adjunctive therapy in selected patients.
Impaired activation of pharyngeal dilator muscles during sleep represents a key neuromuscular mechanism in OSA. Withdrawal of noradrenergic drive during nonrapid eye movement (NREM) sleep, further reduced during rapid eye movement (REM) sleep, along with increased muscarinic inhibition in REM sleep, plays a central role in suppressing dilator muscle activity.8 AD109, an investigational oral neuromuscular modulator combining atomoxetine (a noradrenergic agent) and aroxybutynin (an antimuscarinic), targets these pathways to enhance genioglossus activity and upper airway stability. The antimuscarinic component may also help mitigate noradrenergic-induced sleep disruption. In phase 3 trials, AD109 reduced the AHI by approximately 45% at week 26, with sustained effects through week 51.9 It was generally well-tolerated, with predominantly mild to moderate adverse events (eg, insomnia, dry mouth, dizziness, palpitations, nausea). A new drug application is anticipated for regulatory approval, positioning AD109 as a potential first-in-class therapy targeting neuromuscular dysfunction in OSA.
High loop gain describes an oversensitive ventilatory control system that generates exaggerated compensatory responses to respiratory disturbances. This can lead to hyperventilation, lowering arterial CO₂ below the apneic threshold, reducing ventilatory drive and predisposing to recurrent obstruction.1 Carbonic anhydrase inhibitors, such as acetazolamide and sultiame, have been shown to reduce loop gain and improve OSA severity by approximately 30% to 40%.10 Interestingly, noradrenergic agents, including atomoxetine, may also exert modest stabilizing effects on ventilatory control.11 The current evidence for these pharmacologic approaches remains limited and in early stages of development.
Given the multifactorial nature of OSA, combination pharmacotherapy targeting multiple endotypes is a logical next step. AD109 is one such example. Also demonstrating encouraging results are early-phase trials of other combination approaches, including atomoxetine with the serotonin 2A receptor inverse agonist-antagonist pimavanserin and acetazolamide with dronabinol.12 The former targets pharyngeal dilator muscle responsiveness and arousal threshold, whereas the latter targets muscle responsiveness and ventilatory control instability.
Sleep medicine is entering a promising era in which individualized, endotype-driven therapy is increasingly feasible. However, important barriers remain. Endotyping has not yet been translated into clinical practice, therapeutic thresholds are not fully defined, and long-term outcomes including cardiovascular end points require further investigation. PAP will likely remain the foundational therapy. Nevertheless, precision pharmacotherapy may expand options, particularly for individuals who are intolerant of or unwilling to use conventional treatments. Future efforts should focus on quantifying the relative contributions of individual pathophysiologic endotypes to guide treatment selection and on defining the risk-benefit profile of long-term pharmacotherapy, ensuring that sustained therapeutic gains outweigh potential adverse effects.
References
1. Raphelson JR, Fuentes AL, Holloway B, Malhotra A. Obstructive sleep apnea endophenotypes. Sleep Sci. 2024;18(1):e109-e113. doi:10.1055/s-0044-1788287
2. Edwards BA, Landry SA, Thomson LDJ, Joosten SA. Sleep apnea endotypes and their implications for clinical practise. Sleep Med. 2025;126:260-266. doi:10.1016/j.sleep.2024.12.021
3. Tolbert TM, Schmickl CN, Gell LK, et al. Research priorities for translating endophenotyping of adult obstructive sleep apnea to the clinic: an official American Thoracic Society research statement. Am J Respir Crit Care Med. 2025;211(9):1562-1583. doi:10.1164/rccm.202507-1574ST
4. Eckert DJ, Eckert DJ. Developments in pharmacotherapy for obstructive sleep apnoea: unlocking the potential for targeted treatment. Drugs. 2026;86(2):143-159. doi:10.1007/s40265-025-02268-9
5. Taranto-Montemurro L, Messineo L, Wellman A. Targeting endotypic traits with medications for the pharmacological treatment of obstructive sleep apnea: a review of the current literature. J Clin Med. 2019;8(11):1846. doi:10.3390/jcm8111846
6. 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
7. Messineo L, Sands SA, Labarca G. Hypnotics on obstructive sleep apnea severity and endotypes: a systematic review and meta-analysis. Am J Respir Crit Care Med. 2024;210(12):1461-1474. doi:10.1164/rccm.202403-0501OC
8. Grace KP, Hughes SW, Horner RL. Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am J Respir Crit Care Med. 2013;187(3):311-319. doi:10.1164/rccm.201209-1654OC
9. Patel S, Farkas R, Taranto L, Cronin JW, Strollo PJ. The LUNAIRO trial: a 51-week phase 3, randomized, double-blind, placebo-controlled study of aroxybutynin and atomoxetine (AD109) in obstructive sleep apnea. Chest. 2025;168(4):A7249-A7250. doi:10.1016/j.chest.2025.09.074
10. Randerath W, Grote L, Stenlöf K, et al. Sultiame once per day in obstructive sleep apnoea (FLOW): a multicentre, randomised, double-blind, placebo-controlled, dose-finding, phase 2 trial. Lancet. 2025;406(10514):1983-1992. doi:10.1016/S0140-6736(25)01196-1
11. Taranto-Montemurro L, Messineo L, Azarbarzin A, et al. Effects of the combination of atomoxetine and oxybutynin on OSA endotypic traits. Chest. 2020;157(6):1626-1636. doi:10.1016/j.chest.2020.01.012
12. Messineo L, Preuss M, Azarbarzin A, et al. Effects of the combination of pimavanserin and atomoxetine on OSA severity: a randomized crossover trial. Chest. 2025;168(1):223-235. doi:10.1016/j.chest.2025.03.013
13. Thomson LDJ, Landry SA, Maddison K, et al. The impact of acetazolamide and dronabinol on the physiological endotypes responsible for obstructive sleep apnea. Sleep Med. 2025;132:106542. doi:10.1016/j.sleep.2025.106542
