As CPAP challenges persist, sleep specialists turn to endotyping and alternative therapies to personalize OSA care.

By Lindsey Nolen

CPAP remains the gold standard for obstructive sleep apnea (OSA) therapy and is the most commonly prescribed first-line therapy for newly diagnosed patients. After all, “it’s effective for almost everybody, starts to work straight away, and shows strong evidence of improving people’s symptoms and quality of life,” notes sleep specialist Robert Adams, MD, FAASM, MBBS. 

But, due to the ongoing challenge of CPAP adherence, the shortage of positive airway pressure devices in 2022 and 2023 after the Philips Respironics recall, and advances in endotyping, the landscape of OSA treatment is evolving. There is a growing emphasis on personalized medicine and alternative therapies. Oral appliances in particular have a growing evidence base, particularly for mild to moderate OSA.

Endotyping for Personalized OSA Therapies

“With CPAP, the concern has always been how to improve adherence. With oral appliance therapy, the concern has always been efficacy,” says Len Liptak, co-founder and CEO of oral appliance maker ProSomnus. “Developments in endotyping help address the efficacy concern about oral appliance therapy.”

Adams, a professor of respiratory and sleep medicine at Flinders University and medical director at the Adelaide Institute for Sleep Health at Flinders Health and Medical Research Institute, explains, “Although everyone with sleep apnea has some degree of narrowing or compromise of their upper airway, up to half have other significant physiological abnormalities that are contributing to the problem. These include impaired upper airway dilator muscle responsiveness, low arousal threshold (which lets people wake up too easily to relatively minor airway narrowing), and high loop gain or unstable breathing regulation.

“The ability to identify these from standard sleep studies using algorithms developed by some of the Flinders sleep team (and elsewhere) opens up the possibility of therapy directed at one or more of the known anatomical mechanistic endotypes. This includes algorithms that identify people who are more likely to respond to oral appliance therapy.”

Adams and co-investigators have done studies to show that oral appliances can be used as first-line therapy for some patients and can be combined with other treatments, such as positional therapy (to avoid the supine sleep position), for most.

Stepwise Therapy Trial at Flinders

A recent study by Flinders University researchers involved 23 people who started OSA therapy with oral appliances but had an incomplete response (an apnea-hypopnea index still above 10). The researchers characterized each participant’s OSA endotype through physiological testing.1

The researchers deployed a stepwise approach of adding therapies targeting the individual’s specific endotype characteristics. First, an expiratory positive airway pressure (EPAP) valve and supine avoidance device addressed anatomical issues. For those who still experienced OSA, additional interventions included oxygen to reduce unstable respiratory control and atomoxetine-oxybutynin to increase pharyngeal muscle tone. If still needed, CPAP was finally added and combined with oral appliance therapy.1

The results revealed that OSA was controlled in 19 of the 20 participants. Seventeen achieved control without needing CPAP. What’s more, oral appliance therapy plus EPAP/positional therapy resolved OSA in half of the participants. Additional oxygen helped 25%, while medications aided others, with only two ultimately requiring CPAP.1

“The trial was in a relatively small number and would need to be reproduced in larger trials to see if it was truly effective across the whole potential population of people who need therapy for their sleep apnea,” Adams says, “but the results are very promising.”

Benefits and Challenges of Precision OSA Therapy

The Flinders University findings helped demonstrate the potential benefits of using precision medicine to personalize OSA therapy based on endotyping rather than using a one-size-fits-all approach. By combining multiple targeted treatments, physicians can better address the diverse pathophysiological causes behind each patient’s OSA.

For physicians, the precision medicine model also represents a transition in sleep medicine. It requires an overhaul of how patients with OSA are evaluated, from endotyping methods to prescribing customized multi-therapy treatment plans.

But most sleep specialists still rely on measures of OSA severity, such as the apnea-hypopnea index (AHI), to determine whether to recommend patients for oral appliances, giving oral appliance preferences to patients with lower AHIs. “Second most common is probably the site of pharyngeal collapse, as determined from a drug-induced sleep endoscopy,” says Daniel P. Vena, PhD, an investigator in the division of Sleep and Circadian Disorders at Brigham and Women’s Hospital. “However, it is probably still very uncommon for a patient to have undergone a sleep endoscopy prior to getting an oral appliance.”

Endotyping for traits such as loop gain and arousal threshold “is still not available clinically,” says Vena, who has published a paper on the pathophysiology underlying determinants of sleep apnea severity.2 “It is possible that some very savvy sleep doctors look at the sleep study to estimate if a patient has a ‘low arousal threshold’ or ‘high loop gain’—both traits that would predict a poor [oral appliance] response. But unlikely this is widespread to a meaningful degree.” 

Adams points out that monitoring response to therapy can also be challenging. But advances in home monitoring also mean researchers can identify who’s doing well or not more easily. 

Managing Oral Appliances Challenges

Even when patients respond to oral appliance therapy for OSA, the therapy modality is not immune to adherence challenges. 

Jennifer Q. Le, DMD, DABDSM, CPCC, a dentist at Wake Dental Sleep in Raleigh, NC, says, “One primary reason patients may discontinue use of oral appliance therapy is discomfort or pain of the jaw, teeth, or temporomandibular joint…The benefits of oral appliance therapy can sometimes take longer to become evident; this delay may cause some patients to doubt the effectiveness of [oral appliance therapy].”

To increase oral appliance adherence, Le recommends “a custom fit oral appliance that is fitted to the patient to minimize the discomfort and introduce the appliance gradually, allowing the patient to get used to wearing it for longer periods. Schedule regular follow-up appointments to assess the fit of the appliance and monitor patient progress. This helps to alleviate discomforts before they get to a part of discontinuance.” 

Also, unlike CPAP and other therapies with built-in adherence monitoring, when patients use oral appliances, sleep physicians currently “have to judge adherence based on what the patient tells them and treatment satisfaction subjectively,” Vena says. 

Technology is likely to bridge this gap soon. ProSomnus and Achaemenid LLC seek to commercialize embedded intraoral sensors.

Choosing First-Line Sleep Apnea Therapy

CPAP remains first-line therapy for good reasons, says Adams. But for mild/moderate cases and for people who find CPAP difficult to tolerate, he says an oral appliance can be “a very effective, well-tolerated, and convenient therapy for their sleep apnea.”

The rise of endotyping and combination therapies could expand the role of oral appliances and other non-CPAP therapies for OSA. Precision OSA medicine has the potential to revolutionize management for physicians and patients by enhancing efficacy, adherence, and patient-centered care.

“It’s very important to recognize that alternatives to CPAP devices do exist and that clinicians and patients shouldn’t give up at the first hurdle if initial management is difficult,” Adams says. “It’s important that oral devices are managed by dentists trained and experienced in their use and that there is ongoing monitoring by a dentist to manage any problems or complications and to allow for adjustments that might be needed over time to ensure continued effectiveness.”


1. Aishah A, Tong BKY, Osman AM, et al. Stepwise add-on and endotype-informed targeted combination therapy to treat obstructive sleep apnea: a proof-of-concept study. Ann Am Thorac Soc. 2023;20(9):1316-25. 

2. Sands SA, Alex RM, Mann D, et al. Pathophysiology underlying demographic and obesity determinants of sleep apnea severity. Ann Am Thorac Soc. 2023 Mar;20(3):440-9.

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