New Approaches to Treating Obstructive Sleep Apnea Today

Obstructive sleep apnea (OSA) is a prevalent chronic sleep-related breathing disorder, affecting approximately 13% of men and 6% of women aged 30–70 in the U.S. [1]. It is characterized by recurrent episodes of upper airway obstruction during sleep, resulting in apneas or hypopneas that lead to intermittent hypoxemia, sleep fragmentation, and recurrent arousals. OSA has been associated with excessive daytime sleepiness, cognitive impairment, mood disturbance, and reduced quality of life, as well as an increased risk of hypertension, cardiovascular events, type 2 diabetes, and all-cause mortality [2,3,4]. Given its chronic nature and potential serious health consequences, effective and sustainable long-term management therapies are essential.

Continuous positive airway pressure (CPAP) remains the first-line therapy for OSA. When used consistently, CPAP acts by splinting the upper airway and preventing its collapse, thereby improving daytime sleepiness, neurocognitive performance, and blood pressure regulation [5,6]. In patients with severe OSA, effective CPAP treatment has been shown to reduce the risk of cardiovascular events; however, its real-world effectiveness is often limited by suboptimal adherence to therapy. Studies indicate that approximately 25–50% of patients discontinue CPAP therapy within the first year, and even among those who continue, the average nightly use frequently falls below the recommended duration of 4 h per night [7,8]. Overall, between 46% and 83% of OSA patients are considered non-adherent to CPAP therapy [9]. In the SAVE trial, the mean CPAP use among participants with cardiovascular disease was approximately three h per night [6]. Despite these adherence challenges, when CPAP is utilized diligently, it effectively normalizes the AHI, alleviates symptoms, improves quality of life, and may reduce cardiovascular risk in patients with severe OSA [4,6].

This persistent challenge with adherence leaves a substantial proportion of patients either untreated or inadequately managed. Given that OSA is a chronic condition necessitating lifelong therapy, many individuals ultimately fail or discontinue CPAP therapy, prompting the need for alternative treatment options. Over the past decade, significant advancements have emerged across multiple domains, including oral appliance therapy, innovative surgical and neurostimulation approaches, daytime training interventions, positional therapy, and novel pharmacologic strategies targeting OSA pathophysiology (Table 1).

This review provides a comprehensive and up-to-date analysis of recent progress in OSA management. We first address the current status and limitations of positive airway pressure (PAP) therapy, followed by an appraisal of evidence supporting mandibular advancement devices (MADs), surgical interventions, neuromuscular electrical stimulation therapies, and novel modalities such as tongue-base cryotherapy and positional devices. Additionally, we evaluate emerging pharmacotherapies ranging from sedative agents designed to raise the arousal threshold to carbonic anhydrase inhibitors aimed at lowering ventilatory loop gain, as well as metabolic treatments addressing obesity. Throughout this review, we compare efficacy data from pivotal randomized controlled trials, examine adherence and tolerability considerations, and identify persisting gaps in evidence. Collectively, these developments reflect a broader shift in OSA management from a historically CPAP-centric model toward a more personalized, multimodal framework aligned with underlying pathophysiology. Contemporary clinical practice guidelines and systematic reviews increasingly recognize oral appliances, hypoglossal nerve stimulation, surgical interventions, positional therapy, and pharmacologic strategies as complementary components of OSA management in appropriately selected patients, rather than simply alternatives reserved for CPAP failure [10,11,12]. Moreover, advances in endotype characterization, including the roles of upper-airway anatomy, ventilatory loop gain, and arousal threshold, have provided a mechanistic basis for phenotype-guided therapy selection [13,14]. Together, these developments support a precision-based approach in which treatment is matched to dominant pathophysiologic contributors rather than relying exclusively on positive airway pressure therapy. Future research directions and clinical recommendations are discussed to enhance long-term treatment adherence and optimize patient outcomes.

Mandibular advancement devices are custom-fitted oral appliances designed to advance the mandible during sleep, thereby enlarging and stabilizing the upper airway. By anteriorly displacing the retroglossal and retropalatal airway caliber and subsequently reducing the propensity of upper airway collapse (Figure 1). MADs are typically indicated for patients with mild to moderate OSA or for those who are unable to tolerate CPAP therapy. Over the past two decades, they have become an established second-line treatment supported by substantial clinical and physiological evidence (Table 2).

During sleep, MADs advance the mandible to approximately 50–75% of the individual’s maximal protrusion, and some designs include components that simultaneously advance the tongue [24]. This anterior traction of the tongue and hyoid musculature enlarges the pharyngeal airway [24]. By repositioning the jaw forward, MADs also tense the soft tissues attached to the mandible, including the tongue, palatal muscles, and lateral pharyngeal walls [25]. This results in an enlarged retroglossal airway space, with reduced collapsibility during sleep. Imaging and endoscopic studies demonstrate increased velopharyngeal cross-sectional area and reduced pharyngeal compliance with a MAD in place [26].

In contrast to CPAP, which pneumatically splints the airway open, MADs act by mechanically and anatomically modifying upper airway geometry during sleep. Therapeutic response varies depending on craniofacial structure and site of obstruction. MADs are generally most effective in patients with positional OSA or retrognathia with tongue base collapse [27,28,29]. Contemporary devices are titratable, allowing gradual mandibular advancement to optimize efficacy while minimizing jaw discomfort. Additionally, many patients and bed partners report improved comfort and satisfaction with MADs compared with CPAP, owing to the absence of noise, tubing, and facial masks, as well as greater portability for travel [30].

Across the literature, clinical trials have consistently demonstrated that MAD therapy significantly reduces the severity of OSA compared with placebo or non-advancing devices, and, in many cases, approaches the effectiveness of CPAP for mild to moderate disease [31,32]. While CPAP remains superior in its ability to reduce the AHI across all severities, MAD therapy frequently produces clinically meaningful improvements and achieves comparable symptom relief [33,34,35,36].

Across controlled trials comparing MAD with CPAP, CPAP consistently achieved greater improvement in objective respiratory indices, with MAD associated with higher residual AHI or ODI (MAD − CPAP differences ranging approximately +6 to +9 events/h for AHI and −11.4 events/h for ODI when reported as CPAP superiority). In contrast, subjective sleepiness outcomes were broadly similar between therapies, with small and inconsistent differences in ESS.

Across placebo-controlled trials, MAD demonstrated clear absolute efficacy beyond placebo, reducing AHI relative to sham by approximately 6–13 events/h across follow-up intervals ranging from 1 week to 3 months, and producing modest improvements in sleepiness where reported. Collectively, these findings support MAD as an effective therapy compared with sham while reinforcing that CPAP remains more physiologically efficacious for normalizing objective OSA severity measures. Beyond improvements in AHI and symptoms, recent studies have examined whether MADs provide cardiovascular benefits similar to those of CPAP. An RCT involving 220 hypertensive patients with OSA comparing MAD and CPAP therapy over a period of 6 months revealed that MAD therapy reduced 24 h mean arterial pressure by 2.5 mmHg, versus no change with CPAP, and the between-group difference met the predefined noninferiority margin, establishing MAD as noninferior to CPAP for blood pressure reduction [39,40]. These findings suggest that, in properly selected patients, MAD therapy may not only alleviate OSA symptoms but also favorably impact cardiovascular risk factors, such as blood pressure. That said, CPAP remains more consistently effective for severe OSA or in patients with minimal mandibular protrusive capacity [11].

When adherence to therapy is accounted for, studies have shown that short-term health outcomes at one month of optimal therapy were comparable between groups [36]. Notably, MAD users also reported greater improvement in some general vitality domains of quality of life, suggesting that CPAP’s superior physiologic efficacy can be offset by its lower adherence relative to MAD, leading to similar overall treatment effectiveness in patients with mild to moderate OSA [36,41].

A central clinical challenge in obstructive sleep apnea management is balancing maximal physiologic efficacy with long-term treatment adherence, a tension most clearly illustrated by the comparison between continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) [10]. CPAP reliably produces the largest reductions in apnea–hypopnea index (AHI) across all severity strata and remains the most effective therapy for normalizing upper airway obstruction when used consistently [9]. However, long-term adherence to CPAP is frequently suboptimal, with a substantial proportion of patients using therapy for insufficient duration or discontinuing treatment altogether, thereby attenuating real-world effectiveness [9].

In contrast, MADs typically achieve smaller per-night reductions in AHI compared with CPAP, particularly in moderate-to-severe disease [36]. Despite this lower physiologic efficacy, MADs often demonstrate higher nightly use and long-term persistence, resulting in comparable improvements in patient-reported outcomes such as daytime sleepiness and quality of life in patients with mild-to-moderate OSA [24,36]. This apparent paradox: lower physiologic efficacy but similar clinical benefit, reflects the importance of adherence as a determinant of treatment effectiveness. When adherence is incorporated into outcome assessment, the cumulative therapeutic exposure of MAD therapy may approximate or exceed that of inconsistently used CPAP [42]. For many patients, particularly those with mild-to-moderate OSA, a slightly less efficacious but well-tolerated therapy may yield superior long-term outcomes compared with a highly efficacious therapy that is poorly adhered to.

From a precision-medicine perspective, the choice between CPAP and MAD should therefore be individualized, taking into account disease severity, anatomic predictors of MAD response, patient preference, and likelihood of sustained adherence. Phenotypic characteristics can determine the efficacy of MAD therapy to some extent, as shown by drug-induced sleep endoscopy (DISE) studies, suggesting that patients with predominantly retrolingual airway collapse respond more favorably to MAD therapy than those with retropalatal or lateral pharyngeal wall collapse [43,44]. Additionally, in clinical practice, titration is often required to optimize therapeutic benefit. Most devices are adjustable, allowing for gradual mandibular advancement until satisfactory control of OSA is achieved or jaw discomfort limits further protrusion (Figure 2).

Consistent with the AASM recommendations, efficacy should be objectively confirmed with follow-up sleep testing after titration. Across RCTs, approximately 50–70% of appropriately selected patients experience a clinically significant reduction in AHI with MAD use, while complete remission (AHI < 5 events per h) is achieved in a smaller subset, typically 40–50% of those with mild to moderate OSA, with lower success rates observed in more severe cases [11,31,45]. Emerging techniques such as remotely controlled mandibular protrusion during sleep studies allow real-time assessment of upper airway responsiveness, potentially enabling the prediction of MAD efficacy before fabrication. Additionally, combination approaches, such as MAS with positional therapy or MAD with tongue myofunctional therapy, are being explored to provide additive therapeutic benefit. Modern developments allow embedding microsensors, such as temperature sensors, within mandibular advancement devices to yield objective nightly usage data, which can provide compliance data to ensure therapeutic protrusion is maintained [46]. Concurrently, the use of intraoral scanning and computer-aided design and manufacturing (CAD/CAM) technologies has improved device fit, comfort, and reproducibility, representing a significant step toward individualized treatment of OSA [47].

The efficacy of MAD therapy is inherently variable, with some patients achieving near complete resolution of OSA and others experiencing only modest improvement [36]. Predictors of a favorable response to MAD therapy include milder baseline OSA, positional (supine-dependent) OSA, lower body mass index (BMI), and certain craniofacial characteristics, such as that can be functionally corrected by mandibular protrusion [28,36,48] (Table 3).

Primary clinical and longitudinal studies indicate that MADs are generally well tolerated, with most adverse effects being mild and reversible. Common short-term side effects include jaw or tooth discomfort, dry mouth, excessive salivation, and transient temporomandibular joint (TMJ) pain or stiffness [49]. With prolonged use, gradual dental or occlusal changes, such as reduced overjet or overbite and mesial migration of lower teeth, can occur, though these changes are typically gradual and clinically insignificant for most patients [50]. Overall, serious complications are rare, but regular dental follow-up is recommended to detect and manage occlusal changes early.

In summary, CPAP remains the preferred therapy for patients with severe OSA or high cardiometabolic risk when adherence can be achieved, whereas MADs represent a rational first-line or alternative option for patients with mild-to-moderate disease who are unlikely to tolerate CPAP. Importantly, this trade-off does not imply equivalence of therapies but rather underscores the need to distinguish physiologic efficacy from clinical effectiveness in therapeutic decision-making. The choice between CPAP and MAD should be individualized, weighing the severity of OSA, the patient’s craniofacial anatomy, and patient preference. Emerging innovations in device design, digital modeling, custom 3D-printed appliances, and built-in sensors for adherence and precision in candidate selection will likely further enhance the role of oral appliances in OSA management.

Surgical interventions for OSA are designed to remove, reposition, or modify upper airway structures to enlarge the airway lumen and reduce its tendency to collapse during sleep. In contrast to nightly therapies such as CPAP or MAD, surgical procedures can provide a fixed anatomical correction, offering long-term benefit without the need for ongoing device use. Surgical management is particularly attractive for patients who are unable or unwilling to tolerate CPAP or MAD. However, surgical success depends heavily on patient characteristics, including anatomy, BMI, and collapse sites. The major surgical advances for OSA include uvulopalatopharyngoplasty (UPPP) and variants of soft palate surgery, as well as skeletal jaw advancements such as maxillomandibular advancement (MMA) (Table 4). Neurostimulation-based techniques, particularly hypoglossal nerve stimulation (HNS), have emerged as an increasingly common and effective therapeutic modality. The following section will review these modalities in greater detail, with particular attention to evolving techniques, including unilateral versus bilateral HNS systems and targeted stimulation strategies.

Historically, tracheotomy was the first definitive and highly effective surgical treatment for severe obstructive sleep apnea, bypassing upper airway obstruction entirely and eliminating obstructive events. Early reports in the 1960s and 1970s demonstrated dramatic reversal of hypersomnolence and cardiopulmonary complications following tracheotomy in patients with severe OSA [54]. However, due to its significant lifestyle impact, stoma care requirements, and complication profile, tracheotomy is now reserved for life-threatening or refractory cases. Subsequent surgical efforts, therefore, focused on modifying upper airway anatomy, leading to the development of uvulopalatopharyngoplasty and later multilevel and skeletal advancement procedures.

Uvulopalatopharyngoplasty (UPPP) was one of the earliest surgical interventions developed for the treatment of OSA and remains the most commonly performed oropharyngeal surgery worldwide. The procedure involves resection or trimming of the uvula, a portion of the soft palate, and redundant pharyngeal tissue to enlarge the retropalatal airway and reduce upper airway collapsibility. Tonsillectomy is frequently performed concurrently with UPPP [59]. Figure 3. Numerous case series have reported success in some patients, particularly those with large tonsils or obvious soft palate elongation [58]. However, outcomes have been highly variable owing to heterogeneity in surgical technique, patient anatomy, selection criteria, and the procedure carries moderate morbidity in terms of postoperative pain, velopharyngeal dysfunction, swallowing or voice changes, and bleeding [60,61]. To enhance efficacy and minimize complications, several modifications of the original UPPP technique have been developed. Among these, expansion sphincter pharyngoplasty (ESP) and lateral pharyngoplasty aim to improve lateral pharyngeal wall tension and airway stability. ESP, in particular, has demonstrated superior outcomes compared to traditional UPPP, with cohort studies and systematic reviews reporting surgical success rates of approximately 60–80% [62,63]. These refinements represent a significant evolution in palatal surgery, emphasizing tailored anatomic correction to optimize both efficacy and safety in OSA management.

In appropriately selected patients, UPPP can lead to substantial improvement in the severity and symptoms of OSA. See Table 3 and Table 4.

Across randomized controlled trials noted in Table 5 and Table 6, UPPP-based surgery resulted in clinically meaningful short-term reductions in OSA severity compared with non-surgical comparators. In the SAMS randomized clinical trial, multilevel upper airway surgery reduced AHI by 17.6 events/h more than medical management at 6 months and was associated with a large improvement in daytime sleepiness [64]. Similarly, in a randomized controlled trial of tonsillectomy with UPPP, surgical treatment reduced AHI by approximately 11 events/h more than control at 3 months [58]. However, the long-term durability of UPPP appears limited. In prospective cohorts with extended follow-up, initial reductions in AHI at 1–2 years were not sustained, with AHI returning toward baseline by 8 years [65].

These findings, as noted in Table 5, show that UPPP provides meaningful short-term physiologic and symptomatic benefit in carefully selected patients with oropharyngeal obstruction and CPAP intolerance. Randomized trials demonstrate reductions in AHI comparable to or exceeding those seen with conservative medical management over short follow-up intervals. In contrast, durability is a major limitation. Long-term observational data consistently show attenuation or loss of benefit, suggesting that UPPP primarily modifies dynamic soft-tissue behavior rather than addressing fixed anatomic or neuromuscular contributors to airway collapse. This mechanistic limitation likely explains the inferior long-term outcomes observed relative to therapies that provide continuous pneumatic splinting (CPAP), neuromodulation (hypoglossal nerve stimulation), or skeletal expansion (maxillomandibular advancement).

Across additional case series and systematic reviews, UPPP has demonstrated surgical success in a majority of appropriately selected patients with OSA, particularly in those with favorable anatomic features such as enlarged tonsils or elongated soft palates [61,67]. These findings emphasize the importance of meticulous patient selection, often aided by preoperative drug-induced sleep endoscopy (DISE) to identify specific sites and patterns of upper airway collapse. In contrast, outcomes tend to be less favorable in patients with macroglossia, retrognathia, or obesity, as these features contribute to persistent airway obstruction at nonpalatal levels. Technique variability and inconsistent inclusion or exclusion of tonsillectomy have historically limited the generalizability of UPPP outcomes [61]. While some studies suggest that patients with BMI values approaching 40 kg/m² may still benefit under specific circumstances, most surgeons remain cautious in operating on markedly obese patients, as obesity related tongue base collapse may blunt the benefit of isolated palatal surgery [68,69]. To address these limitations and expand indications, a range of UPPP variants have been developed, including the uvulopalatal flap, lateral pharyngoplasty, Z-palatoplasty, and expansion sphincter pharyngoplasty. Multilevel approaches that combine palatal surgery with tongue base reduction or nasal surgery have also been introduced to target complex, multilevel obstruction and enhance surgical consistency and outcomes [70,71,72,73,74].

Adverse effects following uvulopalatopharyngoplasty (UPPP) are generally mild and transient, though a range of potential complications has been described. Common side effects include postoperative pain, velopharyngeal insufficiency, persistent throat dryness, and changes in voice quality. More serious complications, such as bleeding or infection, are rare but can occur [75]. UPPP often results in a durable reduction in snoring; however, if residual OSA persists, the surgically altered anatomy may complicate subsequent management, and adjunctive therapies—such as CPAP, oral appliance therapy, or weight reduction—may still be required. Despite these limitations, UPPP remains a valuable therapeutic option for patients unable to tolerate CPAP or MADs, particularly when anatomical findings are favorable for palatal intervention. Patient satisfaction tends to be highest when expectations are appropriately set, and residual OSA is modest. Overall, UPPP should be performed by experienced surgeons using an individualized, anatomy-driven approach. Preoperative counseling is essential, as approximately 40–50% of patients may have residual OSA postoperatively, necessitating follow-up sleep testing and possible adjunctive therapy [76].

In summary, UPPP remains a valuable treatment option for appropriately selected patients—most commonly those with moderate OSA, evident palatal obstruction, and intolerance or poor adaptation to CPAP or MAD therapy. When performed with careful technique, UPPP can achieve significant reductions in AHI and ODI, with high patient satisfaction. Optimal outcomes depend on meticulous patient selection and surgical execution that maximizes airway enlargement while minimizing postoperative scarring. Within a comprehensive, multimodal management strategy, UPPP may also be combined with complementary procedures such as nasal septoplasty, tongue-base reduction, or subsequent hypoglossal nerve stimulation to address multi-level airway obstruction and enhance overall treatment efficacy.

Maxillomandibular advancement (MMA) is an orthopedic surgical procedure that advances both the maxilla and mandible anteriorly, thereby enlarging the skeletal framework of the upper airway. Figure 4. This forward repositioning effectively expands the entire pharyngeal airway, from the nasal passages to the hypopharynx, by concurrently pulling the soft palate forward via maxillary advancement and the tongue base forward through mandibular advancement. As such, MMA provides a multilevel airway enlargement in a single operation. The procedure is often performed in conjunction with genial tubercle advancement and suspension of the suprahyoid muscles to further augment airway patency [56,77]. Although MMA is a major surgical intervention typically requiring intraoral incisions, rigid fixation with plates and screws, and a postoperative recovery period involving jaw stabilization, it yields the highest cure and response rates among all surgical treatments for OSA. MMA is particularly appropriate for patients with moderate to severe OSA who have underlying craniofacial skeletal deficiencies that contribute to airway restriction. Careful patient selection, based on craniofacial structure and severity of disease, is crucial to optimize surgical outcomes and minimize unnecessary intervention in those less likely to benefit [78]. MMA has demonstrated robust and durable efficacy in patients with moderate to severe obstructive sleep apnea (OSA).

Across controlled trials noted in Table 7 and Table 8, MMA produced large reductions in objective OSA severity and achieved physiologic efficacy comparable to positive airway pressure therapy. In a randomized trial comparing MMA with APAP, no statistically significant differences were observed between groups in improvement in AHI or Epworth Sleepiness Scale scores, indicating comparable short-term efficacy [79]. Similarly, in a prospective within-patient comparison, residual disease severity following MMA was nearly identical to that observed during CPAP therapy [80]. Comparative surgical data demonstrate that MMA is significantly more effective than palatal surgery alone [17]. In a baseline-adjusted cohort, MMA reduced AHI by approximately 21 events/h more than UPPP, and the addition of palatal surgery to MMA did not confer additional benefit [17]. Real-world comparative effectiveness data further show that MMA achieves the highest mean disease alleviation among CPAP, MAD, hypoglossal nerve stimulation, and MMA, reflecting adherence-independent disease control [81]. Prospective mechanistic studies indicate that MMA often results in near-normalization of AHI and high cure rates [82]. Additionally, across multiple meta-analyses, MMA has been associated with a mean reduction in AHI of approximately 77%, with nearly half of patients (47%) achieving complete remission, defined as an AHI < 5 events per h [83]. Meta-analyses have consistently confirmed these findings, reporting surgical success rates of 80–90%, usually defined as a ≥50% reduction in AHI to <20 events per h, with mean reductions in AHI often exceeding 30–40 events per h [84,85]. Long-term follow-up investigations further confirm the durability of these outcomes, demonstrating sustained improvements in AHI, oxygen saturation, and symptom relief at five years or more postoperatively [86]. In addition to ameliorating sleep-disordered breathing, MMA has been associated with improvements in cardiovascular risk factors and reductions in daytime sleepiness as measured by validated self-report instruments [87].

Collectively, these findings establish MMA as the most efficacious surgical therapy for moderate to severe obstructive sleep apnea in appropriately selected patients. Unlike soft-tissue procedures, MMA addresses fixed skeletal and tongue-base contributors to airway collapse, producing large and often durable reductions in disease severity. The absence of additional benefit from concomitant palatal surgery underscores the dominant role of skeletal advancement in achieving airway stability. Importantly, randomized and physiologic comparisons indicate that MMA can achieve disease control comparable to CPAP, while offering an adherence-independent treatment option. Real-world effectiveness analyses further support MMA’s clinical impact, demonstrating superior mean disease alleviation relative to non-surgical therapies and other surgical modalities. These advantages must be balanced against the invasiveness of the procedure and the need for careful patient selection, but for patients with severe OSA, craniofacial restriction, or CPAP intolerance, MMA represents a definitive and durable therapeutic strategy.

MMA is commonly performed by oral and maxillofacial surgeons and often in collaboration with orthodontists when preoperative dental alignment or postoperative occlusal adjustments are required. The procedure is conducted under general anesthesia and generally necessitates a brief hospital stay. Rigid fixation of the osteotomized segments is achieved using titanium plates and screws; with modern techniques, stable fixation can be accomplished without prolonged maxillomandibular wiring, although a soft diet is recommended for several weeks during recovery. Postoperative swelling and discomfort are expected and may be significant in the early period. Potential surgical risks include infection, malocclusion, and transient or, less commonly, persistent sensory changes. Because the jaws are advanced anteriorly, most patients experience some degree of facial alteration, which should be thoroughly discussed during preoperative counseling. Despite its invasiveness, serious complications from MMA are relatively uncommon. Permanent sensory nerve deficits may occur, but are generally mild, and minor occlusal discrepancies can often be corrected with secondary orthodontic adjustments or limited revision procedures.

Because MMA simultaneously addresses multiple levels of airway obstruction through skeletal repositioning, it is generally reserved for patients with moderate to severe OSA, particularly those with identifiable craniofacial abnormalities such as maxillary or mandibular retrusion, or as a salvage option following unsuccessful soft-tissue surgeries Current clinical guidelines typically recommend MMA for severe or refractory cases due to its complexity; however, it may also serve as a primary surgical intervention in patients with favorable craniofacial anatomy [12]. By advancing both the maxilla and mandible, MMA corrects multisegmental airway collapse without removing soft tissue, thereby preserving the option for adjunctive therapies if needed postoperatively. In addition to its anatomic benefits, MMA has been shown to improve OSA-related outcomes such as hypertension and daytime sleepiness to a degree comparable to, or even exceeding, that achieved with CPAP [83]. However, not all patients are ideal candidates. The procedure is most effective in individuals with craniofacial skeletal deficiencies or occlusal abnormalities that can be simultaneously corrected. In contrast, patients with normal jaw structure and obesity-related airway narrowing may derive less benefit, as excess soft tissue and tongue fat remain potential sources of obstruction. For such patients, weight reduction and metabolic optimization remain important complementary strategies to enhance overall treatment success.

In summary, MMA represents one of the most effective and durable surgical treatments for OSA, particularly in patients with craniofacial skeletal deficiencies or severe disease who are CPAP intolerant. The procedure achieves substantial reductions in AHI and high cure rates, accompanied by meaningful improvements in blood pressure, daytime symptoms, and overall quality of life. Although MMA is a major surgical intervention requiring specialized expertise, complication rates are relatively low, and patient satisfaction is high when appropriately selected and executed. MMA should be considered an integral part of the therapeutic discussion, especially in those with anatomic phenotypes conducive to skeletal advancement.

Hypoglossal nerve stimulation (HNS) is a relatively new surgical therapy for OSA that involves implanting a neurostimulator to electrically activate the hypoglossal nerve during sleep. The hypoglossal nerve innervates the genioglossus and other tongue muscles responsible for tongue protrusion and upper airway stiffening. Figure 5, Figure 6 and Figure 7. By delivering synchronized stimulation with each inspiration, HNS promotes forward tongue movement and stabilization, thereby preventing upper airway collapse without the need for an external mask or positive airway pressure [19]. Over the past decade, HNS has emerged as a promising alternative for patients with moderate to severe OSA who are unable to tolerate CPAP. The therapy received U.S. Food and Drug Administration (FDA) approval in 2014 following the pivotal STAR trial, and several HNS systems have since been developed and evaluated. Current indications generally include patients with moderate to severe OSA, a BMI below 32 kg/m², and the absence of complete concentric palatal collapse as determined by drug-induced sleep endoscopy [88]. Recent technological advances include bilateral stimulation systems, refined electrode configurations, and targeted activation of specific hypoglossal nerve branches to enhance efficacy and comfort.

The unilateral HNS system, the most widely used device in the United States, comprises three implanted components placed under general anesthesia. The first is a stimulation lead that encircles the hypoglossal nerve, usually in the medial branches, which are responsible for tongue protrusion, on one side of the neck. The second is a sensing lead positioned between the intercostal muscles to detect respiratory effort and timing. The third component is an implantable pulse generator, similar in design to a cardiac pacemaker, which is positioned subcutaneously in the chest. This generator receives input from the respiratory sensor and delivers synchronized stimulation to the hypoglossal nerve during each inspiratory phase [19]. The system functions by activating the genioglossus and related muscles during inspiration, thereby advancing the tongue forward to maintain airway patency, and ceasing stimulation during expiration. Following implantation, the device is calibrated during a postoperative polysomnography to optimize stimulation amplitude and timing, maximizing airway opening while minimizing arousals or discomfort. Patients control the device externally, turning it on before sleep and off upon awakening, with a built-in delay that allows sufficient time to fall asleep comfortably.

Across prospective trials (Table 9), long-term follow-up studies, and real-world registries, hypoglossal nerve stimulation was associated with large and sustained reductions in obstructive sleep apnea severity. In the pivotal STAR cohort, median AHI decreased by 68% at 12 months, accompanied by parallel reductions in ODI and normalization of daytime sleepiness. These improvements were durable, with a 5-year follow-up demonstrating sustained reductions in AHI (mean change approximately −20 events/h) and stable responder rates between 63–75%, even under conservative missing-data assumptions. Overall, 66% of participants met responder criteria, defined as a ≥50% reduction in AHI and a post-treatment AHI < 20 events per h. In a randomized therapy withdrawal sub-study, temporary cessation of stimulation led to the recurrence of OSA severity and associated symptoms, confirming that the observed benefits were directly attributable to active neurostimulation. Serious adverse events occurred in fewer than 2% of subjects. The most common side effects included tongue soreness, mild incisional discomfort, and transient tongue weakness, and were typically mild and self-limited. These findings strongly establish unilateral HNS as an effective, durable, and well-tolerated therapy for appropriately selected CPAP-intolerant patients with OSA.

Long-term follow-up of hypoglossal nerve stimulation (HNS) supports sustained therapeutic effect, adherence, and safety in appropriately selected OSA patients [89]. At five years, participants from the STAR cohort continued to exhibit significant reductions in AHI, along with persistent improvements in daytime sleepiness, as measured by the ESS, and in quality-of-life assessments, without evidence of increased stimulation thresholds or notable tongue-related injury [89]. Similarly, data from the ADHERE registry have confirmed strong real-world adherence, with average nightly device use of approximately 5.6 h, high patient satisfaction, and durable improvements in objective sleep parameters through 12 months of follow-up [90]. Device durability is also favorable; battery replacement analyses indicate that implantable pulse generators typically last approximately 10 years before requiring replacement, reflecting strong long-term reliability [91]. Although HNS carries a considerable initial cost, health economic models suggest it is cost-effective in CPAP-intolerant populations, given the substantial improvements in sleep quality, daytime function, and overall quality-adjusted life years gained [92]. However, patient candidacy remains limited by anatomic and phenotypic factors. Individuals with severe obesity, complete concentric palatal collapse, or neuromuscular tongue weakness are generally poor candidates, underscoring that HNS serves as a selectively applicable alternative CPAP therapy in well-defined patient populations.

Not all patients with OSA are eligible for HNS. The optimal candidacy is limited to those with moderate to severe OSA who are CPAP intolerant, have an upper airway collapse pattern primarily amenable to tongue protrusion rather than circumferential palatal collapse, and are not markedly obese. In the STAR trial, the device’s enrollment criteria restricted BMI to ≤32 kg/m² and excluded patients who exhibited complete concentric collapse (CCC) at the soft palate on DISE, based on early evidence that CCC undermines the response to tongue-based stimulation [19]. Subsequent observational and predictive modeling analyses consistently reinforced CCC as a major exclusion criterion, highlighting the critical role of DISE in preoperative patient selection [93]. While more recent data suggest that the candidate pool for HNS may be gradually expanding, most clinical investigations continue to exclude patients with very high AHI values or severe obesity, recognizing that, in such cases, the degree of soft-tissue loading and airway collapsibility may exceed the compensatory capacity of neurostimulation. Thus, HNS remains a highly effective yet selectively applicable therapy, best reserved for carefully selected patients whose anatomical and physiological profiles predict a favorable response to tongue-protrusive stimulation. Recent innovations in HNS have sought to simplify implantation and broaden patient eligibility beyond the traditional system utilized in the STAR trial, which requires an implanted pulse generator and intercostal sensing lead.

One of the most promising developments is a bilateral HNS device that eliminates the need for an implanted battery or chest leads. Compared with earlier hypoglossal nerve stimulation systems, this device offers several structural and procedural advantages. It eliminates the need for implanted leads connecting sensing electrodes to a pulse generator and requires only a single surgical incision without subcutaneous tunneling [94]. In addition, stimulation is delivered to both hypoglossal nerves simultaneously and is regulated by an externally worn controller [94]. This controller activates a compact, battery-free stimulator implanted in the submental region, delivering therapy at a preset but adjustable frequency and duty cycle. The BLAST OSA trial (Table 9) followed 27 adults with moderate-to-severe OSA who were CPAP-intolerant. After 6 months of therapy, the mean AHI decreased by about 54%, and the ODI decreased from 23.7 to 12.9 events per h [94]. Patients also reported significant improvement in daytime sleepiness, with a significant decrease in ESS and improvements in sleep-specific quality of life, as measured by the Functional Outcomes of Sleep Questionnaire (FOSQ) [94]. No serious device-related adverse events occurred, and the few complications observed, such as minor incision discomfort or tongue tingling during early titration, resolved spontaneously or with adjustment of stimulation parameters. From a usability perspective, adherence to HNS therapy has been excellent, with the majority of participants using the system consistently by activating the external controller before sleep and deactivating it upon awakening. Notably, efficacy outcomes from the BLAST OSA trial are comparable to those achieved with the unilateral implanted HNS system, despite the bilateral device’s markedly simplified design. Should long-term durability data and broader clinical trials confirm these findings, bilateral, battery-free stimulation systems have the potential to substantially expand access to neurostimulation therapy for obstructive sleep apnea while simultaneously reducing surgical complexity, procedural risk, and long-term maintenance requirements.

A more recent HNS technology has been evaluated in the THN3 trial, which investigated proximal targeted hypoglossal neurostimulation (THN), a system that stimulates the hypoglossal nerve more proximally using a multiconduct cuff electrode to deliver asynchronous stimulation. Mechanistically, this design allows co-activation of both tongue protrudor and retrudor intrinsic muscle groups, producing overall stiffening and stabilization of the tongue rather than solely anterior displacement. This dual muscle recruitment strategy may enhance airway patency even in anatomically complex or multilevel collapse scenarios.

In the THN3 trial, 138 patients with moderate to severe OSA who were CPAP intolerant were randomized 2:1 to early device activation versus delayed start (Table 10). At four months, 52.3% of patients in the active treatment group met the responder criterion, which was defined as a ≥50% reduction in AHI and a post-treatment AHI ≤ 20 events per hour, compared with 19.6% in the control arm, confirming the efficacy of stimulation. Over 11 months of therapy, 42.5% of the pooled cohort met the AHI responder definition, and 60.4% achieved the corresponding ODI criteria. Significant improvements were also observed across multiple patient-reported outcomes, including daytime sleepiness, sleep-related quality of life, and overall health utility [95]. Longitudinal follow-up extending to 36 months demonstrated that improvements in AHI, ODI, ESS, and quality-of-life metrics were largely sustained, with a low incidence of serious device-related complications and predominantly mild adverse effects, such as transient tongue discomfort or stimulation-related paresthesia [96]. These effects were statistically robust (Table 10), with confidence intervals excluding the null for both AHI and ODI responder outcomes. Longer-term pooled analyses demonstrated sustained responder proportions at 12–15 months, supporting persistence of benefit beyond the randomized comparison period.

In summary, HNS provides robust and durable within-patient improvement in both objective respiratory indices and patient-reported outcomes. Unlike soft-tissue surgical procedures, the durability of benefit through five years suggests that neuromodulatory stabilization of upper airway tone produces a persistent physiologic effect rather than transient symptom relief. At the same time, residual AHI following HNS typically remains higher than that observed with CPAP under optimal adherence or with maxillomandibular advancement, positioning HNS as a moderately efficacious but durable therapy. The consistency of effect across controlled trials, long-term follow-up, and large registries underscores the external validity of HNS outcomes. Importantly, the magnitude of benefit appears phenotype-dependent, with baseline physiological characteristics such as lower ODI and lower BMI predicting long-term response. These findings reinforce a precision-medicine framework, in which HNS is most appropriately deployed in carefully selected CPAP-intolerant patients rather than as a universal alternative.

Another emerging approach to treating OSA involves neuromuscular electrical stimulation (NMES) of the upper airway musculature. In contrast, HNS, which requires implanted electrodes on the nerve, these therapies stimulate the muscles more peripherally, either via intraoral or transcutaneous surface electrodes. The therapeutic objective is to enhance baseline muscle tone and responsiveness of these airway-stabilizing muscles, thereby reducing airway collapsibility during sleep. Two distinct strategies have been investigated: (1) daytime training stimulation in which electrical impulses are applied while the patient is awake to strengthen upper-airway muscles over time, and (2) nighttime stimulation, which delivers rhythmic electrical pulses during sleep to maintain airway patency dynamically. The following sections review major developments in this field, including evidence from clinical trials of daytime intraoral stimulation devices and emerging data from nocturnal transcutaneous stimulation systems currently under investigation.

Beyond the mainstream therapies discussed previously, several innovative techniques have recently emerged that target specific physiological mechanisms underlying OSA. These include experimental and device-based approaches, such as tongue base cryotherapy to reduce tongue volume, advanced positional therapy devices designed to discourage supine sleep, and various adjunctive measures, including nasal expiratory valves and structured myofunctional exercises to enhance upper airway tone. While each of these strategies may be most appropriate for patients with mild disease or as complementary interventions alongside other treatments, together they exemplify the expanding toolkit available for individualized, mechanism-based OSA management. The following section highlights several of these emerging therapies and reviews the current evidence supporting their clinical use.

Pharmacologic therapy for obstructive sleep apnea (OSA) has historically been limited, reflecting the dominant role of upper airway anatomy in disease pathogenesis. However, contemporary models recognize that OSA severity and persistence are strongly influenced by non-anatomical physiological traits, including obesity-related mechanical load, ventilatory control instability (loop gain), and arousal threshold (Table 13). Advances in understanding these endotypes have enabled the development of targeted pharmacologic strategies that modulate specific contributors to airway collapse. Rather than replacing mechanical therapies, these agents are best conceptualized as disease-modifying or adjunctive interventions within a precision-medicine framework.

The landscape of OSA management is rapidly evolving from a one-size-fits-all model, as in CPAP therapy, to an individualized, multimodal approach. This review highlights a fundamental shift in the management of obstructive sleep apnea (OSA): from a historically CPAP-centric paradigm toward a precision-guided, multimodal framework that aligns treatment with the dominant anatomic and physiological drivers of disease in individual patients. While continuous positive airway pressure remains the most physiologically efficacious therapy when used optimally, real-world adherence limitations necessitate alternative strategies capable of achieving durable disease control across diverse phenotypes (Figure 11).

Across non-CPAP therapies, our synthesis demonstrates clear heterogeneity in both magnitude and durability of effect. Mandibular advancement devices (MADs) consistently reduce OSA severity relative to placebo and provide symptom relief comparable to CPAP in mild-to-moderate disease, largely due to superior adherence. These findings are concordant with prior systematic reviews and meta-analyses, including Papageorgiou et al., which similarly concluded that MADs represent an effective second-line therapy in appropriately selected patients. However, by incorporating standardized directionality across trials and explicitly distinguishing physiologic efficacy from real-world effectiveness, our review extends prior work by clarifying why MADs often achieve comparable clinical outcomes despite inferior per-night AHI reduction.

Surgical therapies illustrate the importance of matching mechanism to anatomy. Palatal surgery, including UPPP and its variants, provides meaningful short-term improvement in selected patients with retropalatal obstruction, consistent with findings from earlier reviews. However, our synthesis emphasizes a key distinction often under-represented in prior reviews: limited long-term durability. Longitudinal cohort data demonstrate attenuation of benefit over time and, in population-level analyses, inferior survival compared with CPAP. In contrast, maxillomandibular advancement (MMA) stands apart as the most efficacious and durable surgical intervention, achieving reductions in AHI comparable to CPAP and superior outcomes relative to other surgical modalities. While Papageorgiou et al. acknowledged the high efficacy of MMA, our review expands on this by integrating randomized comparisons, real-world effectiveness metrics, and long-term durability data to position MMA as a definitive, adherence-independent therapy for carefully selected patients with skeletal restriction.

Hypoglossal nerve stimulation (HNS) represents a major advance in neuromodulatory therapy for OSA. Consistent with prior systematic reviews, including Papageorgiou et al., we confirm that HNS produces substantial and sustained improvements in AHI, oxygenation, and daytime symptoms with high adherence. Importantly, this review advances the field by integrating randomized responder-based metrics, long-term durability data, and real-world registry outcomes to quantify both magnitude and persistence of benefit. Furthermore, emerging bilateral and proximal-targeted stimulation systems suggest that the therapeutic envelope of HNS may continue to expand, reinforcing its role as a durable alternative for CPAP-intolerant patients with favorable anatomy.

Neuromuscular electrical stimulation (NMES) and positional therapy occupy a distinct niche. Our findings are consistent with prior reviews in demonstrating modest average reductions in respiratory event burden, particularly in mild or positional OSA. However, by separating daytime training-based NMES from nocturnal transcutaneous stimulation and contrasting both with implanted HNS, this review provides greater mechanistic clarity regarding why these therapies should be viewed as adjunctive or early-stage interventions, rather than substitutes for definitive airway stabilization in moderate-to-severe disease.

A major breakthrough highlighted in this review, largely absent from earlier summaries such as Papageorgiou et al., is the emergence of metabolic and endotype-targeted pharmacotherapy as disease-modifying treatment for OSA. Longitudinal observational data establish a dose-dependent relationship between weight change and progression or regression of sleep-disordered breathing, while randomized trials of GLP-1-based therapies demonstrate that pharmacologic weight loss can produce clinically meaningful reductions in OSA severity. The magnitude of AHI reduction observed with dual GLP-1/GIP agonism approaches that of some device-based therapies, marking a qualitative advance beyond earlier weight-loss strategies. Similarly, carbonic anhydrase inhibitors and sedative agents targeting ventilatory loop gain and arousal threshold represent a mechanistically novel class of therapies that directly address non-anatomical contributors to airway instability.

Taken together, these data support a model in which no single therapy universally dominates, but rather where optimal management arises from aligning therapy with phenotype—anatomic, neuromuscular, ventilatory control, arousal threshold, and metabolic load (Figure 12). This perspective extends prior reviews by integrating emerging pharmacologic therapies and by emphasizing combination strategies capable of addressing multiple pathophysiologic traits simultaneously (Figure 11).

The management of OSA continues to evolve with ever-increasing therapeutic possibilities. No longer is CPAP the only answer; instead, we now have a spectrum of effective treatments, from oral appliances and upper-airway surgeries to neurostimulation devices, muscle training tools, and pharmacologic agents, each with unique benefits that can be matched to patient needs. The onus is on clinicians to stay informed of these advances and practice multidisciplinary, personalized care. For patients, this expansion means more hope for a therapy they can live with, ultimately leading to better long-term adherence and better health outcomes. As the field progresses, the OSA patient of the future will likely undergo a comprehensive evaluation and receive a tailored combination of interventions, perhaps including a weight-loss medication, a custom oral appliance, a nighttime positional buzzer, and some throat exercises for good measure. CPAP, of course, remains an available option for those poor responders to less invasive interventions.

Realizing this vision will require continued research, patient education, and, often, a combination strategy addressing both the cause and the consequence. The advances in treatment, from PAP to pills, are closing the gap toward making OSA a controllable and, in some cases, a reversible condition for most patients. The next decade will likely bring even more integration of these therapies, guided by data on what improves not just the AHI but the patient’s life and long-term health. By embracing a multimodal approach now and refining it with future evidence, clinicians can ensure that the right treatment, or mix of treatments, is delivered to the right patient at the right time, thereby fulfilling the ultimate goal of OSA management: effective therapy that patients will actually use.

J.R.: Conceptualization; Methodology; Data curation; Visualization; Writing—original draft; Writing—review & editing. K.B.A.: Writing—review & editing; Supervision. A.R.A.: Writing—review & editing; Supervision; Project administration; Resources. All authors have read and agreed to the published version of the manuscript.

Ethical review and approval were waived for this study because it involved analysis of previously published data and did not constitute human subjects research.

Not applicable.

This manuscript is a narrative review based on previously published literature. No new datasets were generated or analyzed during the current study.

The authors declare no conflicts of interest.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.