Highlight
The STAR trial secondary analysis demonstrates that hypoglossal nerve stimulation therapy results in a significant reduction of hypoxic burden (HB) in patients with moderate to severe obstructive sleep apnea (OSA). This HB reduction correlates strongly with improvements in daytime sleepiness measured by the Epworth Sleepiness Scale (ESS), independently of Apnea-Hypopnea Index (AHI) or Arousal Index changes. Intriguingly, substantial HB improvement occurred even among participants classified as nonresponders by traditional criteria, underscoring HB as a valuable complementary biomarker for assessing treatment efficacy.
Study Background
Obstructive sleep apnea (OSA) is a prevalent disorder characterized by recurrent upper airway collapse during sleep, causing intermittent hypoxia and sleep fragmentation. These events contribute to excessive daytime sleepiness and increased risks of cardiovascular and metabolic diseases. The Apnea-Hypopnea Index (AHI), quantifying respiratory event frequency, has traditionally been the primary metric for OSA severity and therapeutic response. However, AHI does not fully capture the physiological consequences of OSA, including cumulative hypoxia exposure.
Hypoxic burden (HB) quantifies the integrated extent and duration of oxygen desaturations during sleep, providing a physiologic measure linked more directly to morbidity risk. Positive airway pressure (PAP) therapy effectively lowers AHI and HB but suffers from adherence challenges. Hypoglossal nerve stimulation (HNS) offers an alternative therapy for PAP-intolerant patients by electrically activating upper airway dilator muscles to maintain airway patency during sleep, primarily reducing AHI. Whether HNS effectively reduces HB and how HB changes relate to symptomatic improvements remains insufficiently characterized.
Study Design
The Stimulation Therapy for Apnea Reduction (STAR) trial was a multicenter, nonrandomized investigation including a randomized withdrawal phase. It enrolled adults with moderate to severe OSA who were intolerant to positive airway pressure therapy. For this secondary analysis, 108 participants with comprehensive polysomnography data pre-treatment and at 12 months post-implantation were analyzed. The intervention consisted of hypoglossal nerve stimulation applied over a 12-month period.
The primary outcome was the change in hypoxic burden, defined as percentage of minutes per hour (%min/h) of oxygen desaturation exposure. Secondary outcomes included daytime sleepiness measured by the Epworth Sleepiness Scale (ESS) and the relationship between changes in HB and ESS. The analysis also compared responder status as defined by Sher criteria (AHI reduction ≥50% and AHI <20 events/hour) with HB changes.
Key Findings
The cohort’s mean age was 54.5 years, predominantly male (84.3%), with a baseline median hypoxic burden of 63.4 %min/h (IQR, 47.8-96.6). After 12 months of hypoglossal nerve stimulation, the median HB reduction was 76.6% (IQR, 33.1%-90.7%), decreasing the median post-treatment HB to 21.2 %min/h in the initially high HB group and 11.3 %min/h in the low HB group.
In the high HB subgroup, reductions in HB correlated positively with ESS score improvements (β=1.25; 95% CI, 0.02-2.48). Notably, ESS improvements did not correlate significantly with reductions in AHI, Arousal Index, or conventional oxygen metrics, suggesting HB captures clinically meaningful physiological benefits not reflected by traditional indices.
Responder status by Sher-20 criteria identified 36 responders and 18 nonresponders among those with high baseline HB. Importantly, 44 participants (81.5%) transitioned from high to low HB post-treatment, including nine classified as nonresponders, indicating that traditional responder criteria may underestimate beneficial physiological effects of HNS. In the low HB group, all 36 responders maintained low HB, and 61.1% of nonresponders also demonstrated low HB levels.
This dissociation highlights that HB may serve as a complementary and possibly superior marker for evaluating treatment efficacy, especially in symptomatic improvement.
Expert Commentary
This secondary analysis of the STAR trial advances our understanding of hypoglossal nerve stimulation’s physiological impact beyond AHI reduction. The findings align with emerging evidence that hypoxic burden is a more relevant biomarker for predicting cardiovascular risk and daytime symptoms in OSA than event frequency alone.
By demonstrating that HB reduction correlates with symptom improvement independently of AHI changes, the study underscores the limitation of relying solely on AHI for treatment evaluation. Moreover, the observation that many nonresponders per AHI criteria achieve meaningful HB improvement opens avenues for a nuanced approach to therapy assessment and patient selection.
Limitations include the nonrandomized design, which may introduce selection bias, and the predominantly male study population limiting generalizability. Long-term cardiovascular outcomes related to HB reduction with HNS remain to be established.
Conclusion
Hypoglossal nerve stimulation significantly reduces hypoxic burden in patients with moderate to severe OSA intolerant of PAP therapy, with reductions closely associated with improvements in daytime sleepiness. These benefits may occur even without substantial AHI changes, indicating that hypoxic burden is a vital complementary physiologic metric for assessing treatment response.
Incorporating HB into clinical practice and research may refine patient monitoring, optimize treatment decisions, and ultimately improve outcomes in OSA management. Further studies should confirm these findings across diverse populations and evaluate long-term clinical benefits linked to HB reduction.
Funding and Trial Registration
The original STAR trial was registered at ClinicalTrials.gov (NCT01161420). Funding sources and detailed trial support are reported in the primary publication.
References
1. Xu J, Hajipour Z, Aloia MS, et al. Hypoglossal Nerve Stimulation and Hypoxic Burden in Patients With Obstructive Sleep Apnea: A Secondary Analysis of the STAR Trial. JAMA Otolaryngol Head Neck Surg. 2026;152(7):696-704. doi:10.1001/jamaoto.2026.1234
2. Azarbarzin A, Sands SA, Stone KL, et al. The hypoxic burden of sleep apnea predicts cardiovascular disease-related mortality: The sleep heart health study. Am J Respir Crit Care Med. 2019;200(8):919-927. doi:10.1164/rccm.201812-2410OC
3. Strollo PJ Jr, Soose RJ, Maurer JT, et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med. 2014;370(2):139-149. doi:10.1056/NEJMoa1308659
4. Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: The challenge to effective treatment. Proc Am Thorac Soc. 2008;5(2):173-178. doi:10.1513/pats.200707-119MG
