Hypoglossal Nerve Stimulation Linked to Reduced Hypoxic Burden in OSA

Hypoglossal nerve stimulation (HGNS) was associated with a 76.6% median reduction in hypoxic burden (HB) among adults with moderate to severe obstructive sleep apnea who were intolerant of positive airway pressure (PAP) therapy, according to a secondary analysis of the STAR (Stimulation Therapy for Apnea Reduction; NCT01161420) trial published in JAMA Otolaryngology–Head & Neck Surgery.¹ Notably, half of participants classified as nonresponders by traditional Apnea-Hypopnea Index (AHI) criteria still showed a meaningful shift from high to low HB, raising questions about how treatment response to HGNS should be defined.

How Was Hypoxic Burden Measured?

HB is a physiologic metric that quantifies the cumulative area under the oxygen desaturation curve during respiratory events, expressed as percentage of minutes per hour (%min/h). The metric was introduced in a 2019 analysis of the Sleep Heart Health Study (NCT00005275) and Osteoporotic Fractures in Men Study (NCT00070681) cohorts, which found that HB predicted cardiovascular disease–related mortality even though AHI, a purely frequency-based measure, did not.² Building on that established link between HB and cardiovascular risk, the STAR trial analysis classified 108 participants (mean [SD] age, 54.5 [10.3] years; 91 [84.3%] men) with pretreatment and 12-month polysomnography data into high- and low-HB groups using the cohort median of 63%min/h as the cutoff.¹

How Much Did Hypoxic Burden Improve After 12 Months?

Baseline median (IQR) HB was 63.4 (47.8-96.6) %min/h, falling to a median reduction of 76.6% (33.1%-90.7%) at 12 months. Overall, 77 participants (71.3%) achieved an HB reduction greater than 50%. Among those with high baseline HB, 44 of 54 (81.5%) transitioned to the low HB category at follow-up, while 7 of 54 participants (13.0%) with low baseline HB moved into the high-HB group.

Do AHI Nonresponders Still Benefit?

Among the 54 participants with high baseline HB, 36 met Sher-20 responder criteria (≥ 50% AHI reduction and 12-month AHI < 20 events/h) and 18 did not. Even so, 9 of those 18 nonresponders (50%) transitioned to low HB, with AHI reductions of just 9.7 (8.3-15.7) events/h alongside HB reductions of 39.6% (18.5%-50.0%) min/h. The authors noted that HGNS may convert some apneas into hypopneas, potentially improving oxygenation without substantially lowering overall event frequency, since AHI counts apneas and hypopneas equally despite their differing physiologic impact on tissue hypoxia.

Does Hypoxic Burden Reduction Track With Sleepiness?

In the high-HB subgroup, improvements in Epworth Sleepiness Scale scores were associated with HB reduction (β = 1.25; 95% CI, 0.02-2.48) but not with changes in AHI, Arousal Index, or conventional oxygenation metrics such as T90 or oxygen nadir. No such associations emerged among participants with low baseline HB. The authors cautioned that this finding stemmed from a subgroup analysis with a limited sample size and should be confirmed in larger cohorts.

What Happened With Therapy Withdrawal?

In a substudy of Sher-20 responders randomized to 1-week therapy withdrawal (n = 18) vs continued maintenance (n = 19), 82.4% of withdrawal patients still had HB values below their own baseline 1 week after stopping stimulation, suggesting a possible sustained effect on upper airway function even after brief cessation.

What Are the Clinical Implications?

The authors concluded that HB may serve as a complementary physiologic marker alongside AHI for evaluating HGNS treatment response, particularly since patients receiving HGNS have already failed first-line PAP therapy. They noted several limitations, including the study's retrospective design, small subgroup sizes, single-night polysomnography assessment, and use of a first-generation HGNS device that has since been modified, which may limit generalizability to current systems.

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. Published online May 21, 2026. doi:10.1001/jamaoto.2026.1049
2. Azarbarzin A, Sands SA, Stone KL, et al. The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study. Eur Heart J. 2019;40(14):1149-1157. doi:10.1093/eurheartj/ehy624