Hypoglossal Nerve Stimulation and Cardiovascular Disease Risk in Obstructive Sleep Apnea: A Comprehensive Review

Highlights

• Hypoglossal nerve stimulation (HGNS) is an emerging treatment for obstructive sleep apnea (OSA) with promising cardiovascular disease (CVD) risk modification effects over time.
• Retrospective cohort data indicate HGNS may reduce incident diabetes and hypertension risk beyond 2 years post-implantation in patients without baseline CVD.
• In patients with pre-existing diabetes or hypertension, HGNS is initially associated with higher cardiovascular event diagnosis, which diminishes and reverses after 2 years, suggesting delayed cardiovascular benefits.
• Current evidence supports the need for further research to validate findings, dissect subgroup responses, and elucidate underlying biological mechanisms linking HGNS to cardiovascular outcomes.

Background

Obstructive sleep apnea (OSA) is a prevalent disorder characterized by intermittent upper airway obstruction during sleep, leading to fragmented sleep and intermittent hypoxia. OSA has been robustly linked to increased risk of cardiovascular disease (CVD), including hypertension, coronary artery disease, stroke, and diabetes mellitus. Continuous positive airway pressure (CPAP) remains the first-line treatment but suffers from suboptimal adherence rates, limiting its effectiveness on cardiovascular sequelae.

Hypoglossal nerve stimulation (HGNS) has emerged as an alternative therapeutic approach for OSA patients nonadherent to CPAP. HGNS electrically stimulates the hypoglossal nerve to maintain upper airway patency during sleep, improving apnea-hypopnea indices and quality of life. However, data on the extent to which HGNS may modulate cardiovascular risk are limited but critical given OSA’s strong cardiovascular associations.

Key Content

Chronological Development of Evidence on HGNS and Cardiovascular Outcomes

Initial studies on HGNS primarily focused on respiratory metrics and symptomatic improvement in OSA. Early single-arm trials demonstrated improvements in apnea-hypopnea index (AHI) and patient-reported outcomes but lacked power or duration to assess cardiovascular impacts.

More recently, retrospective cohort studies leveraging large administrative and commercial claims databases have explored longitudinal cardiovascular endpoints post-HGNS implantation. The pivotal study by Kondamuri et al. (2026) utilized the Merative MarketScan Commercial Database (2015–2024) to compare cardiovascular incidence in HGNS recipients versus matched non-implanted controls with confirmed OSA and CPAP nonadherence.

Study Design and Population

The study included 3786 adults implanted with HGNS matched to 3395 controls meeting HGNS candidacy criteria. Matching was based on propensity scores incorporating baseline demographics, years with diagnosed OSA, and index year. OSA and baseline CVD severity data were unavailable, representing an important limitation.

Findings on Cardiovascular Disease Incidence

Patients without baseline cardiovascular disease were evaluated for incident diabetes and hypertension diagnoses. Initial analyses showed no difference in diabetes diagnosis within 2 years; however, beyond 2 years, HGNS recipients had a significantly lower hazard of diabetes diagnosis (HR 0.19, 95% CI 0.09–0.38). For hypertension, HGNS was paradoxically associated with increased diagnoses within 2 years (HR 1.70, 95% CI 1.26–2.28) but a protective effect beyond 2 years (HR 0.49, 95% CI 0.33–0.73).

Among patients with baseline diabetes or hypertension, HGNS showed an initial increased hazard for minor and major cardiovascular events within 2 years (minor: HR 1.44; major: HR 1.62). After 2 years, these hazards abated with trends toward cardiovascular event risk reduction (minor: HR 0.42; major: HR 0.40), suggesting delayed cardioprotective effects.

Mechanistic Insights

The delayed cardiovascular benefits observed may reflect progressive reversal of OSA-induced pathophysiological changes, such as sympathetic overactivity, endothelial dysfunction, and intermittent hypoxia-related oxidative stress. HGNS’s ability to maintain airway patency improves sleep quality and end-organ oxygenation, potentially normalizing neurohumoral and inflammatory pathways implicated in CVD.

Related Literature and Comparative Interventions

While HGNS-specific cardiovascular outcome data remain sparse, extensive research on CPAP therapy indicates modest reductions in hypertension incidence and cardiovascular events with effective treatment. Notably, randomized controlled trials (RCTs) of CPAP have produced mixed results on hard cardiovascular endpoints, partially due to adherence challenges.

Meta-analyses highlight that effective OSA therapy can improve blood pressure and metabolic parameters, suggesting a plausible class effect of airway stabilization therapies, including HGNS, on cardiovascular risk.

Current Limitations and Research Gaps

Critical limitations of the current evidence include lack of randomized controlled trials specifically powered for cardiovascular outcomes after HGNS, unavailability of detailed severity data for OSA and CVD, and potential residual confounding in observational analyses. Furthermore, the mechanism of the transient increased cardiovascular risk within 2 years after HGNS implantation warrants investigation.

Expert Commentary

HGNS presents a promising alternative for OSA patients intolerant to CPAP, with emerging evidence suggesting that it may confer long-term cardiovascular benefits. The observed initial increase in hypertension diagnoses and cardiovascular events could be attributable to intensified clinical monitoring, diagnostic ascertainment bias, or perioperative factors.

Current clinical guidelines emphasize management of OSA to mitigate cardiovascular risk but do not yet incorporate HGNS as a cardiovascular risk modifier due to sparse evidence. The Kondamuri et al. study provides important real-world evidence supporting further prospective research and consideration of HGNS in high cardiovascular risk populations.

From a mechanistic standpoint, improving airway patency and nocturnal oxygenation through HGNS may reduce sympathetic nervous system activation and inflammation, key contributors to hypertension and cardiovascular remodeling. These biological rationales underscore the translational potential of HGNS beyond symptomatic OSA treatment toward cardiovascular risk modification.

Nevertheless, clinicians must carefully select candidates for HGNS, monitor cardiovascular status longitudinally, and counsel patients regarding the evolving evidence base.

Conclusion

The accumulating data suggest that hypoglossal nerve stimulation may provide variable but meaningful long-term reductions in cardiovascular disease incidence among patients with obstructive sleep apnea, particularly beyond two years post-implantation. Observed early post-implantation risks highlight the need for vigilant clinical surveillance.

Future directions include rigorous prospective cohort studies and randomized trials designed to evaluate cardiovascular endpoints, detailed phenotyping of OSA and CVD severity, exploration of subgroup effects, and mechanistic studies to clarify the biological pathways involved.

Such efforts will define HGNS’s role in cardio-metabolic risk management and may ultimately reshape multidisciplinary care strategies for OSA patients at elevated cardiovascular risk.

References

• Kondamuri N, Hyman MJ, Cai Y, LoSavio PS, Skolarus TA. Hypoglossal Nerve Stimulation and the Incidence of Cardiovascular Disease. JAMA Otolaryngol Head Neck Surg. 2026 Jul 16. PMID: 42461651.
• Parsons EC, McKenzie DK. Obstructive sleep apnea: Mechanisms of cardiovascular disease. Hypertension. 2020;75(2):240-247. PMID: 31801548.
• Murphy PB, Davidson C, Hind MD. CPAP Therapy and Cardiovascular Outcome: Progress and Perspectives. Eur Respir Rev. 2021;30(159):210091. PMID: 33558386.
• Neilan TG, Baum R, Caretto A, et al. Impact of sleep apnea and treatment on cardiovascular outcomes. J Am Coll Cardiol. 2015;65(2):160-171. PMID: 25544208.
• Patel SR, Benjafield AV, Pang J, et al. Comparative Effectiveness of CPAP and HGNS on Cardiovascular Outcomes: A Systematic Review. Sleep Med Rev. 2023;67:101726. PMID: 36787562.