Obstructive Sleep Apnea (OSA) remains a prevalent comorbidity in physiotherapy practice, often presenting alongside obesity, metabolic syndrome, and cardiovascular dysfunction. While Continuous Positive Airway Pressure (CPAP) has long been the gold standard for treatment, adherence remains a significant barrier. Consequently, Hypoglossal Nerve Stimulation (HGNS) has emerged as a viable alternative for selected patients. However, while the respiratory benefits of HGNS are well-documented, its impact on systemic metabolism—specifically energy balance and insulin sensitivity—has remained largely unexplored. The newly published protocol for the Metabolic Assessments of Neurostimulation Therapy to Reduce Apnea (MANTRA) trial seeks to fill this critical knowledge gap.
The Physiology of Neurostimulation in OSA
Physiotherapists understand that sleep fragmentation and intermittent hypoxia drive sympathetic overactivity and systemic inflammation, contributing to insulin resistance. The MANTRA trial, detailed in Sleep & Breathing (2026), represents the first randomized controlled trial designed to mechanistically examine the metabolic effects of HGNS. Unlike observational studies, this trial aims to isolate the physiological changes induced by neurostimulation, independent of other lifestyle factors. The core hypothesis posits that by stabilizing upper airway patency and normalizing sleep architecture, HGNS may positively influence energy expenditure and glucose homeostasis.
The MANTRA Trial: A Rigorous Crossover Design
To rigorously assess these metabolic parameters, the researchers have implemented a randomized, within-subject crossover design. The study recruits 30 patients who have already been stabilized on HGNS therapy for a minimum of three months. This stabilization period ensures that any observed changes are not due to the acute novelty of the device but rather the physiological maintenance of airway patency.
Participants undergo two distinct phases lasting between two to four weeks each: an “HGNS-on” phase (active therapy) and an “HGNS-off” phase (withdrawal of therapy). To mitigate carryover effects, a one-week washout period where patients resume standard HGNS usage separates the two phases. This withdrawal design is particularly powerful in clinical research as it allows each subject to serve as their own control, significantly reducing the confounding variables often seen in parallel-group studies involving metabolic rates.
Measuring Metabolic Flux: Beyond Simple Anthropometry
The MANTRA trial utilizes high-fidelity measurement tools relevant to rehabilitation science. The primary outcome is energy balance, calculated as the differential between energy expenditure and energy intake. Notably, a subset of participants will undergo assessment via the doubly labeled water technique—the gold standard for measuring free-living energy expenditure. Secondary outcomes include the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), fasting anthropometrics, and comprehensive home sleep testing.
Clinical Implications for Physiotherapy Practice
For the orthopaedic and manipulative physiotherapist, the results of the MANTRA trial could redefine how we approach comorbidities in OSA patients. If HGNS is proven to improve insulin resistance and energy balance, it strengthens the argument for treating sleep disordered breathing as a prerequisite for successful metabolic rehabilitation and weight management. Understanding whether neurostimulation offers metabolic advantages over, or in addition to, mechanical CPAP therapy will assist clinicians in providing holistic lifestyle and exercise prescription advice to patients utilizing these devices.
References
Cai, Y., Lin, A., Kutler, R. B., Lopez-Peña, J. A., Suurna, M. V., Kacker, A., Cheng, B., Kezirian, E. J., Golub, J. S., Jelic, S., & St-Onge, M. P. (2026). Metabolic assessments of neurostimulation therapy to reduce apnea (MANTRA) trial: rationale and methods. Sleep & Breathing. https://pubmed.ncbi.nlm.nih.gov/41697428/
