Atomoxetine plus oxybutynin
Combination therapy with atomoxetine (a selective noradrenaline-reuptake inhibitor) plus oxybutynin significantly improved OSA severity in patients with moderate pharyngeal collapsibility in a phase 2, randomised, placebo-controlled crossover study.[204]Schweitzer PK, Maynard JP, Wylie PE, et al. Efficacy of atomoxetine plus oxybutynin in the treatment of obstructive sleep apnea with moderate pharyngeal collapsibility. Sleep Breath. 2023 May;27(2):495-503.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098382
http://www.ncbi.nlm.nih.gov/pubmed/35551600?tool=bestpractice.com
The presumptive mechanism is enhanced genioglossus responsiveness.[205]Taranto-Montemurro L, Messineo L, Sands SA, et al. The combination of atomoxetine and oxybutynin greatly reduces obstructive sleep apnea severity. A randomized, placebo-controlled, double-blind crossover trial. Am J Respir Crit Care Med. 2019 May 15;199(10):1267-76.
https://www.atsjournals.org/doi/10.1164/rccm.201808-1493OC?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed
http://www.ncbi.nlm.nih.gov/pubmed/30395486?tool=bestpractice.com
Phase 2, randomised, double-blind, placebo-controlled trials report short-term improvement of OSA among patients who received atomoxetine plus aroxybutynin (an [R]-isomer of oxybutynin).[206]Schweitzer PK, Taranto-Montemurro L, Ojile JM, et al. The combination of aroxybutynin and atomoxetine in the treatment of obstructive sleep apnea (MARIPOSA): a randomized controlled trial. Am J Respir Crit Care Med. 9 Oct 2023 [Epub ahead of print].
https://www.atsjournals.org/doi/epdf/10.1164/rccm.202306-1036OC?role=tab
http://www.ncbi.nlm.nih.gov/pubmed/37812772?tool=bestpractice.com
[207]Rosenberg R, Abaluck B, Thein S. Combination of atomoxetine with the novel antimuscarinic aroxybutynin improves mild to moderate OSA. J Clin Sleep Med. 2022 Dec 1;18(12):2837-44.
http://www.ncbi.nlm.nih.gov/pubmed/35975547?tool=bestpractice.com
Novel implantable hypoglossal neurostimulation systems
Include systems that do not require a respiratory sensor (aura6000), instead using selective, cyclical, near tonic stimulation of the hypoglossal nerve’s trunk via multiple contacts. Drug-induced sleep endoscopy (DISE) is not needed for patient selection. AHI and oxygen desaturation index (ODI) reduction of 52% and 62%, and clinical improvement in sleepiness and quality of life have been demonstrated in a randomised-controlled trial (RCT).[208]Schwartz AR, Jacobowitz O, Eisele DW, et al. Targeted hypoglossal nerve stimulation for patients with obstructive sleep apnea: a randomized clinical trial. JAMA Otolaryngol Head Neck Surg. 2023 Jun 1;149(6):512-20.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080405
http://www.ncbi.nlm.nih.gov/pubmed/37022679?tool=bestpractice.com
An additional system (Genio) utilises an implantable receiver that stimulates the terminal hypoglossal nerve to the genioglossus muscles bilaterally. This system is unique in that the pulse generator is external, applied to the skin on a patch. In a case series of 22 patients, significant AHI and ODI reduction, and improvement in quality of life, was reported after 6 months.[209]Eastwood PR, Barnes M, MacKay SG, et al. Bilateral hypoglossal nerve stimulation for treatment of adult obstructive sleep apnoea. Eur Respir J. 2020 Jan 9;55(1):1901320.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949509
http://www.ncbi.nlm.nih.gov/pubmed/31601716?tool=bestpractice.com
Clinical trials are recruiting or ongoing.[210]ClinicalTrials.gov. Safety and effectiveness of the Genio® bilAteral Stimulation for treatment of Complete Concentric CollapsE and OSA. (ACCCESS). ClinicalTrials.gov Identifier: NCT05592002. Feb 2023 [internet publication].
https://classic.clinicaltrials.gov/ct2/show/study/NCT05592002
[211]ClinicalTrials.gov. Dual-sided Hypoglossal neRvE stimulAtion for the treatMent of Obstructive Sleep Apnea (DREAM) (DREAM). ClinicalTrials.gov Identifier: NCT03868618. 19 Apr 2023 [internet publication].
https://classic.clinicaltrials.gov/ct2/show/NCT03868618
Ansa cervicalis co-stimulation
Co-stimulation of the ansa cervicalis nerve with hypoglossal nerve stimulation resulted in a greater benefit than hypoglossal neurostimulation alone, in one small study.[212]Kent DT, Zealear D, Schwartz AR. Ansa cervicalis stimulation: a new direction in neurostimulation for OSA. Chest. 2021 Mar;159(3):1212-21.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097630
http://www.ncbi.nlm.nih.gov/pubmed/33065104?tool=bestpractice.com
The mechanism may be longitudinal stabilisation of the upper airway. Further trials are recruiting.[213]ClinicalTrials.gov. Ansa cervicalis and hypoglossal nerve stimulation in OSA. ClinicalTrials.gov Identifier: NCT05501236. Aug 2022 [internet publication].
https://clinicaltrials.gov/study/NCT05501236?cond=OSA&intr=%20ansa%20cervicalis%20stimulation&rank=1
Pharmacotherapy for concurrent obesity
Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, increases insulin secretion, suppresses glucagon secretion, and slows gastric emptying. In one RCT in moderate-to-severely obese OSA patients, liraglutide (as adjunct to diet and exercise) significantly reduced AHI, body weight, systemic blood pressure, and HbA1c compared with placebo.[214]Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (Lond). 2016 Aug;40(8):1310-9.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973216
http://www.ncbi.nlm.nih.gov/pubmed/27005405?tool=bestpractice.com
Liraglutide was generally well tolerated. One small trial to investigate the effect of liraglutide on cardiometabolic outcomes in patients with OSA is ongoing.[215]ClinicalTrials.gov. Effect of liraglutide vs CPAP on cardiometabolic outcomes in obstructive sleep apnea. ClinicalTrials.gov Identifier: NCT04186494. 31Jan 2022 [internet publication].
https://clinicaltrials.gov/study/NCT04186494?cond=OSA&intr=Liraglutide&rank=2