Why the ‘Take a Pill’ Approach Makes Sense for Some OSA Patients
Tirzepatide isn’t the only pharmacologic approach to treating obstructive sleep apnea (OSA). Several drugs are in development that promise to mitigate some of the root causes of the disorder.
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August 2024“Patients often ask me whether there is a pill they could take for their sleep apnea—particularly those who can’t tolerate CPAP,” said Kathleen L. Yaremchuk, MD, chair of otolaryngology/head and neck surgery and a member of the division of sleep medicine at Henry Ford Health in Detroit. “In the past, I’d sort of laugh and explain that a pill can’t address an anatomic blockage of the upper airway. Well, in a year or two, my answer will be different, because we do in fact have medications that increase the tone of the upper airway.”
This development “reminds us that although we call this disorder obstructive sleep apnea, it’s also physiologic,” Dr. Yaremchuk said. “This is a sea change in how we are viewing future treatments of OSA.”
One example is AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine. Dr. Yaremchuk participated in the phase 2 randomized, double-blind, placebo-controlled, parallel-group, Mariposa trial assessing the combination in 181 patients (Am J Respir Crit Care Med. 2023;208:1316-1327). The investigators reported significant improvement in several OSA markers. For example, AHI with a 4% desaturation criterion (primary outcome) was reduced from a median of 20.5 (12.3–27.2) to 10.8 (5.6–18.5) in a 2.5/75-mg drug combination arm (−47.1%), and from 19.4 (13.7–26.4) to 9.5 (6.1–19.3) in a 5/75 mg arm (−42.9%; both P<0.0001 versus placebo).
Subjectively, there was an improvement in fatigue with the 2.5/75 mg dosage (P<0.05 versus placebo and atomoxetine). The most common adverse events were dry mouth, insomnia, and urinary hesitancy.
Dr. Yaremchuk underscored why this pharmacologic approach “will be a game changer” for certain OSA patients. For some of them, she noted, “the upper airway muscles are incompetent. When an individual goes to sleep, their muscles relax and their upper airway collapses.” The atomoxetine component of AD109 “acts on the brainstem and increases muscle tone during sleep and keeps the airway open.” The antimuscarinic component is needed, she added, to ensure that patients aren’t stimulated during sleep with insomnia, because atomoxetine has been shown to increase heart rate—an adverse reaction observed in the Mariposa trial, although to a lesser degree than in previous studies (Drug Saf. 2003;26:729-740).
As for how AD109 and other drug therapies might ultimately fit into OSA treatments, Dr. Yaremchuk said a multimodal approach is most likely. It’s not unusual, she noted, for patients with diabetes, hypertension, or a host of other chronic conditions to require two different medications to control their disease. “OSA is no different,” she said. “Maybe they will need an oral mandibular device. Maybe they need CPAP or perhaps some form of surgery. Now, we have drugs in the pipeline that also can help—including a novel TASK channel antagonist nasal spray that reduces sleep apnea severity [Am J Physiol Heart Circ Physiol. 2024;326:H715-H723]. This gives us even more treatment options we can titrate until OSA symptoms are finally under control.”
Thomas M. Kaffenberger, MD, an assistant professor in the department of otolaryngology–head and neck surgery at the University of Pittsburgh School of Medicine, agreed that the AD109 results “are encouraging, but we don’t yet know whether OSA patients actually will be able to tolerate these medications long term.” If follow-up data confirm safety and efficacy, he noted, “Fantastic; maybe we can combine atomoxetine and oxybutynin with tirzepatide or some other weight loss options, which is great news for all of the OSA patients who we know can’t tolerate CPAP.”