Novel Sleep Apnea Pill More Effective After Menopause?

PHOENIX — A novel oral drug targeting neuromuscular dysfunction in obstructive sleep apnea (OSA) appeared to work particularly well among postmenopausal women, a post hoc analysis of randomized controlled trials showed.

Aroxybutynin/atomoxetine (AD109) reduced Apnea-Hypopnea Index (AHI) by 6.9 more events per hour than placebo at 26 weeks among postmenopausal women compared with 5.7 among men and non-menopausal women, with relative 52.8% versus 36.8% reductions from baseline.

Hypoxic burden dropped by a relative 62.1% among postmenopausal women compared with 43.6% among other trial participants, reported Reena Mehra, MD, of the University of Washington in Seattle, at the CHEST annual meeting hosted by the American College of Chest Physicians. No statistical interaction analysis was formally done.

For women, prevalence of OSA increases about threefold after menopause, although it is underrecognized in this group, “because their symptoms tend to be different,” Mehra said. “You have like an obese white male sleepy in your waiting room, you think of obstructive sleep apnea. You see a postmenopausal woman who maybe has some insomnia, maybe has some fatigue, depression, and you’re thinking ‘Oh, it’s postmenopausal-related symptoms. The obstructive sleep apnea is not in the forefront of your mind.'”

Prior research has not shown clear evidence of sex-specific differences in treatment responsiveness to other OSA treatments, she said.

“We are quite keen to have some new treatment option for them, which is oral, simple,” said session moderator Hoi Yee Kwan, MBChB, chief of respiratory medicine at Kowloon Hospital in Hong Kong, who was not involved in the trials.

However, she expressed skepticism that the drug really was more effective in postmenopausal women, suggesting the association could just reflect confounding from how the researchers designed the study and also the inclusion criteria.

The researchers pooled data across the SynAIRgy and LunAIRo trials that had included a total of 1,306 patients with symptomatic mild-to-severe OSA (AHI 5 events per hour or more, PROMIS-Fatigue score at least 17) and a body mass index (BMI) of 18.5 to 42 for women or 18.5 to 40 for men. Participants had been randomized to the once-daily tablet containing 2.3 mg aroxybutynin and 75 mg atomoxetine or placebo at bedtime.

Among the participants, 492 women had a menopause-related medical history or were age 55 or older, comprising the postmenopausal group. In the non-menopausal group, 15.4% were women.

The postmenopausal group was older (median 62 vs 54), with a slightly higher baseline BMI (32.5 vs 31.9), and somewhat less severe OSA (AHI 18.5 vs 20.6 events/hour, hypoxic burden 30.3 vs 35.4). The proportion randomized to aroxybutynin/atomoxetine was 53.3% versus 48.5% in the non-menopausal group.

Response rate as marked by a reduction of at least 50% in AHI was a model-adjusted 26.9% in the postmenopausal women compared with 15.3% in the non-menopausal group at week 26. The proportion with at least a 70% relative reduction in AHI was 21.3% versus 12.7%.

Overall treatment-emergent adverse event rates and discontinuation due to these events were similar between the two groups. However, certain aroxybutynin/atomoxetine-linked events were disproportionately more common in the postmenopausal group than in the non-menopausal group, including dry mouth (45.8% vs 32.0%), insomnia (23.7% vs 20.5%), nausea (17.6% vs 8.7%), constipation (9.5% vs 2.8%), and urinary tract infection (6.9% vs 2.8%).

Differences in side effects could affect adherence, particularly things like insomnia, which are already increased after the menopausal transition, Mehra said.

Limitations of the study included lack of statistical analysis of the descriptive findings, no data on hormone therapy use, and heterogeneity in the non-menopausal group.

The study couldn’t determine why there were differences across groups or even that the differences weren’t due to some other confounding factor, Mehra acknowledged.

“We know that men have, obviously, a greater degree of sleep apnea. They have different underlying contributors to their sleep apnea compared to women,” she said. “We need to stratify and break out the premenopausal women and compare that to postmenopausal women and even compare the women to men.”