Acetazolamide Plus Atomoxetine for Obesity Hypoventilation Syndrome Treatment.

Abstract

A subgroup of patients with obesity exhibits hypoventilation as a result of, among other mechanisms, a narrow, collapsible upper airway (UA), a reduced ventilatory drive during both wakefulness and sleep, and the loss of pharyngeal muscle tone during sleep. These features characterize obesity-hypoventilation syndrome (OHS). If left untreated, OHS is associated with significant morbidity and mortality. Besides lifestyle modifications, positive airway pressure (PAP) is the only available treatment, and it is often not well tolerated. Drugs designed to activate UA muscles such as atomoxetine and to stimulate breathing such as acetazolamide represent a potential novel strategy for treating OHS. Is 2 weeks of 500 mg acetazolamide plus 100 mg atomoxetine daily effective for OHS severity (reduction in mean nocturnal CO₂ as the primary outcome)? In a randomized, double-masked crossover trial, we compared 2 weeks of acetazolamide plus atomoxetine with placebo in patients with OHS not treated with PAP. Patients with a BMI of ≥ 35 kg/m² underwent polysomnography with transcutaneous overnight measurement of CO₂ (Ptcco₂) and morning blood test to evaluate sleep-related and diurnal hypercapnia at baseline and after each treatment sequence. Fifteen patients with a median age of 53 years (interquartile range [IQR], 36-59 years; 8 female patients; median BMI, 44 kg/m² [IQR, 42-53 kg/m²]; baseline median Ptcco₂, 49 mm Hg [IQR, 44-55 mm Hg]; median apnea-hypopnea index (AHI), 64 events/h [IQR, 36-83 events/h], and median nocturnal peripheral capillary oxygen saturation (Spo₂), 84% [IQR, 79%-89%]) were randomized. Acetazolamide plus atomoxetine decreased nocturnal Ptcco₂ by a mean of -5.8 mm Hg (95% CI, -7.8 to -3.7 mm Hg; P < .001) and diurnal CO₂ compared with placebo. Median AHI decreased by -20.9 events/h (95% CI, -26.7 to -15.1 events/h; P < .001) and mean overnight Spo₂ increased by 4.3% (95% CI, 2.8%-5.7%; P < .001). No serious adverse events occurred. Our results show that the administration of acetazolamide plus atomoxetine significantly improved sleep-related hypoventilation, oxygen parameters, and AHI in treatment-naive patients with OHS. This proof-of-concept study provides encouraging results for a potential pharmacotherapy for OHS. ClinicalTrials.gov; No.: NCT05448443; URL: www. gov.