Acetazolamide Plus Atomoxetine for Obesity Hypoventilation Syndrome Treatment

Background: 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. Research question: 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)? Study design and methods: 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. Results: 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 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. Interpretation: Our results show that the administration of acetazolamide plus atomoxetine significantly improved sleep-related hypoventilation, oxygen parameters, and AHI in treatment-naïve patients with OHS. This proof-of-concept study provides encouraging results for a potential pharmacotherapy for OHS.