Acetazolamide Plus Atomoxetine for Obesity Hypoventilation Syndrome Treatment

ABSTRACT Background A subgroup of obese patients exhibits hypoventilation due to, 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 the obesity-hypoventilation syndrome (OHS). If left untreated, OHS is associated with significant morbidity and mortality. Beside 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 Will 2 weeks of 500mg acetazolamide plus 100mg atomoxetine (AZ) daily be effective on OHS severity (reduction in mean nocturnal CO2 as primary outcome)? Methods In a randomized, double-blind crossover trial we compared 2 weeks of AZ with placebo in OHS subjects not treated with PAP. Subjects with a body mass index (BMI) ≥ 35 kg/m2 performed a 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 15 subjects with median [IQR] age 53 [36, 59] years, 8 females, BMI 44 [42, 53] kg/m², baseline PtcCO₂ 49 [44, 55] mmHg, apnea-hypopnea index (AHI) 64 [36, 83]/h and average nocturnal SpO2 84 [79, 89] % were randomized. AZ decreased nocturnal PtcCO₂ by mean (95% confidence interval) −5.8 (−7.8, −3.7) mmHg (p<0.001) and diurnal CO₂ compared with placebo. The AHI decreased by −20.9 (−26.7, −15.1) events/h (p<0.001) and mean overnight SpO₂ increased by 4.3 (2.8, 5.7)%, p<0.001. No serious adverse events occurred. Interpretation The administration of AZ significantly improved sleep-related hypoventilation, oxygen parameters and AHI in treatment-naïve OHS patients. This proof-of-concept study provides encouraging results for a potential pharmaco-therapy for OHS.