The impact of acetazolamide and dronabinol on the physiological endotypes responsible for obstructive sleep apnea

To investigate the effect of differing doses of the combination of acetazolamide and dronabinol (Aceta-Dro) on the obstructive sleep apnea (OSA) endotypes and their relationship to OSA severity. We retrospectively analysed data from a double-blind, randomized, placebo-controlled trial of 3 different doses of Aceta-Dro [Low(125mg/2.5 mg), Medium(250mg/5 mg), High(500mg/10 mg)] in OSA patients. OSA endotypes (collapsibility [V PASSIVE ], Loop gain [LG], Arousal threshold [ArTH], and muscle compensation [V COMP ]) were extracted from polysomnography signals using validated algorithms. Linear mixed models were employed to assess the impact of treatment condition on the endotypes. Linear regressions assessed the relationship between the changes in endotypes vs. apnea-hypopnea index (AHI) and to predict treatment response from baseline endotypes. Relative to placebo, Aceta-Dro dose-dependently reduced LG by 11 % (p = 0.18), 18.5 % (p = 0.022) and 20.5 % (p = 0.016). The reduction in LG was associated with a decrease in AHI in only the high dose condition (R 2 = 0.78, p = 0.004). Aceta-Dro improved V PASSIVE in the low dose condition (+13 %, p = 0.005) only, which was strongly associated with AHI reduction (R 2 = 0.71, p = 0.005). Aceta-Dro had no impact on V COMP or ArTH. A higher baseline LG predicted treatment response in the high dose (R 2 = 0.56, p = 0.03), with a similar trend observed in the low dose group. More severe collapsibility (lower V PASSIVE ) predicted treatment response to both low (R 2 = 0.46, p = 0.07) and medium dose (R 2 = 0.50, p = 0.03) conditions. Mechanistically, our findings suggest that medium and high doses of Aceta-Dro primarily reduce OSA severity by lowering loop gain, while the efficacy of the low dose was due to improved airway collapsibility. • Recently, acetazolamide + dronabinol (Aceta-Dro) was shown to improve OSA severity. • However, the exact mechanisms behind this improvement remained unclear. • Medium/high doses of Aceta-Dro improve OSA severity by lowering loop gain. • Low doses of Aceta-Dro improve OSA severity by improving airway collapsibility. • Loop gain and collapsibility were useful predictors of response to therapy.