Aims and objective: Improved understanding of endotypic traits has added potential targets for drug treatments in OSA. The carbonic anhydrase inhibitor sulthiame (STM) has been shown to be both safe and efficacious in OSA (Hedner 2022). A deeper understanding of STM-induced changes of endotypic traits would be of value in the continued STM development.

Methods: Post-hoc analysis of a RCT with inclusion criteria: BMI >20 to <35 kg/m², age 18-75 years, apnea-hypopnea index (AHI) >15/h, Epworth sleepiness scale >6 and non-acceptance of CPAP treatment. Exclusion criteria: central sleep apnea, uncontrolled hypertension or severe hypoxia. The study duration was 4 weeks, and patients were randomized to placebo (n=22), STM 200 mg (n=12) or 400 mg (n=24). Polysomnography (PSG) was applied twice at baseline and follow-up. Endotypic traits were derived from PSG (Terrill 2015). STM plasma concentration was analysed. Differences at baseline to follow-up (?) were analysed with ANCOVA/Kruskal-Wallis H-test and Pearson/Spearman correlation (r /r_s).

Results: STM (200+400 mg groups) consistently reduced loop gain (LG₁) (mean -0.16, 95% CI -0.18 to -0.13, p <0.05), increased V_min and V_passive (median +11.6, 95% CI 5.5 to 19.7 and +3.5, 95% CI 0.5 to 4.8, both p <0.05). ?LG₁ correlated with ?AHI% (200 mg: r 0.65, p<0.05) and ?V_min/?V_passive with ?AHI (all STM: r_s -0.59 / r_s -0.65, all p<0.05). The reduction of AHI and LG₁ after STM was seen in a lower concentration range, while changes in V_min and V_passive peaked in a higher range.

Conclusions: STM reduced AHI in OSA already in the lower concentration range. The effect of STM in OSA may be explained by reduced ventilatory instability and improved upper airway collapsibility.