Modification of Endotypic Traits in OSA by the Carbonic Anhydrase Inhibitor Sulthiame

Background

The carbonic anhydrase inhibitor sulthiame reduces OSA severity, increases overnight oxygenation, and improves sleep quality. Insights into how sulthiame modulates OSA pathophysiologic features (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation.

Research Question

How does sulthiame treatment modify endotypic traits in OSA?

Study Design and Methods

Per-protocol tertiary analysis of a randomized controlled trial with the inclusion criteria as follow: BMI, ≥ 20 to ≤ 35 kg/m²; age, 18-75 years; apnea-hypopnea index (AHI) ≥ 15 events/h; Epworth sleepiness scale score, ≥ 6; as well as nonacceptance or nontolerance of positive airway pressure treatment. Patients were randomized to receive placebo (n = 22), sulthiame 200 mg (n = 12), or sulthiame 400 mg (n = 24) during 4 weeks of treatment. Polysomnography was applied twice, at baseline and follow-up. Endotypic traits were determined from polysomnography tracings (PUPBeta). Sulthiame plasma concentration was analyzed. Differences from baseline to follow-up (Δs) were analyzed with the analysis of covariance or Kruskal-Wallis H test and Pearson or Spearman correlations.

Results

Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain response to 1-cycle/min disturbance (LG₁; mean, –0.16 [95% CI, –0.18 to –0.13]; P < .05) in addition to increased ventilation at lowest decile of ventilatory drive (V_min; median, +12 [95% CI, 4-20]; P < .05) and median ventilation at eupneic ventilatory drive (V_passive; median, +4 [95% CI, 0-5]; P < .05). ΔLG₁ correlated with ΔAHI% (200 mg: r = 0.65; P < .05) and V_min / V_passive with ΔAHI (all sulthiame: r_s = –0.59 / r_s = –0.65; P < .05 for all). The reduction of LG₁ was seen already in the lower sulthiame concentration range, whereas changes in V_min peaked in the higher range.

Interpretation

The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG₁) as well as upper airway collapsibility (V_min / V_passive).

Trial Registry

European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu