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

Abstract

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 (r) or Spearman correlations (r_s).

Results: Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain (response to a 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 percentage (200 mg: r = 0.65; P < .05). V_min and V_passive correlated with ΔAHI (all sulthiame: r_s = -0.59 and 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 and V_passive).

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

Keywords: OSA; drug treatment; endotypic traits; sulthiame.