Carbonic Anhydrase Inhibitors: A New Dawn for the Treatment of Obstructive Sleep Apnea

To the Editor:

With interest, we read the paper of Hedner and colleagues (1), which confirms that sulthiame (a carbonic anhydrase inhibitor [CAI]) showed a satisfactory safety profile in moderate and/or severe obstructive sleep apnea (OSA) and reduced OSA, on average, by more than 20 events/h, one of the strongest reductions reported in a drug trial in OSA. OSA causes a series of brief, severe episodes of hypoxia and hypercapnia, resulting in persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system. Although passive critical closing pressure of the upper airway-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA (2). An important factor in OSA is high circulatory gain, which is not only a driver of central sleep apnea but also a major contributor to the pathogenesis of OSA in 30–40% of patients (3). Individuals with high loop gain tend to experience periodic declines in respiratory drive, resulting in decreased activation of the upper airway dilator muscles, leading directly to repetitive breathing events (i.e., OSA), an important ventilatory regulator of which is carbonic anhydrase, which is also the rationale for CAIs in the treatment of individuals with OSA (4, 5). The results of this study and previous studies (6, 7) provide a solid theoretical basis for exploring long-term treatment with CAIs for OSA and determining the most effective dose, with cross-generational significance.

In Hedner and colleagues’ study (1), 4 weeks of sulthiame treatment had therapeutic effects (on apnea–hypopnea index [AHI] and sleep quality) on all patients with OSA, but at this time point, AHI has not yet decreased to the normal range. We believe the reasons why sulthiame treatment of OSA could not reduce AHI to normal may include the following: the time period of 4 weeks was too short, the selected patients were too ill, and the patient phenotype may not have been high loop gain. To address these influencing factors, we can begin with the following approaches: increase the treatment observation time and include patients with high loop gain and mild OSA. If CAIs have a better treatment effect on these phenotypes in patients with OSA, then the precise treatment of these patients will be more readily undertaken. We believe that suitable populations for sulthiame treatment for OSA include mainly individuals with high loop gain type, patients with mild OSA, patients with moderate to severe OSA who cannot tolerate continuous positive airway pressure therapy, patients with OSA who are not suitable for pharyngeal surgery, and individuals with postoperative residual OSA. Thereafter, we can continue to explore whether it is better to use CAIs combined with mandibular advancement devices or combined with tongue and facial muscles.

In view of the foregoing considerations, although the sample size of Hedner and colleagues’ study (1) was small, the study shows that CAIs can be used as a new drug treatment to reduce disease severity and complications among patients with OSA. A long-term, multicenter study, with a large sample size, of the efficacy of CAI treatment is expected. In future studies, patients who are suitable for sulthiame treatment may be screened for precise treatment, which may have better therapeutic effects.