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

Abstract

BackgroundThe 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 QuestionHow does sulthiame treatment modify endotypic traits in OSA?Study Design and MethodsPer-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.ResultsSulthiame (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 (Vmin; median, +12 [95% CI, 4-20]; P < .05) and median ventilation at eupneic ventilatory drive (Vpassive; median, +4 [95% CI, 0-5]; P < .05). ΔLG1 correlated with ΔAHI% (200 mg: r = 0.65; P < .05) and Vmin / Vpassive with ΔAHI (all sulthiame: rs = –0.59 / rs = –0.65; P < .05 for all). The reduction of LG1 was seen already in the lower sulthiame concentration range, whereas changes in Vmin peaked in the higher range.InterpretationThe effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG1) as well as upper airway collapsibility (Vmin / Vpassive).Trial RegistryEuropean Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu 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. How does sulthiame treatment modify endotypic traits in OSA? 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. 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 (Vmin; median, +12 [95% CI, 4-20]; P < .05) and median ventilation at eupneic ventilatory drive (Vpassive; median, +4 [95% CI, 0-5]; P < .05). ΔLG1 correlated with ΔAHI% (200 mg: r = 0.65; P < .05) and Vmin / Vpassive with ΔAHI (all sulthiame: rs = –0.59 / rs = –0.65; P < .05 for all). The reduction of LG1 was seen already in the lower sulthiame concentration range, whereas changes in Vmin peaked in the higher range. The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG1) as well as upper airway collapsibility (Vmin / Vpassive). European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu Take-home PointsStudy Question: How does sulthiame treatment modify endotypic traits in OSA?Results: During a 4-week randomized controlled trial, sulthiame reduced ventilatory loop gain and increased the passive upper airway stability (ventilation at lowest decile of ventilatory drive and median ventilation at eupneic ventilatory drive) in comparison with placebo.Interpretation: The effect of sulthiame in OSA may be explained by both a reduction of ventilatory instability as well as a reduction in upper airway collapsibility. Study Question: How does sulthiame treatment modify endotypic traits in OSA? Results: During a 4-week randomized controlled trial, sulthiame reduced ventilatory loop gain and increased the passive upper airway stability (ventilation at lowest decile of ventilatory drive and median ventilation at eupneic ventilatory drive) in comparison with placebo. Interpretation: The effect of sulthiame in OSA may be explained by both a reduction of ventilatory instability as well as a reduction in upper airway collapsibility. OSA is a common disorder with an estimated global prevalence of 1 billion.1Benjafield A.V. Ayas N.T. Eastwood P.R. et al.Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis.Lancet Respir Med. 2019; 7: 687-698Abstract Full Text Full Text PDF PubMed Scopus (1570) Google Scholar The disease is characterized by repetitive collapse of the upper airway during sleep that leads to oxygen desaturation and frequent awakenings.2Gottlieb D.J. Punjabi N.M. Diagnosis and management of obstructive sleep apnea.JAMA. 2020; 323: 1389Crossref PubMed Scopus (489) Google Scholar Short-term and long-term consequences of OSA include daytime sleepiness, cognitive impairment, or both3Stranks E.K. Crowe S.F. The cognitive effects of obstructive sleep apnea: an updated meta-analysis.Arch Clin Neuropsychol. 2016; 31: 186-193PubMed Google Scholar; metabolic disorders4Barros D. García-Río F. Obstructive sleep apnea and dyslipidemia: from animal models to clinical evidence.Sleep. 2019; 42Crossref PubMed Scopus (59) Google Scholar, 5Hedner J. Grote L. Bonsignore M. et al.The European Sleep Apnoea Database (ESADA): report from 22 European sleep laboratories.Eur Respir J. 2011; 38: 635-642Crossref PubMed Scopus (106) Google Scholar, 6Reutrakul S. Mokhlesi B. Obstructive sleep apnea and diabetes.Chest. 2017; 152: 1070-1086Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar; as well as an increased risk of cardiovascular disease (eg, hypertension, stroke, and ischemic heart disease).7Gottlieb D.J. Yenokyan G. Newman A.B. et al.Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure.Circulation. 2010; 122: 352-360Crossref PubMed Scopus (1169) Google Scholar, 8Kendzerska T. Gershon A.S. Hawker G. Leung R.S. Tomlinson G. Obstructive sleep apnea and risk of cardiovascular events and all-cause mortality: a decade-long historical cohort study.PLoS Med. 2014; 11e1001599Crossref PubMed Scopus (303) Google Scholar, 9Redline S. Yenokyan G. Gottlieb D.J. et al.Obstructive sleep apnea–hypopnea and incident stroke.Am J Respir Crit Care Med. 2010; 182: 269-277Crossref PubMed Scopus (973) Google Scholar, 10Peppard P.E. Young T. Palta M. Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension.N Engl J Med. 2000; 342: 1378-1384Crossref PubMed Scopus (4083) Google Scholar Positive airway pressure (PAP) is the dominating therapy in OSA. PAP reduces OSA by effectively splinting the upper airway, reducing collapsibility, and thereby efficiently preventing breathing disturbances. However, long-term compliance is insufficient.2Gottlieb D.J. Punjabi N.M. Diagnosis and management of obstructive sleep apnea.JAMA. 2020; 323: 1389Crossref PubMed Scopus (489) Google Scholar,11Kohler M. Smith D. Tippett V. Stradling J.R. Predictors of long-term compliance with continuous positive airway pressure.Thorax. 2010; 65: 829-832Crossref PubMed Scopus (184) Google Scholar A great need exists for new, efficacious, and well-tolerated treatments to reduce OSA-related morbidity and mortality. A deeper understanding of the pathophysiologic mechanisms in OSA has increased the number of potential treatment targets.12Taranto M. Messineo Wellman Targeting endotypic traits with medications for the pharmacological treatment of obstructive sleep apnea. A review of the current literature.J Clin Med. 2019; 8: 1846Crossref PubMed Scopus (55) Google Scholar,13Hedner J. Zou D. Turning over a new leaf—pharmacologic therapy in obstructive sleep apnea.Sleep Med Clin. 2022; 17: 453-469Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The detailed pathophysiologic characteristics still are not understood completely, but involve multiple mechanisms (endotypic traits) such as compromised anatomic features, reduced upper airway muscle responsiveness, ventilatory instability (increased loop gain), and low arousal threshold.14Eckert D.J. White D.P. Jordan A.S. Malhotra A. Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets.Am J Respir Crit Care Med. 2013; 188: 996-1004Crossref PubMed Scopus (740) Google Scholar A better understanding of the mechanisms involved is expected to enable a personalized therapy in OSA by targeting specific trait patterns. Defining the endotypic traits in patients with OSA has been complex and laborsome, but developments in polysomnography analysis have facilitated these approximations and et polysomnography in patients with obstructive sleep J Respir Crit Care Med. PubMed Scopus Google Scholar, S. et the ventilatory to sleep Respir J. 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