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In people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first-line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (BF2.649 in Patients With OSA and Treated by CPAP But Still Complaining of EDS [HAROSA 1]) and the other in patients refusing or not tolerating CPAP (BF2.649 in Patients With OSA, Still Complaining of EDS and Refusing to be Treated by CPAP [HAROSA 2]). Does the efficacy and safety of pitolisant persist when these patients take it long-term? All adults included in the HAROSA 1 and HAROSA 2 RCTs (both pitolisant and placebo arms) were offered pitolisant (up to 20 mg/d) after completion of the short-term double-anonymized phase (ie, from week 13) in an open-label cohort study. The primary efficacy outcome was the change in Epworth Sleepiness Scale score between baseline and week 52. Safety outcomes were treatment-emergent adverse event(s) (TEAE[s]), serious TEAEs, and special interest TEAEs. Out of 512 adults included in the two RCTs, 376 completed the 1-year follow-up. The pooled mean difference in Epworth Sleepiness Scale score from baseline to 1 year for the intention-to-treat sample was −8.0 (95% CI, −8.3 to −7.5). The overall proportions of TEAEs, serious TEAEs, and TEAEs of special interest were 35.1%, 2.0%, and 11.1%, respectively, without any significant difference between patients in the initial pitolisant and placebo arms. No cardiovascular safety issues were reported. Pitolisant is effective in reducing daytime sleepiness over 1 year in adults with OSA, with or without CPAP treatment. Taken for 1 year, it has a good safety profile (including cardiovascular). ClinicalTrials.gov; Nos.: NCT01071876 and NCT01072968; URL: www.clinicaltrials.gov [Display omitted] [ABSTRACT FROM AUTHOR]

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 (r) or Spearman correlations (r s). Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain (response to a 1-cycle/min disturbance, LG 1 ; 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). ΔLG 1 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 LG 1 was seen already in the lower sulthiame concentration range, whereas changes in V min peaked in the higher range. The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG 1) as well as upper airway collapsibility (V min and V passive). European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu [ABSTRACT FROM AUTHOR]

Emerging data suggest that determination of physiologic endotypic traits (eg, loop gain) may enable precision medicine in OSA. Does a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in moderate to severe OSA? Two consecutive in-lab polysomnography tests from a clinical trial (n = 67; male, 69%; mean ± SD age, 61 ± 10 years; apnea-hypopnea index [AHI] 53 ± 22 events/h) were used for the reliability analysis. Endotypic traits, reflecting upper airway collapsibility (ventilation at eupneic drive [V passive ]), upper airway dilator muscle tone (ventilation at the arousal threshold [V active ]), loop gain (stability of ventilatory control, LG1), and arousal threshold (ArTh) were determined. Reliability was expressed as an intraclass correlation coefficient (ICC). Minimal detectable differences (MDDs) were computed to provide an estimate of maximum spontaneous variability. Further assessment across four repeated polysomnography tests was performed in a subcohort (n = 22). Reliability of endotypic traits between the two consecutive nights was moderate to good (ICC: V passive = 0.82, V active = 0.76, LG1 = 0.72, ArTh = 0.83). Variability in AHI, but not in body position or in sleep stages, was associated with fluctuations in V passive and V active (r = –0.49 and r = –0.41, respectively; P <.001 for both). MDDs for single-night assessments were: V passive = 22, V active = 34, LG1 = 0.17, and ArTh = 21. Multiple assessments (mean of two nights, n = 22) further reduced MDDs by approximately 20% to 30%. Endotypic trait analysis using a single standard polysomnography shows acceptable reliability and reproducibility in patients with moderate to severe OSA. The reported MDDs of endotypic traits may facilitate the quantification of relevant changes and may guide future evaluation of interventions in OSA. [ABSTRACT FROM AUTHOR]

Background: Excessive sleepiness (ES) is a common symptom of OSA, which often persists despite primary OSA therapy. This phase III randomized withdrawal trial evaluated solriamfetol (JZP-110) for the treatment of ES in adults with OSA.Methods: After 2 weeks of clinical titration (n = 174) and 2 weeks of stable dose administration (n = 148), participants who reported improvement on the Patient Global Impression of Change (PGI-C) and had numerical improvements on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) were randomly assigned to placebo (n = 62) or solriamfetol (n = 62) for 2 additional weeks. Coprimary end points were change from weeks 4 to 6 in MWT and ESS.Results: In the modified intention-to-treat population (n = 122), MWT mean sleep latencies and ESS scores improved from baseline to week 4 (from 12.3-13.1 to 29.0-31.7 minutes and from 15.3-16.0 to 5.9-6.4, respectively). From weeks 4 to 6, participants treated with solriamfetol maintained improvements (least squares [LS] mean [SE] changes of -1.0 [1.4] minutes on MWT and -0.1 [0.7] on ESS), whereas participants treated with placebo worsened (LS mean [SE] change of -12.1 [1.3] minutes on MWT and 4.5 [0.7] on ESS); LS mean differences between treatments were 11.2 minutes (95% CI, 7.8-14.6) and -4.6 (95% CI, -6.4 to -2.8) on MWT and ESS, respectively. Fewer participants treated with solriamfetol reported worsening on the PGI-C from weeks 4 to 6 (20% vs 50%; P = .0005). Common adverse events included headache, dry mouth, nausea, dizziness, and insomnia.Conclusions: This study demonstrated maintenance of solriamfetol efficacy and safety over 6 weeks.Trial Registry: ClinicalTrials.gov; No.: NCT02348619; URL: www.clinicaltrials.gov; EudraCT No.: 2014-005515-16. [ABSTRACT FROM AUTHOR]

Background: The impact of treating OSA on renal function decline is controversial. Previous studies usually included small samples and did not consider specific effects of different CPAP modalities. The aim of this study was to evaluate the respective influence of fixed and autoadjusting CPAP modes on estimated glomerular filtration rate (eGFR) in a large sample of patients derived from the prospective European Sleep Apnea Database cohort.Methods: In patients of the European Sleep Apnea Database, eGFR prior to and after follow-up was calculated by using the Chronic Kidney Disease-Epidemiology Collaboration equation. Three study groups were investigated: untreated patients (n = 144), patients receiving fixed CPAP (fCPAP) (n = 1,178), and patients on autoadjusting CPAP (APAP) (n = 485).Results: In the whole sample, eGFR decreased over time. The rate of eGFR decline was significantly higher in the subgroup with eGFR above median (91.42 mL/min/1.73 m2) at baseline (P < .0001 for effect of baseline eGFR). This decline was attenuated or absent (P < .0001 for effect of treatment) in the subgroup of patients with OSA treated by using fCPAP. A follow-up duration exceeding the median (541 days) was associated with eGFR decline in the untreated and APAP groups but not in the fCPAP group (P < .0001 by two-way ANOVA for interaction between treatment and follow-up length). In multiple regression analysis, eGFR decline was accentuated by advanced age, female sex, cardiac failure, higher baseline eGFR, and longer follow-up duration, whereas there was a protective effect of fCPAP.Conclusions: fCPAP but not APAP may prevent eGFR decline in OSA. [ABSTRACT FROM AUTHOR]

Background: OSA is associated with an increased risk of cardiovascular morbidity. A driver of this is metabolic dysfunction and in particular type 2 diabetes mellitus (T2DM). Prior studies identifying a link between OSA and T2DM have excluded subjects with undiagnosed T2DM, and there is a lack of population-level data on the interaction between OSA and glycemic control among patients with diabetes. We assessed the relationship between OSA severity and T2DM prevalence and control in a large multinational population.Methods: We performed a cross-sectional analysis of 6,616 participants in the European Sleep Apnea Cohort (ESADA) study, using multivariate regression analysis to assess T2DM prevalence according to OSA severity, as measured by the oxyhemoglobin desaturation index. Patients with diabetes were identified by previous history and medication prescription, and by screening for undiagnosed diabetes with glycosylated hemoglobin (HbA1c) measurement. The relationship of OSA severity with glycemic control was assessed in diabetic subjects.Results: T2DM prevalence increased with OSA severity, from 6.6% in subjects without OSA to 28.9% in those with severe OSA. Despite adjustment for obesity and other confounding factors, in comparison with subjects free of OSA, patients with mild, moderate, or severe disease had an OR (95% CI) of 1.33 (1.04-1.72), 1.73 (1.33-2.25), and 1.87 (1.45-2.42) (P < .001), respectively, for prevalent T2DM. Diabetic subjects with more severe OSA had worse glycemic control, with adjusted mean HbA1c levels 0.72% higher in patients with severe OSA than in those without sleep-disordered breathing (analysis of covariance, P < .001).Conclusions: Increasing OSA severity is associated with increased likelihood of concomitant T2DM and worse diabetic control in patients with T2DM. [ABSTRACT FROM AUTHOR]

The article discusses a research study on the importance of oximeter-based autonomic state indicator (ASI) algorithm to cardiovascular (CV) risk assessment. The procedure included the use of a novel photoplethysmographic sensor to study 148 sleep clinic patients. The European Society of Hypertension/European Society of Cardiology (ESH/ESC) risk factor matrix was used to classify CV risk. A detailed discussion on the research findings is presented.

The article explores the effects of continuous positive airway pressure (CPAP) treatment and withdrawal in patients with obstructive sleep apnea on arterial stiffness and central blood pressure (BP). Results reveal that in the intervention group, there were reductions in arterial stiffness and central systolic BP. The change in arterial stiffness was related to CPAP compliance. In the withdrawal group, there were no overall changes in arterial stiffness or BP.

Study Objective: To investigate whether a dose-effect relationship exists between the severity of obstructive sleep apnea (OSA) and subclinical indicators of myocardial or vascular dysfunction.Design: Cross-sectional study using correlation analysis.Participants: Twenty subjects referred to our sleep laboratory for screening or therapy of OSA but without regular medication and without known cardiovascular disease.Measurements: Severity of OSA was quantified by polysomnography. Moreover, nocturnal excretion of norepinephrine was determined. Left ventricular (LV) myocardial function was assessed with Doppler echocardiography. Using ultrasonographic measurements, endothelium-dependent and endothelium-independent conduit artery dilation were measured as flow-mediated and glyceryltrinitrate-induced changes in brachial artery diameter.Results: Worsening nocturnal hypoxemia, measured as nocturnal oxygen saturation nadir or percentage of sleep time spent in hypoxemia (< 90% hemoglobin oxygen saturation), predicted increased interventricular septum thickness (corrected for age and body mass index), prolonged isovolumetric relaxation time, decreased ratio between peak early and late mitral flow velocities, as well as reduced endothelium-dependent dilatory capacity of the brachial artery (all relationships corrected for cofactor age and with p < 0.05) were observed. Associations between these cardiovascular function markers and nocturnal excretion of norepinephrine followed the same trend, but relations with interventricular septum thickness and flow-mediated artery dilation missed significance (p = 0.064 and p = 0.061, respectively). LV posterior wall thickness, measures of LV systolic function, early mitral flow deceleration time, and endothelium-independent artery dilation were not significantly related to the degree of nocturnal hypoxemia or norepinephrine excretion. None of the correlations with apnea-hypopnea index were statistically significant.Conclusions: The severity of apnea-related hypoxemia is associated with a gradual deterioration of LV diastolic function as well as large-artery endothelial function. [ABSTRACT FROM AUTHOR]