Hypnotics on Obstructive Sleep Apnea Severity and Endotypes: A Systematic Review and Meta-Analysis

Rationale: Low arousal threshold and poor muscle responsiveness are common determinants of obstructive sleep apnea (OSA). Hypnotics were hypothesized as an alternative OSA treatment via raising the arousal threshold and possibly genioglossus responsiveness. Objectives: To examine the effect of common hypnotics on arousal threshold, OSA severity, and genioglossus responsiveness. Methods: We searched MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov for randomized clinical trials, and we ran meta-analyses to determine the effect of oral hypnotics on arousal threshold, OSA severity, and genioglossus responsiveness. The Grades of Recommendation Assessment, Development and Evaluation was used to rate the quality of evidence (QoE). The association between post-treatment apnea-hypopnea index (AHI) and arousal threshold percentage reductions was explored in individual patient data meta-analyses (overall sample and low arousal threshold subgroups). Measurements and Main Results: On the basis of our analysis (27 studies; 25 for AHI, 11 for arousal threshold, 4 for genioglossus responsiveness), hypnotics minimally raised arousal threshold (mean difference [95% confidence interval], 2.7 [1.5, 3.8] cm H₂O epiglottic pressure swings; moderate QoE) but did not change OSA severity (-1.4 [-3.5, 0.7] events/h; moderate QoE). Individual patient data meta-analysis (N = 114) showed no association between changes in arousal threshold and AHI, independent of arousal threshold subgrouping. However, people with very low arousal threshold or those who exhibited a 0-25% arousal threshold increase from placebo experienced the greatest, yet still modest, post-treatment AHI reductions (∼10%). Hypnotics did not affect genioglossus responsiveness (high QoE). Conclusions: Further research testing or clinical use of hypnotics as OSA alternative treatments should be discouraged, unless in the presence of comorbid insomnia or as part of combination therapy in individuals with very low arousal threshold.