Abstract Introduction Obstructive sleep apnea (OSA) is driven by four primary physiological endotypes which include upper airway collapsibility, impaired pharyngeal muscle responsiveness, high loop gain, and a low arousal threshold. These traits contribute to inter individual variability in clinical presentation and treatment response. Pharmacologic therapies that target these mechanisms represent an emerging precision medicine approach. This systematic analysis evaluates how medications modify OSA endotypes and the potential therapeutic implications. Methods Databases searched included PubMed covering the period from 2020 to 2024. All search results were imported into Rayyan for blinded dual screening. Two independent reviewers screened 178 titles and abstracts, followed by full text review. Disagreements were resolved by consensus. 9 studies met inclusion criteria, consisting of randomized trials, and physiologic investigations examining medication effects on OSA endotypes. Data were extracted on endotypic changes, AHI reduction, physiologic responses, and safety. Results Low arousal threshold: Hypnotics such as zolpidem and eszopiclone increased arousal threshold without worsening airway collapsibility. Pimavanserin selectively increased respiratory arousal threshold and reduced respiratory related arousals. Impaired pharyngeal muscle responsiveness: Atomoxetine based combinations with oxybutynin, fesoterodine, or a hypnotic enhanced upper airway muscle tone and produced AHI reductions of 30 to 50 percent in patients with moderately collapsible airways. High loop gain: Acetazolamide and sulthiame consistently reduced loop gain and improved ventilatory stability. Dronabinol demonstrated variable effects with inconsistent benefit across traits. Airway sensory and chemoreceptor dysfunction: Gefapixant, a P2X3 receptor antagonist, and a TASK channel antagonist nasal spray improved OSA severity in physiologically responsive individuals by modifying sensory and chemosensory pathways. Across included studies, pharmacotherapies produced AHI reductions ranging from 15 to 60%, with the greatest improvements observed when therapy aligned with the patient’s physiological endotype. Conclusion This systematic analysis demonstrates that endotype targeted pharmacotherapy can produce meaningful improvements in OSA severity by modulating specific physiological traits. Benefits are most pronounced when medications are selected based on endotype profile. Larger and long term studies are required to define treatment durability and to integrate pharmacologic strategies into individualized OSA management. Support (if any)
Medina et al. (Fri,) studied this question.