阻塞性睡眠呼吸暂停的精准药物治疗：将靶向药物与患者内型相匹配

文献信息

中文摘要

背景： 阻塞性睡眠呼吸暂停（OSA）仍治疗不足，因为持续气道正压通气虽有效，但常因耐受性和依从性差而受限。OSA长期被视为一种纯粹解剖性疾病且对药物耐药，现在被理解为四种可测量内型的共同终点——可塌陷的上气道、咽部扩张肌反应性差、高环路增益和低觉醒阈值——每一种都是独特的药理学靶点。本综述综合了针对这些靶点的机制原理和临床证据。方法：在这篇叙述性综述中，我们检索了PubMed/MEDLINE、Embase和Cochrane对照试验中心注册库（2000年1月至2026年2月）中的随机试验、荟萃分析和机制性内型分型研究，并以叙述方式评价证据。结果：替尔泊肽成为首个获批用于OSA的药物，通过减重减少肥胖相关的机械负荷，而去甲肾上腺素能-抗毒蕈碱组合AD109通过靶向扩张肌活动而不依赖体重，在一项关键3期试验中达到主要终点。然而，两者均使用基于AHI的终点，在临床定义而非内型选择的人群中；AD109的安慰剂校正效应 modest（-4.0事件/小时），且21.2%对3.1%的参与者因不良事件停药。因此，它们最好被描述为机制信息驱动而非内型验证。碳酸酐酶抑制（乙酰唑胺或舒噻胺）和选定的镇静剂针对通气不稳定性和低觉醒阈值，而索利氨酚和匹托利生可缓解残余嗜睡。结论：OSA的机制信息驱动药物治疗现在临床上可信，但在治疗可被称为内型指导之前，需要可扩展的床旁内型分型、对耐受性的关注以及特征分层试验。

英文摘要

Background: Obstructive sleep apnea (OSA) remains under-treated because continuous positive airway pressure, though efficacious, is frequently limited by poor tolerance and adherence. Long considered a purely anatomical disease refractory to drugs, OSA is now understood as the shared endpoint of four measurable endotypes-a collapsible upper airway, poor pharyngeal dilator-muscle responsiveness, high loop gain, and a low arousal threshold-each a distinct pharmacological target. This review synthesizes the mechanistic rationale and clinical evidence for targeting them. Methods: In this narrative review, we searched PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (January 2000 to February 2026) for randomized trials, meta-analyses, and mechanistic endotyping studies, appraising the evidence narratively. Results: Tirzepatide became the first drug approved for OSA, acting through weight loss to reduce obesity-related mechanical loading, and the noradrenergic-antimuscarinic combination AD109 met its primary endpoint in a pivotal phase 3 trial by targeting dilator-muscle activity independently of weight. Both, however, used AHI-based endpoints in clinically defined rather than endotype-selected populations; AD109's placebo-corrected effect was modest (-4.0 events/h), and 21.2% versus 3.1% of participants discontinued for adverse events. They are therefore best described as mechanism-informed rather than endotype-validated. Carbonic anhydrase inhibition with acetazolamide or sultiame and selected sedating agents address ventilatory instability and a low arousal threshold, while solriamfetol and pitolisant relieve residual sleepiness. Conclusions: Mechanism-informed pharmacotherapy for OSA is now clinically credible, but scalable bedside endotyping, attention to tolerability, and trait-stratified trials are needed before treatment can be called endotype-guided.