GLP-1與GIP/GLP-1雙重受體促效劑用於治療阻塞型睡眠呼吸中止症的統合分析與臨床試驗計畫書

Abstract

研究背景：阻塞型睡眠呼吸中止症（obstructive sleep apnea, OSA）是一種常見且具高度心血管與代謝風險的慢性疾病。持續性正壓呼吸器（CPAP）雖為標準治療，但長期依從性不佳，顯示仍有發展疾病修飾型治療的必要。由於肥胖與OSA之間具有強烈且可逆的病理連結，兼具減重與代謝改善效果的glucagon-like peptide-1 receptor agonists（GLP-1RA）遂成為具高度潛力的藥物治療策略。 目的：本論文第一章透過系統性文獻回顧與統合分析，評估GLP-1RA於OSA患者之療效與相關心代謝指標變化；第二章據此提出一項以亞洲族群為核心之隨機分派臨床試驗計畫，以驗證semaglutide對過重或輕中度肥胖成人OSA之治療效益。 方法：本研究依PRISMA 2020原則進行文獻回顧，搜尋PubMed、MEDLINE、EMBASE與Cochrane等資料庫，納入對象為成人中重度OSA患者，介入措施為任一GLP-1或雙重GIP/GLP-1受體促效劑，主要終點 apnea-hypopnea index (AHI)變化。統合分析採隨機效應模型，估計平均差與95%信賴區間，並以I²評估異質性。另就研究設計與藥物別進行次群分析。 研究結果：共納入6篇研究、1,028名受試者，其中包括4篇隨機對照試驗與2篇非隨機研究。整體分析顯示，GLP-1類藥物可顯著降低AHI，合併平均差為−10.23 events/hour (95% CI −14.85至−5.61；I² = 91.8%)。體重百分比變化為−12.46%，BMI變化為−1.60 kg/m²；收縮壓與舒張壓亦分別下降−4.85與−2.67 mmHg。HbA1c、總膽固醇與三酸甘油酯則未達顯著差異。此外，次群分析顯示，隨機對照試驗之效果較非隨機研究更為明顯：RCT為−13.39 events/hour，non-RCT為−3.46 events/hour。依藥物別分析，liraglutide之AHI合併效果為−5.88 events/hour，tirzepatide為−21.89 events/hour。綜合現有資料，AHI改善大致與體重下降幅度呈方向一致關係，支持減重可能為主要治療中介機轉。 結論：GLP-1 及雙重 GIP/GLP-1 受體促效劑在阻塞性睡眠呼吸中止症（OSA）患者中，可顯著改善呼吸功能以及心血管與代謝相關指標。本結果顯示，OSA應由傳統所認知的單純上氣道塌陷疾病，重新定位為一種與代謝失衡高度相關之全身性疾病。針對亞洲族群，考量到獨特的顱顏結構和解剖特徵，OSA可於較低身體質量指數（BMI）下發生；惟現階段相關實證數據有限。有鑑於此，本文進一步提出以 semaglutide 為主之隨機、雙盲、安慰劑對照臨床試驗計畫，旨在評估其於亞洲過重 OSA 患者族群中的治療成效與臨床可行性。

Background: Obstructive sleep apnea (OSA) is a common chronic disorder associated with substantial cardiovascular and metabolic risk. Although continuous positive airway pressure (CPAP) remains the standard therapy, long-term adherence is frequently suboptimal, underscoring the need for disease-modifying therapeutic strategies. Given the strong and potentially reversible pathophysiologic relationship between obesity and OSA, glucagon-like peptide-1 receptor agonists (GLP-1RAs), which confer both weight reduction and metabolic benefits, have emerged as promising pharmacologic interventions for OSA. Objectives: The first part of this thesis aimed to evaluate the efficacy of GLP-1RAs in patients with OSA through a systematic review and meta-analysis, with particular emphasis on respiratory and cardiometabolic outcomes. The second part proposed a randomized clinical trial protocol specifically designed for Asian populations to assess the therapeutic efficacy of semaglutide in overweight or mildly to moderately obese adults with OSA. Methods: This study was conducted in accordance with the PRISMA 2020 statement. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched. Eligible studies included adults with moderate-to-severe OSA treated with either GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists. The primary outcome was change in the apnea–hypopnea index (AHI). A random-effects model was used to estimate pooled mean differences and 95% confidence intervals, and heterogeneity was assessed with the I² statistic. Subgroup analyses were performed according to study design and pharmacologic agent. Results: A total of six studies involving 1,028 participants were included, comprising four randomized controlled trials and two nonrandomized studies. Overall, GLP-1–based therapies significantly reduced AHI, with a pooled mean difference of −10.23 events per hour (95% confidence interval [CI], −14.85 to −5.61; I² = 91.8%). Mean body-weight reduction was 12.46%, and body-mass index (BMI) decreased by 1.60 kg/m². Systolic and diastolic blood pressure decreased by 4.85 mmHg and 2.67 mmHg, respectively. No statistically significant differences were observed in glycated hemoglobin, total cholesterol, or triglyceride levels. Subgroup analyses demonstrated greater treatment effects in randomized controlled trials than in nonrandomized studies (−13.39 vs. −3.46 events per hour, respectively). Drug-specific analyses showed pooled AHI reductions of −5.88 events per hour with liraglutide and −21.89 events per hour with tirzepatide. Across studies, improvements in AHI appeared directionally consistent with the magnitude of weight reduction, supporting weight loss as a principal mechanistic mediator of therapeutic benefit. Conclusions: GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists significantly improved respiratory parameters as well as cardiovascular and metabolic outcomes in patients with OSA. These findings support a conceptual shift in the understanding of OSA, from a disorder characterized solely by upper-airway collapse to a systemic disease closely linked to metabolic dysfunction. In Asian populations, distinctive craniofacial and upper-airway anatomical characteristics may predispose individuals to OSA at lower BMI thresholds; however, clinical evidence in this population remains limited. Accordingly, this thesis further proposes a randomized, double-blind, placebo-controlled clinical trial of semaglutide to evaluate its efficacy and clinical feasibility in overweight Asian adults with OSA.