GLP-1 受體促效劑相較甲狀腺素受體β致效劑在代謝功能異常相關脂肪肝炎輕至中度纖維化之療效：系統性文獻回顧、統合分析與臨床試驗計畫書

Abstract

代謝功能異常相關脂肪性肝炎(Metabolic-dysfunction associated steatohepatitis; MASH)是代謝功能異常相關脂肪肝病（MASLD）進展至肝纖維化階段的嚴重表現，通常合併伴隨肥胖、第二型糖尿病、高血壓及高血脂等代謝症候群特徵。MASH 患者因長期慢性肝臟發炎與纖維化，未來可能進一步演變至肝硬化甚至肝癌，對患者健康構成重大的威脅。肝纖維化嚴重度以分期F1至F4為分類，其中F2-F3（中度至中重度纖維化）為疾病進展的關鍵階段，未經治療可能演變為肝硬化（F4）。據統計，目前亞洲成人代謝相關脂肪肝病盛行率約為 38%，預計於 2030 年前可能進一步增加 6% 至 20%；其中進展至代謝功能異常相關脂肪性肝炎的患者預計增加 20% 至 35%（Younossi et al., 2023）。 現階段治療主要以體重控制及生活型態介入為基礎，若體重減輕達 7-10% 可以對肝脂肪堆積及肝功能有較明顯的改善療效。藥物治療方面，2024年 FDA 核准甲狀腺激素受體 β 促效劑 Resmetirom 成為首個代謝異常相關脂肪肝肝炎患者的治療藥物，另外 GLP-1受體促效劑與多種機轉藥物也正在大規模臨床試驗階段研發中。其中以GLP-1受體促效劑首先發表第三期中期試驗報告結果。 Resmetirom 雖剛通過FDA加速核准應用於中度至中重度纖維化患者，但整體治療反應率只有三成。在現有開發藥物中，GLP-1 受體促效劑已為臨床核准提供肥胖及第二型糖尿病患者使用之藥物，現階段針對MASH已在三期試驗後期階段，雖然可有效降低體重並改善代謝指標，並同時部分改善肝臟脂肪堆積和發炎，但其對纖維化改善的實際結果還需多方試驗結果累積。有鑒於 MASH 涉及多重的代謝機轉，單方的治療方式可能無法全面性的阻斷病程進展，若採用聯合治療模式，則有機會透過機轉的協同作用來增進治療成效。但現階段針對 GLP-1 受體促效劑以及甲狀腺激素受體 β 促效劑兩者療效還需要更多的文獻及試驗分析。 本研究透過 PubMed、Web of Science 與 Embase 共蒐集 525 篇相關文獻，篩選符合條件的隨機對照試驗（randomized controlled trials），最終納入 5篇研究進行統合分析（見圖 1）。本研究聚焦於探討glucagon like peptide-1 (GLP-1) 受體促效劑（GLP-1 RA）及甲狀腺激素受體 β 促效劑對於代謝功能異常相關性脂肪性肝炎（MASH）患者在組織學結果的療效，評估代謝功能異常相關性脂肪性肝炎逆轉與肝纖維化改善程度。 統合分析結果顯示，本系統性回顧與統合分析顯示，GLP-1 受體促效劑（GLP-1 RAs）與甲狀腺荷爾蒙受體-β（THR-β）促效劑皆能顯著改善 MASH（代謝功能異常相關脂肪性肝炎）患者的肝纖維化。GLP-1 RAs 組的總合併比值比為 1.92（95% CI: 1.42–2.60），THR-β 組則為 2.21（95% CI: 1.53–3.18），整體合併效益為 OR = 2.03（95% CI: 1.61–2.56，P < 0.00001），兩組間無顯著差異（P = 0.57）。在代謝異常相關脂肪肝炎逆轉方面，GLP-1 RAs 顯示更明顯療效（OR = 4.21, 95% CI: 2.48–7.16, P < 0.00001），THR-β 組則雖呈現趨勢但未達顯著（OR = 2.59, 95% CI: 0.93–7.17, P = 0.07）。此外，藥物名稱（liraglutide、semaglutide、resmetirom）之子群分析均顯示療效一致（P > 0.4），且無顯著異質性或期別差異，兩類藥物皆具有穩定的治療潛力。 而進一步的網絡統合分析顯示，GLP-1 RAs 在整體治療效果上排名最高，其 SUCRA 值達 97.4%，遠高於 THR-β（47.3%）與安慰劑（5.3%）。GLP-1 RAs 與 THR-β agonist 間的間接比較結果顯示，GLP-1 RAs 對於肝纖維化緩解的療效為 THR-β 的三倍OR 3.09 (95% CI: 0.68–10.59），具潛在臨床意義，結果支持其進一步進行兩者對比的臨床試驗之可行性。 整體來說，GLP-1 RA與THR-β皆有顯著療效，然而目前針對 GLP-1 RA對比THR-β療法尚無相關試驗結果。因此，我們設計一項開放性第二期臨床試驗，評估 GLP-1 RA 對比 THR-β對於台灣 MASH 病患之療效，並同時納入組織學與非侵入性指標，以驗證其在東亞族群中之治療潛力與臨床可行性。

Background and aim: Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD affects over 30% of adults in Taiwan and driven by rising obesity and diabetes. Formerly known as nonalcoholic steatohepatitis (NASH), MASH poses risk of cirrhosis and hepatocellular carcinoma, with fibrosis stages F1-F3 being pivotal. While semaglutide as glucagon like peptide-1 receptor agonists (GLP-1 RAs) alone have shown promising results in Phase III trials for MASH, the final efficacy is still under investigation, and data on GLP-1 RA-based combination therapies, particularly in the Taiwanese population, remain to be investigated. This trial design aims to address this gap by evaluating the efficacy of GLP-1 RA combination therapies in Taiwanese MASH patients. Method: A total of 525 studies were identified from PubMed, Web of Science, and Embase. Eventually, 5 eligible studies were selected (Figure 1). Results: We found that both GLP-1 receptor agonists and THR-β agonists significantly improved fibrosis without worsening of steatohepatitis in patients with MASH. GLP-1 RAs yielded an odds ratio (OR) of 1.92 (95% CI: 1.42–2.60), while THR-β agonists achieved an OR of 2.21 (95% CI: 1.53–3.18). The overall pooled OR was 2.03 (95% CI: 1.61–2.56, P < 0.00001), with no significant subgroup differences (P = 0.57). We also found that GLP-1 RAs demonstrated a stronger effect on MASH resolution without worsening of fibrosis (OR = 4.21, 95% CI: 2.48–7.16, P < 0.00001), while the THR-β agonist group showed a trend toward benefit that did not reach statistical significance (OR = 2.59, 95% CI: 0.93–7.17, P = 0.07). The pooled estimate favored treatment overall (OR = 3.61, 95% CI: 2.51–5.21, P < 0.00001), with no statistically significant difference between subgroups (P = 0.41), although higher heterogeneity was observed in the THR-β subgroup (I² = 71%). The subgroup analyses showed that both GLP-1 receptor agonists and THR-β agonists (resmetirom) were effective in improving histological MASH and reducing fibrosis progression. GLP-1 receptor agonists showed a significant treatment effect versus placebo (OR = 4.23, 95% CI: 2.11–8.50), with consistent results across liraglutide and semaglutide. The effect of liraglutide was significant but mainly derived from a single study with a wider confidence interval (OR = 6.43, 95% CI: 1.20–34.41), while semaglutide yielded more consistent results based on two studies (OR = 4.23, 95% CI: 2.11–8.50). THR-β agonists (resmetirom) showed a favorable but non-significant trend (OR = 2.59, 95% CI: 0.93–7.17), and no significant subgroup differences were observed (P = 0.60). Furthermore, Bayesian network meta-analysis was performed to compare treatments indirectly. GLP-1 RA ranked highest in efficacy (SUCRA = 97.4%), followed by THR-β agonists (SUCRA = 47.3%) and placebo (SUCRA = 5.3%). The estimated odds ratio for GLP-1 RAs versus THR-β agonists was 3.09 (95% CI: 0.68–10.59), suggesting a potentially clinically meaningful difference favoring GLP-1 RAs, without statistical significance between each group.

Conclusions: Meta-analysis demonstrates that GLP-1 receptor agonists (GLP-1 RAs), including liraglutide and semaglutide, provide histological benefits in MASH patients that are comparable to those of the THR-β agonist resmetirom, which has already received FDA regulatory approval. Subgroup analyses further support the potential of GLP-1 RA as a valuable therapeutic alternative in resolving steatohepatitis and improving fibrosis. Despite these findings, limitations such as variability in trial design, dosing, and patient characteristics must be acknowledged. Since GLP-1 RAs are already FDA-approved for the treatment of patients with obesity or diabetes, the next step is to evaluate the efficacy of combining GLP-1 RAs with THR-β agonists versus GLP-1 RA alone, to explore potential synergistic effects on liver histology in patients with MASH. To demonstrate the efficacy of GLP-1 RA and THR-β agonist in Taiwanese MASH patients, we propose an interventional study with a GLP-1 RA versus THR-β agonist to assess the efficacy in the Taiwanese population.