Histological efficacy of anti-diabetic agents in MASH and the mediating role of weight loss: A network meta-analysis.

IF 5.7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes, Obesity & Metabolism Pub Date : 2025-10-08 DOI:10.1111/dom.70187

Mainak Banerjee, Rimesh Pal, Sandip Pal

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引用次数: 0

Abstract

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with rising global prevalence, closely linked to type 2 diabetes. While several anti-diabetic agents show promise, a comprehensive analysis comparing their efficacy on biopsy-confirmed histological outcomes, including dose-dependent effects and the mediating role of weight loss, remains unexplored.

Methods: A frequentist random-effects network meta-analysis (NMA) was conducted to explore histological efficacy of anti-diabetic agents in biopsy-confirmed MASH without cirrhosis. The primary outcome was fibrosis improvement (≥1 stage) without worsening steatohepatitis; the secondary outcome was MASH resolution without fibrosis worsening. Incretin-based agents were dose-stratified. Treatment ranking used surface-under the cumulative-ranking curve (SUCRA). Meta-regression investigated the impact of percentage weight loss and baseline covariates on the proportion of individuals achieving histological end-points.

Results: Data from five RCTs (N = 1667) were included. All active treatments, including Dapagliflozin 10 mg, Survodutide (2.4 mg/wk, 4.8-6 mg/wk), Tirzepatide (5 mg/wk, 10-15 mg/wk), and Semaglutide (0.7-1.4 mg/wk, 2.4 or 2.8 mg/wk), improved fibrosis versus placebo (I² = 0%). For MASH resolution, dose-dependent effects led to significant heterogeneity (I² = 73%), with lower-dose Semaglutide demonstrating no benefits and Dapagliflozin showing benefits in the F2-F3 subgroup only on sensitivity analysis. Survodutide exhibited the highest ranking (SUCRA = 0.822-0.849), followed by Tirzepatide (SUCRA = 0.622-0.681) and higher-dose Semaglutide (SUCRA = 0.327) for MASH resolution. Meta-regression using data from 16 interventions, including placebo arms, showed that weight loss significantly explained heterogeneity in treatment effects on fibrosis improvement (R² = 54.26%) and MASH resolution (R² = 78.16%).

Conclusions: SGLT2 inhibitor and incretin-based agents improved fibrosis in MASH, with weight loss being a significant mediator. Targeting multiple incretin pathways, especially involving glucagon receptors, may offer greater MASH resolution. Dose-dependent effects were more prominent for MASH resolution than fibrosis improvement, indicating potential weight-loss-independent anti-fibrotic pathways.

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抗糖尿病药物在MASH中的组织学疗效和体重减轻的中介作用：一项网络meta分析。

背景：代谢功能障碍相关脂肪性肝炎（MASH）是一种全球患病率不断上升的进行性肝病，与2型糖尿病密切相关。虽然一些抗糖尿病药物显示出希望，但对其在活检证实的组织学结果（包括剂量依赖效应和体重减轻的中介作用）的疗效进行综合分析仍未得到探索。方法：采用频率随机效应网络meta分析（NMA），探讨抗糖尿病药物对活检证实的无肝硬化的MASH患者的组织学疗效。主要结局为纤维化改善（≥1期），无脂肪性肝炎恶化；次要结局是MASH消退，无纤维化恶化。以肠促胰岛素为基础的药物按剂量分层。处理排序采用累积排序曲线（SUCRA）下表面排序。meta回归研究了体重减轻百分比和基线协变量对达到组织学终点的个体比例的影响。结果：纳入5项rct （N = 1667）的数据。所有有效治疗，包括达格列净10mg、赛伏肽（2.4 mg/周，4.8-6 mg/周）、替西帕肽（5 mg/周，10-15 mg/周）和塞马鲁肽（0.7-1.4 mg/周，2.4或2.8 mg/周），与安慰剂相比，纤维化得到改善（I2 = 0%）。对于MASH分辨率，剂量依赖性效应导致显著的异质性（I2 = 73%），仅在敏感性分析中，低剂量的Semaglutide在F2-F3亚组中显示无益处，而Dapagliflozin显示有益处。磺胺磺肽（SUCRA = 0.822-0.849）对MASH的溶解效果排名最高，其次是替西帕肽（SUCRA = 0.622-0.681）和更高剂量的西马鲁肽（SUCRA = 0.327）。meta回归分析了包括安慰剂组在内的16项干预措施的数据，结果显示体重减轻显著解释了纤维化改善治疗效果的异质性（R2 = 54.26%）和MASH缓解（R2 = 78.16%）。结论：SGLT2抑制剂和基于肠促胰岛素的药物改善了MASH的纤维化，体重减轻是一个重要的中介。针对多种肠促胰岛素途径，特别是涉及胰高血糖素受体，可能提供更高的MASH分辨率。与纤维化改善相比，剂量依赖性作用在缓解MASH方面更为突出，表明潜在的不依赖于体重减轻的抗纤维化途径。

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来源期刊

Diabetes, Obesity & Metabolism 医学-内分泌学与代谢

CiteScore

10.90

自引率

6.90%

发文量

319

审稿时长

3-8 weeks

期刊介绍： Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.