Combination therapies pairing GLP-1 receptor agonists with liver-specific agents like FGF-21 analogues or thyroid hormone receptor agonists show the most promise for comprehensive MASH treatment, addressing both liver fibrosis and systemic metabolic disease.
Multitargeted combination strategiesGLP-1RAs combined with FGF-21 analogues, THR-β agonists, or as GLP-1/glucagon dual agonists aim to achieve comprehensive MASH improvement that no single drug can deliver
What the researchers found
Combination therapies targeting multiple MASH pathways — including GLP-1RAs with FGF-21 analogues or THR-β agonists, and GLP-1/glucagon dual agonists — show promise for improving both liver pathology and systemic metabolic outcomes beyond what single agents can achieve.
Why it matters
MASH affects hundreds of millions worldwide and monotherapy provides only partial benefit. Combination strategies combining systemic metabolic agents (like GLP-1RAs) with liver-directed therapies could finally achieve meaningful fibrosis regression and metabolic improvement together.
How the study worked
Narrative review published in Gut integrating current knowledge on multitargeted and combination therapies for MASH, examining mechanistic rationales, emerging clinical evidence, and practical implementation considerations.
What this study cannot tell us
Most combination strategies are in early-stage clinical trials without long-term efficacy or safety data. The optimal combinations, sequencing, and patient selection criteria remain undefined. Drug-drug interactions and cost considerations for multi-agent regimens were not fully addressed.
How to read the evidence
Published in Gut (a top gastroenterology journal), this is an expert review by leading MASH researchers. While it provides a comprehensive framework, most combination strategies discussed are supported by early-phase clinical data rather than completed phase 3 trials.
When this study was published
Published in 2026, this review captures the MASH treatment landscape after resmetirom's approval and semaglutide's ESSENCE trial success, representing the most current thinking on combination strategies.
The bigger picture
The MASH drug development landscape is at an inflection point. Resmetirom (a THR-β agonist) became the first approved MASH drug in 2024, but it addresses only liver-specific pathways. GLP-1 receptor agonists — semaglutide showed remarkable MASH improvement in the ESSENCE trial — address the systemic metabolic drivers. Combining these approaches could finally deliver comprehensive disease modification. The review frames this as the future of MASH treatment: personalized combinations tailored to each patient's predominant disease drivers, whether metabolic, fibrotic, or inflammatory.
Questions still open
- Which specific GLP-1RA + liver-targeted agent combinations will advance to phase 3 trials first?
- Can combination therapy achieve fibrosis regression in patients who don't respond adequately to monotherapy?
- How will the cost of multi-drug MASH regimens affect treatment access and healthcare system sustainability?
Common questions
What is MASH and why is it hard to treat?
How do GLP-1 drugs help fatty liver disease?
Read the original research
Combination therapies for metabolic dysfunction-associated steatohepatitis: challenges and opportunities.
Gut, 75(4), 815-825
Citation
Zhou, Xiao-Dong; Fan, Qiong-Yue; Byrne, Christopher D; Targher, Giovanni; Muthiah, Mark D; Huang, Daniel Q; Chen, Qin-Fen; Noureddin, Mazen; Li, Wenhao; Ratziu, Vlad; Loomba, Rohit; Francque, Sven M; Sanyal, Arun J; Zheng, Ming-Hua. (2026). Combination therapies for metabolic dysfunction-associated steatohepatitis: challenges and opportunities.. Gut, 75(4), 815-825. https://doi.org/10.1136/gutjnl-2025-337431