National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, UK; Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
Late-stage Development, CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
J Hepatol. 2023 Dec;79(6):1557-1565. doi: 10.1016/j.jhep.2023.07.033. Epub 2023 Aug 9.
The principle pathological drivers of metabolic dysfunction-associated steatohepatitis (MASH) are obesity and associated insulin resistance, rendering them key therapeutic targets. As glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been licensed for the treatment of diabetes and obesity, they were one of the first drug types to be evaluated in patients with MASH, and successful phase IIa and IIb studies have resulted in progression to phase III clinical trials. Alongside GLP-1RAs, newer combinations with glucagon agonists and/or glucose-dependent insulinotropic peptide (GIP) agonists have been explored in related patient groups, with evidence of improvements in weight, insulin resistance and non-invasive liver parameters. Whether GLP-1RAs have direct, independent effects on MASH or whether they impact on pathophysiology through improvements in weight, insulin resistance and glycaemic control remains a matter of debate. Combinations are being explored, although the potential improvement in efficacy will need to be weighed against the cumulative side-effect burden, potential drug-drug interactions and costs. There is also uncertainty regarding the optimal ratio of glucagon and GIP agonism to GLP-1 agonism in combination agents, and as to whether GIP agonism or antagonism is the optimal approach. Finally, there are also multiple hypothetical permutations combining gut hormone agonists with other emerging assets in the field. Given that the likely dominant mode of action of gut hormone agonists is upstream on weight, initial combinations might focus on agents which have been shown to have a more direct effect on fibrosis, which would include FGF21 and pan-PPAR agonists.
代谢功能障碍相关脂肪性肝炎（MASH）的主要病理驱动因素是肥胖和相关的胰岛素抵抗，这使其成为关键的治疗靶点。由于胰高血糖素样肽 1 受体激动剂（GLP-1RAs）已被批准用于治疗糖尿病和肥胖症，因此它们是第一批在 MASH 患者中进行评估的药物类型之一，成功的 IIa 期和 IIb 期研究已进展到 III 期临床试验。除了 GLP-1RAs，新型与胰高血糖素激动剂和/或葡萄糖依赖性胰岛素释放肽（GIP）激动剂的联合用药也在相关患者群体中进行了探索，这些药物在体重、胰岛素抵抗和非侵入性肝脏参数方面都有改善的证据。GLP-1RAs 是否对 MASH 有直接的、独立的影响，或者它们是否通过改善体重、胰岛素抵抗和血糖控制来影响病理生理学，这仍然是一个争论的问题。目前正在探索联合用药，尽管需要权衡疗效的潜在改善与累积的副作用负担、潜在的药物相互作用和成本。在联合用药中，关于胰高血糖素和 GIP 激动剂与 GLP-1 激动剂的最佳比例以及 GIP 激动剂或拮抗剂是否是最佳方法也存在不确定性。最后，还有多种假设组合将肠激素激动剂与该领域的其他新兴资产结合在一起。鉴于肠激素激动剂的可能主要作用模式是在体重方面的上游，最初的组合可能集中在已显示出对纤维化有更直接作用的药物上，这将包括 FGF21 和全 PPAR 激动剂。
