Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver

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.