Metabolic hormones open a new path against metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis, a severe form of liver disease characterized by fat accumulation, inflammation, and cellular damage, represents a major public health challenge. Its global prevalence continues to rise, with projections estimating it could affect more than half of the population by 2040. This disease, often linked to obesity and type 2 diabetes, can progress to cirrhosis, liver cancer, or liver failure, with a poorer prognosis the more advanced the fibrosis.

Until recently, no specific therapy existed to treat this condition. However, the situation has radically changed with the arrival of innovative treatments targeting metabolic hormones, initially developed for diabetes or obesity. Among them, semaglutide, a GLP-1 receptor agonist, received accelerated approval in 2025 for patients with steatohepatitis and moderate to advanced fibrosis. This drug, already used for diabetes and obesity, works by reducing appetite, slowing gastric emptying, and improving insulin sensitivity, leading to significant weight loss. Clinical trials have shown that nearly 63% of patients treated with semaglutide saw their steatohepatitis resolve without fibrosis worsening, compared to only 34% on placebo. Additionally, fibrosis improvement was observed in 37% of treated patients, compared to 22% in the control group.

GLP-1 agonists are not the only ones sparking researchers’ interest. Agonists of the glucose-dependent insulinotropic polypeptide receptor, or GIP, as well as combined GLP-1/GIP agonists, such as tirzepatide, also show promising results. Tirzepatide, for example, enabled more than 60% of patients to achieve steatohepatitis resolution without fibrosis worsening, with an average weight loss of 15% after one year of treatment. These molecules act by regulating blood sugar, reducing caloric intake, and improving overall metabolic function.

Another therapeutic avenue involves combined GLP-1 and glucagon agonists, such as survodutide or pemvidutide. These treatments leverage the complementary effects of the two hormones: GLP-1 reduces appetite and improves insulin sensitivity, while glucagon increases energy expenditure and promotes fatty acid oxidation in the liver. Clinical trials have demonstrated that these dual agonists improve hepatic steatosis, reduce inflammation, and mitigate fibrosis. For example, pemvidutide enabled more than 50% of patients to achieve steatohepatitis resolution, with an additional reduction in fibrosis in nearly one-third of them.

Fibroblast growth factors, or FGFs, represent another family of molecules under study. FGF21, primarily produced by the liver and adipose tissues, regulates lipid and carbohydrate metabolism. It reduces fat accumulation in the liver, improves insulin sensitivity, and promotes weight loss. FGF21 analogs, such as efruxifermin or pegozafermin, are currently being tested in phase 3 clinical trials. Preliminary results show significant fibrosis improvement in nearly 40% of treated patients, with good overall tolerance.

In addition to these hormonal approaches, liver-targeting strategies are being developed to optimize treatment efficacy while limiting side effects. For example, some molecules are designed to specifically bind to receptors on the surface of hepatocytes or hepatic stellate cells, which are responsible for fibrosis. These techniques allow for more direct and safer action on the diseased areas of the liver.

Finally, therapies combining multiple mechanisms of action are under investigation. The idea is to combine metabolic agents, such as GLP-1 agonists, with molecules directly targeting liver fibrosis or inflammation. This approach could yield more durable and comprehensive results by addressing both the causes and consequences of the disease.

These advances mark a turning point in the management of metabolic dysfunction-associated steatohepatitis, offering patients therapeutic solutions where none existed just a few years ago.

Sources Used

Report Source

DOI: https://doi.org/10.1007/s40005-026-00815-4

Title: Emerging metabolic hormone therapeutics for metabolic dysfunction-associated steatohepatitis: incretin-based drugs, fibroblast growth factor analogs, and liver-targeting strategies

Journal: Journal of Pharmaceutical Investigation

Publisher: Springer Science and Business Media LLC

Authors: Sukwoo Han; Jaehee Shin; Jae Cheon Kim; Dong Hee Na