Weight Loss, Obesity Drugs Bring Potential New MASLD, MASH Treatment Strategies

The development of new therapies for diabetes and obesity is leading to important insights and new therapeutic strategies for patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH).

In a new review article in the journal Diabetes, Obesity and Metabolism, investigators explained the latest research into incretin and glucagon signaling in MASLD and MASH as well as the implications of that research for patient care.¹

MASLD has become more common in recent decades as rates of obesity have increased, the authors noted. One meta-analysis suggested that the prevalence of MASLD in adults globally is now 38%.² In addition, MASLD has been linked with type 2 diabetes (T2D), chronic kidney disease, and atherosclerotic cardiovascular disease, they said. In some cases, MASLD progresses to MASH, which has become one of the main reasons for liver transplantation in North America and Europe, the authors said.

Yet, despite its name, the authors explained MASLD is more accurately characterized as a multisystem disorder related to dysregulated communication between the gut, adipose tissue, and liver.

“Excess nutrient flux from the gastrointestinal tract, together with microbial-derived signals, increases hepatic substrate availability and promotes de novo lipogenesis,” they wrote. At the same time, insulin resistance leads to adipose tissue lipolysis, causing increased spillover of circulating non-esterified fatty acids to the liver.

“Together, these processes increase hepatocellular lipid burden, and when combined with diminished mitochondrial function and fatty acid oxidation, they can create an environment that promotes inflammation and fibrogenesis,” they said.

The development of new incretin- and glucagon-based therapies for diabetes and obesity has sparked new interest in finding ways to address MASH. They noted that glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon “signal through distinct receptors with unique expression patterns and biological actions that map directly onto the dysregulated gut-liver and adipose-liver axes and inflammatory pathways that drive MASLD pathogenesis.”

The investigators explained that GLP-1 receptor agonists appear to be able to help resolve MASH without worsening fibrosis. Those findings have been confirmed in mouse models and in multiple studies of semaglutide (Wegovy/Ozempic). Last year, the Food and Drug Administration approved semaglutide for the treatment of adults with MASH, they noted.

Meanwhile, the dual GLP-1/GIP receptor agonist tirzepatide (Zepbound/Mounjaro) and the dual GLP-1/glucagon receptor agonist survodutide have both been found to reduce liver fat and spark MASH improvement without worsening fibrosis. One outstanding question, though, is whether the engagement of the glucagon receptor directly improves hepatic inflammation or fibrosis or indirectly improves it through weight loss and metabolic improvement, the authors said.

LIkewise, triple agonists of GLP-1, GIP, and glucagon receptors may also benefit patients with MASH, though the authors said more research is needed to determine how much of the benefit is simply a byproduct of weight loss.

One theme of the research is that the benefits of incretin- and glucagon-based therapies may vary depending on the patient’s MASLD or MASH subtype and stage, the authors noted. Patients with obesity, diabetes, or early fibrosis appear to see improvement in steatohepatitis and potentially fibrosis when taking incretin- and glucagon-based therapies. It is not yet clear what type of benefit patients will see if they have lean MASLD, do not have diabetes, or have advanced fibrosis.

The investigators further added that disease biology may affect therapeutic responsiveness, and they said combination regimens pairing incretin- or glucagon-based therapies with other agents might help patients with advanced MASH.

A challenge moving forward will be to better define how such therapies affect patients with different disease stages and subtypes and how to channel metabolic improvements into long-term antifibrotic benefits for all patients, the authors noted.

References

1. Tsakiridis EE, Steinberg GR. Incretin and glucagon signalling in MASLD and MASH: Integrating metabolic pathways with disease progression. Diabetes Obes Metab. Published online March 12, 2026. doi:10.1111/dom.70624

2. Ginès P, Serra-Burriel M, Kamath PS. Metabolic dysfunction-associated steatotic liver Disease- the new Epidemic of chronic liver disease. JAMA Netw Open. 2025;8(6):e2516381. doi:10.1001/jamanetworkopen.2025.16381