Understanding MASH and NAFLD
MASH (Metabolic-Associated Steatohepatitis, formerly known as NASH) is a progressive form of fatty liver disease in which excess fat accumulation in the liver leads to inflammation and scarring (fibrosis). Left untreated, MASH can advance to cirrhosis, liver failure, and liver cancer.
MASH exists on a spectrum of conditions collectively called MASLD (Metabolic-Associated Steatotic Liver Disease, formerly NAFLD). Simple fatty liver (steatosis) is common and often benign — but when it progresses to MASH with active inflammation and fibrosis, the condition becomes serious.
Approximately 1 in 4 people worldwide have some degree of liver fat accumulation, and an estimated 20% of those progress to MASH. The condition is tightly linked to obesity, type 2 diabetes, and metabolic syndrome — exactly the patient populations that GLP-1 drugs target.
The treatment gap: Until very recently, there were no FDA-approved drugs specifically for MASH. Resmetirom (Rezdiffra) became the first approved MASH treatment in 2024. Retatrutide, if approved for this indication, would represent a second option — with potentially unique advantages from the glucagon pathway.
Why Retatrutide May Be Uniquely Effective for Liver Disease
All GLP-1 drugs produce some liver fat reduction — primarily as a downstream effect of weight loss and improved insulin sensitivity. When the body loses weight, liver fat tends to decrease. But retatrutide may act on the liver through an additional, more direct mechanism.
GLP-1 Pathway — Indirect Liver Benefit
GLP-1 receptor agonism improves insulin sensitivity and reduces overall caloric intake, which secondarily reduces the flow of fatty acids to the liver. This is the mechanism by which semaglutide and tirzepatide also reduce liver fat — it works, but it's indirect.
Glucagon Pathway — Direct Liver Fat Reduction
This is retatrutide's key differentiator. The liver is rich in glucagon receptors. Glucagon receptor activation directly stimulates hepatic fat oxidation — essentially telling liver cells to burn the fat stored within them for energy. It also reduces de novo lipogenesis (the liver's production of new fat from carbohydrates). This direct hepatic mechanism is additive to the indirect benefits from weight loss, potentially making retatrutide more effective for liver disease than weight-loss-equivalent doses of GLP-1-only drugs.
The Spectrum of Liver Disease
Understanding where retatrutide may help requires understanding how liver disease progresses:
The TRIUMPH-4 Trial
Eli Lilly has specifically initiated a Phase 3 trial — designated TRIUMPH-4 — to evaluate retatrutide in patients with MASH. This is a standalone liver disease trial, separate from the obesity trials, which reflects the degree to which Eli Lilly believes the glucagon mechanism adds distinct value in this indication.
What TRIUMPH-4 Is Measuring
The primary endpoints of the TRIUMPH-4 trial are expected to include MASH resolution on liver biopsy (reduction in inflammation without worsening fibrosis) and fibrosis improvement without worsening of MASH — the same endpoints used by the FDA for MASH drug approval. These endpoints require liver biopsies at baseline and after treatment, making MASH trials among the most rigorous and resource-intensive in metabolic medicine.
What Would Success Look Like?
A positive TRIUMPH-4 result would likely position retatrutide as a treatment option for MASH patients — particularly those who also have obesity or type 2 diabetes, where the drug's multiple mechanisms address multiple underlying drivers of liver disease simultaneously. Given that the MASH patient population heavily overlaps with obesity and diabetes populations, approval in all three indications would make retatrutide an unusually versatile metabolic drug.
How Does It Compare to Existing MASH Treatments?
Resmetirom (Rezdiffra), approved by the FDA in March 2024, is the only currently approved drug specifically for MASH. It works through a thyroid hormone receptor beta agonist mechanism — a completely different pathway from GLP-1 drugs. Resmetirom demonstrated MASH resolution in approximately 26–30% of patients and fibrosis improvement in approximately 24–26% in its pivotal trial.
If retatrutide's TRIUMPH-4 data shows comparable or superior liver outcomes — particularly in patients who also need weight loss and glycemic control — it could become a preferred option for the substantial MASH patient population that also carries obesity or diabetes diagnoses, potentially replacing or complementing resmetirom in certain patients.