Next-Generation Multi-Hormone Peptides Could Be the First Drugs to Treat Fatty Liver Disease | Research

The takeaway

Dual and triple incretin peptide agonists combining GLP-1, GIP, and glucagon receptor activity show promising early results for treating nonalcoholic fatty liver disease, though most clinical studies are still in progress.

No approved NAFLD drugs
Despite affecting roughly 25% of the global population, nonalcoholic fatty liver disease has no regulatory-approved drug treatments — making incretin combination peptides a potential breakthrough.

What the researchers found

Dual and triple agonists show effectiveness on NAFLD biomarkers, but most studies are ongoing.

Why it matters

With no approved treatments for NAFLD, these combination therapies could offer new hope for patients, especially those with diabetes. Understanding their effectiveness could lead to better management of liver disease.

How the study worked

The study involved a literature review of existing research on incretin combination therapies for NAFLD.

What this study cannot tell us

Most studies reviewed are still in progress, and results may not yet be applicable to clinical practice.

How to read the evidence

This is a narrative review of animal studies, pharmacokinetic data, and early proof-of-concept human studies. Most clinical trials for NAFLD outcomes are still in progress. The evidence is promising but largely preclinical and preliminary.

When this study was published

Published in 2023, this review was written before the MASH (formerly NASH) treatment landscape shifted with resmetirom's approval in 2024. The incretin combination therapy pipeline has also advanced significantly since, with tirzepatide and survodutide NASH trial results now available.

The bigger picture

The evolution from single-target GLP-1 agonists to multi-target peptides represents a paradigm shift in metabolic disease treatment. NAFLD/NASH sits at the intersection of obesity, diabetes, and cardiovascular disease — all conditions where incretin peptides have shown benefits. The idea that a single multi-target peptide could address liver fat, insulin resistance, weight, and cardiovascular risk simultaneously makes these combination molecules the most exciting therapeutic development in hepatology in decades.

Questions still open

Will multi-target incretin peptides prove more effective for NASH resolution than single-target liver-specific drugs like resmetirom?
Is the liver benefit of these peptides driven primarily by weight loss, or do they have direct hepatoprotective effects independent of weight change?
Could real-world database analyses of GLP-1 drug users provide earlier evidence of liver outcomes than waiting for long-term clinical trials?

Common questions

What are dual and triple agonist peptides?

Traditional GLP-1 drugs like semaglutide activate one hormone receptor. Dual agonists (like tirzepatide) activate two receptors — GLP-1 and GIP. Triple agonists (like retatrutide) activate three: GLP-1, GIP, and glucagon. By targeting multiple hormone pathways simultaneously, these multi-target peptides can produce more powerful metabolic effects, including potentially reducing liver fat.

Why is there no approved drug for fatty liver disease?

NAFLD develops slowly over decades, making clinical trials expensive and lengthy. The disease also has complex causes involving metabolism, inflammation, and fibrosis — making it hard for any single drug to address all aspects. Until recently, the only effective treatment was weight loss through lifestyle changes. Multi-target incretin peptides are promising because they address multiple disease pathways simultaneously through weight loss and direct metabolic effects.

Read the original research

Looking ahead to potential incretin combination therapies for nonalcoholic steatohepatitis in patients with diabetes.

Expert opinion on pharmacotherapy, 24(9), 989-1000

View on PubMed ↗Publisher’s paper ↗

Citation

Brodosi, Lucia; Petroni, Maria Letizia; Marchesini, Giulio. (2023). Looking ahead to potential incretin combination therapies for nonalcoholic steatohepatitis in patients with diabetes.. Expert opinion on pharmacotherapy, 24(9), 989-1000. https://doi.org/10.1080/14656566.2023.2208746