A 2018 review outlined how GLP-1 receptor agonists reduce liver inflammation and fibrosis in NAFLD, and predicted that dual GLP-1/glucagon co-agonists could provide even greater benefit through added fat burning and thermogenesis.
No approved NAFLD therapy existedThis review identified GLP-1 RAs and dual GLP-1/glucagon agonists as promising NAFLD treatments through anti-inflammatory, anti-fibrotic, and fat-burning mechanisms
What the researchers found
The review identifies multiple mechanisms by which GLP-1-based therapies could treat NAFLD:
- GLP-1 receptor agonists reduce liver inflammation and fibrosis through direct and indirect mechanisms
- GLP-1 RAs reduce body weight, improving NAFLD independently of direct liver effects
- Glucagon receptor agonism increases lipid oxidation and thermogenesis
- Glucagon receptor signaling is disrupted in NAFLD, suggesting a therapeutic target
- Supra-physiological glucagon receptor agonism could represent a novel NAFLD treatment approach
- Dual GLP-1/glucagon co-agonists combine appetite reduction with increased fat burning
- No pharmacotherapy was approved for NAFLD at the time of writing
Why it matters
NAFLD/MASLD is now the most common liver disease globally, and it was long considered untreatable with drugs. This review was among the first to systematically outline how peptide-based therapies targeting both GLP-1 and glucagon receptors could address this unmet medical need. The predictions have been partially validated by subsequent trials of semaglutide and survodutide in NASH/MASLD.
How the study worked
Narrative review covering NAFLD pathophysiology, the roles of GLP-1 and glucagon in liver metabolism, currently available GLP-1 receptor agonists, and emerging dual GLP-1/glucagon co-agonists. The review synthesized preclinical and clinical evidence available through 2018.
What this study cannot tell us
As a 2018 review, it predates the major clinical trial results for GLP-1 drugs in NAFLD/NASH (e.g., semaglutide NASH trials) and the approval of resmetirom. The dual GLP-1/glucagon co-agonist data was largely preclinical at the time. The review could not assess the relative contribution of weight loss versus direct hepatic effects of these drugs.
How to read the evidence
This is a narrative review from 2018 synthesizing primarily preclinical data and limited clinical evidence. The therapeutic hypotheses outlined have since been partially validated by clinical trials.
When this study was published
Published in 2018, this review predates the major NASH/MASLD clinical trials of GLP-1 drugs. Many of its predictions have been validated, making it a useful historical perspective on the field's evolution.
The bigger picture
Since this 2018 review, the NAFLD treatment landscape has evolved significantly. Semaglutide has shown NASH resolution in clinical trials, and resmetirom became the first FDA-approved drug for NASH in 2024. Dual and triple agonists including survodutide (GLP-1/glucagon) are in advanced trials for NASH/MASLD. This review correctly identified the therapeutic potential that is now being realized.
Questions still open
- How do dual GLP-1/glucagon agonists like survodutide compare to GLP-1-only drugs for NASH resolution?
- Can GLP-1-based therapies reverse advanced liver fibrosis, not just steatosis and inflammation?
- Should NAFLD/MASLD screening be recommended for all patients starting GLP-1 therapy for diabetes or obesity?
Common questions
Can GLP-1 drugs treat fatty liver disease?
What is a dual GLP-1/glucagon agonist and why might it help the liver?
Read the original research
Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD.
Frontiers in endocrinology, 9, 649
Citation
Seghieri, Marta; Christensen, Alexander S; Andersen, Andreas; Solini, Anna; Knop, Filip K; Vilsbøll, Tina. (2018). Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD.. Frontiers in endocrinology, 9, 649. https://doi.org/10.3389/fendo.2018.00649