Glucagon-Like Peptide-1 Receptor Agonist Therapy Reduces Fibrosis-4 Index in Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading contributor to liver-related morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown promise in improving MASLD-related outcomes, but their effect on hepatic fibrosis remains unclear. This study evaluated the impact of GLP-1 RA therapy on liver fibrosis, utilizing the validated fibrosis-4 (FIB-4) index as a noninvasive marker of fibrosis severity.

Methods: In this retrospective cohort study, we identified patients within a large academic health system with MASLD, a baseline FIB-4 ≥ 1.3 (indicating intermediate or higher risk of hepatic fibrosis), and at least two GLP-1 RA prescriptions within a 90-day period between 2020 and 2024. Patients with cirrhosis or alcohol use disorder were excluded. Values were collected at treatment initiation and 12 months later. One-tailed paired t-tests assessed differences in FIB-4 and secondary outcomes, and multivariable linear regression identified independent predictors of FIB-4 change.

Results: Among 229 patients with MASLD who were treated with GLP-1 RAs, 29 had a baseline FIB-4 ≥ 1.3. After 12 months, mean FIB-4 decreased by 0.21 from 1.94 to 1.73 (95% confidence interval (CI) −0.38 to −0.05; P = 0.019). Significant reductions were also observed in AST (−15.8 U/L), ALT (−21.9 U/L), body mass index (BMI, −2.6 kg/m²), and hemoglobin A1c (A1c, −1.1%; all P < 0.001). On multivariable analysis, baseline FIB-4 index was the strongest predictor of FIB-4 change (β = −0.538; P < 0.001), and FIB-4 improvement was independent of BMI change (β = 0.020; P = 0.243).

Conclusion: In patients with MASLD at intermediate or higher risk of hepatic fibrosis, GLP-1 RA therapy was associated with significant reductions in FIB-4, AST, ALT, BMI, and A1c over 12 months, supporting a potential antifibrotic effect. The FIB-4 index may serve as a practical noninvasive marker for monitoring fibrosis response in MASLD.