Efficacy, Safety, and Tolerability of Farnesoid X Receptor Agonists in the Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease: A Systematic Review and Meta-analysis.

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease. Farnesoid X receptor (FXR) agonists are emerging as promising therapies for fibrosis, steatosis, and metabolic dysfunctions. However, its efficacy and safety remain unclear.

METHODS

A systematic search of PubMed, Embase, and Cochrane databases identified randomized controlled trials (RCTs) comparing FXR agonists with placebo in patients with MASLD. The main outcomes included improvement in fibrosis without worsening steatohepatitis, changes in liver chemistry and lipid profiles, and liver fat content (LFC). The safety outcomes assessed included side effects and treatment discontinuation rates. Heterogeneity was evaluated using I² statistics, with a random-effects model applied to the pooled analyses.

RESULTS

Ten RCTs involving 3,779 patients were included, of which 2,527 (67%) were randomized to receive FXR agonists. FXR agonists significantly improved fibrosis by ≥ 1 stage (RR, 1.52; 95% CI: [1.23, 1.88];  < 0.0001) and reduced LFC (mean difference: -4.9%; 95% CI: [-8.26, -1.55];  < 0.001). A higher proportion of patients achieved a ≥30% reduction in LFC (42.8% vs. 18.4%; RR, 2.42; 95% CI: [1.69, 3.46];  < 0.00001). Significant reductions in alanine aminotransferase and gamma glutamyltransferase levels were observed, whereas alkaline phosphatase levels were increased. FXR agonists were associated with a slight reduction in High-Density Lipoprotein (HDL) cholesterol levels and a higher incidence of pruritus (37.8% vs. 18.7%; RR, 2.67; 95% CI: [1.63, 4.38];  < 0.00001), leading to higher treatment discontinuation rates.

CONCLUSION

FXR agonists have the potential to improve fibrosis and steatosis in MASLD patients. However, safety concerns still remain. Further research is required to determine the long-term efficacy and tolerability of these drugs.