Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder worldwide. The therapeutic landscape in NAFLD is rapidly evolving, with several agents under investigation. The use of noninvasive biomarkers is highlighted in recent guidelines

Aims & Methods

To assess the comparative efficacy of pharmacologic interventions in patients with NAFLD based on magnetic resonance imaging (MRI) biomarkers. We searched Medline, Embase and CENTRAL up to January 2023. We included randomized controlled trials (RCTs) with > 12 weeks of intervention. Eligible trials assessed the efficacy of pharmacologic interventions in patients with NAFLD diagnosed by liver biopsy or MRI. The primary outcome was absolute reduction in liver fat content (LFC) as assessed by means of either MRI–Proton Density Fat Fraction or MR-Spectroscopy. Secondary efficacy outcome was absolute reduction in liver stiffness (LS) assessed by MR-Elastography. We performed random-effects frequentist network meta-analyses to estimate mean differences (MD) with 95% confidence intervals (CIs). We ranked treatments based on P-scores.

Results

Thirty RCTs (2,511 participants) contributed data in the network meta-analysis. Among drug classes, thiazolidinediones (MD -7.4%; 95% CI -11.4 to -3.3), fibroblast growth factor (FGF) analogues (-5.8%; -8.8 to -2.8), glucagon-like peptide-1 receptor agonists (GLP1-RAs) (-4.3%; -7.5 to -1.1), farnesoid X receptor (FXR) agonists (-3.6%; -7.1 to -0.05), and combination treatment with vitamin E plus thiazolidinediones (-11%; -18.3 to -3.6) were more efficacious compared to placebo regarding absolute reduction of LFC. Vitamin E plus thiazolidinedione co-administration (P-score 0.90) was ranked as the most efficacious treatment followed by GLP1-RA-based combinations, thiazolidinedione (0.77) and vitamin E monotherapy (0.69). In terms of individual agents, efruxifermin, aldafermin, semaglutide, liraglutide, pioglitazone, vitamin E, tropifexor and resmetirom were superior to placebo with MDs ranging from -13.5% for efruxifermin to -4.0% for liraglutide. Combination treatments with semaglutide, and vitamin E plus pioglitazone were also superior to placebo. Based on P scores, Efruxifermin (0.97) was the most efficacious agent followed by vitamin E plus pioglitazone (0.91) and semaglutide-based combination therapies. All interventions were equally efficacious to placebo for LS reduction.

Conclusion

Pioglitazone and semaglutide are the most efficacious glucose-lowering agents for LFC reduction in patients with NALFD. Among non-glucose-lowering agents, efruxifermin, vitamin E and tropifexor can lead to significant steatosis reduction. Combination treatments, from different drugs classes seem promising for the management of NAFLD. Although no treatment was superior to placebo for LS reduction, duration of included trials was too small to draw firm conclusions.

Disclosure

Tsapas and E. Sinakos have received research support from Boehringer Ingelheim. E. Sinakos has participated in clinical trials funded by Novo Nordisk