Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging

Abstract

Background: Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD).

Aims: To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods.

Methods: This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE.

Results: Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA_1c were also observed with semaglutide.

Conclusions: The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380.

FIGURE 1

Changes from baseline in (A) liver stiffness by magnetic resonance elastography (MRE),* (B) proportion of subjects with a ≥ 15% reduction in liver stiffness by MRE,^† (C) liver steatosis by magnetic resonance imaging‐proton density fat fraction (MRI‐PDFF) and (D) proportion of subjects with a ≥ 30% reduction in liver steatosis by MRI‐PDFF^† at weeks 24, 48 and 72 with semaglutide 0.4 mg once daily and placebo. *Change from baseline to week 48 represents the primary endpoint. ^†Proportions of subjects are based on observed data with missing data imputed by mixed model for repeated measures predicted values. Two‐sided P value from logistic regression. Data (A and C) are estimated treatment ratios (95% confidence intervals). ETR, estimated treatment ratio

FIGURE 2

Changes from baseline (estimated treatment ratios and 95% confidence intervals) in total liver volume, liver fat volume, abdominal subcutaneous (s.c.) adipose tissue and visceral adipose tissue assessed by magnetic resonance imaging at weeks 24, 48 and 72 with semaglutide 0.4 mg once daily and placebo. Data from on‐treatment period. Estimates are from mixed model for repeated measures. EOT, end of treatment; SD, standard deviation

FIGURE 3

Changes from baseline (estimated treatment ratios and 95% confidence intervals) in (A) liver enzymes and (B) exploratory biomarkers at weeks 24, 48 and 72 with semaglutide 0.4 mg once daily and placebo. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK‐18, cytokeratin 18 fragments; EOT, end of treatment; FGF‐21, fibroblast growth factor 21; GGT, gamma‐glutamyl transferase, IL‐1RA, interleukin‐1 receptor antagonist; MCP1, monocyte chemoattractant protein‐1; mRNA, messenger RNA; Pro‐C3, released N‐terminal pro‐peptide of type III collagen; Pro‐C6, neo‐epitope in C‐terminal of type VI collagen; SD, standard deviation