Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials

Abstract

To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Three large electronic databases were systematically searched (up to 15 December 2020) to identify placebo-controlled or active-controlled RCTs using different GLP-1 RAs. We included eleven placebo-controlled or active-controlled phase-2 RCTs (involving a total of 936 middle-aged individuals) that used liraglutide (n = 6 RCTs), exenatide (n = 3 RCTs), dulaglutide (n = 1 RCT) or semaglutide (n = 1 RCT) to specifically treat NAFLD or NASH, detected by liver biopsy (n = 2 RCTs) or imaging techniques (n = 9 RCTs). Compared to placebo or reference therapy, treatment with GLP-1 RAs for a median of 26 weeks was associated with significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques (pooled weighted mean difference: -3.92%, 95% confidence intervals (CI) -6.27% to -1.56%) and serum liver enzyme levels, as well as with greater histological resolution of NASH without worsening of liver fibrosis (pooled random-effects odds ratio 4.06, 95% CI 2.52-6.55; for liraglutide and semaglutide only). In conclusion, treatment with GLP-1 RAs (mostly liraglutide and semaglutide) is a promising treatment option for NAFLD or NASH that warrants further investigation.

Keywords: GLP-1 receptor agonists; NAFLD; NASH; dulaglutide; exenatide; liraglutide; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; semaglutide; type 2 diabetes mellitus.

Figure 1

Forest plot and pooled estimates of the effects of different glucagon-like peptide-1 receptor agonists (GLP-1 Ras) on serum liver enzyme levels (i.e., serum alanine aminotransferase (ALT) (n = 11 RCTs included, panel (A)), aspartate aminotransferase (AST) (n = 10 RCTs included, panel (B)), and gamma-glutamyltransferase (GGT) (n = 7 RCTs included, panel (C))) as compared with placebo or reference therapy. The pooled (green diamond) and individual effect sizes for all RCTs included were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI).

Figure 1

Forest plot and pooled estimates of the effects of different glucagon-like peptide-1 receptor agonists (GLP-1 Ras) on serum liver enzyme levels (i.e., serum alanine aminotransferase (ALT) (n = 11 RCTs included, panel (A)), aspartate aminotransferase (AST) (n = 10 RCTs included, panel (B)), and gamma-glutamyltransferase (GGT) (n = 7 RCTs included, panel (C))) as compared with placebo or reference therapy. The pooled (green diamond) and individual effect sizes for all RCTs included were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI).

Figure 2

Forest plot and pooled estimates of the effect of different GLP-1 RAs on the absolute percentage of liver fat content as assessed by magnetic resonance-based techniques (n = 7 RCTs included) as compared with placebo or reference therapy. The pooled (green diamond) and individual effect sizes for all RCTs included were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI). The blue square in the figure represents the WMD for each single RCT.

Figure 3

Forest plot and pooled estimates of the effect of GLP-1 RAs (n = 2 RCTs included using either liraglutide 1.8 mg/day or semaglutide at a dose of 0.1 mg, 0.2 mg or 0.4 mg/day subcutaneously) on histologic resolution of NASH with no worsening of liver fibrosis (panel (A)), and improvement in liver fibrosis stage without worsening of NASH (panel (B)) as compared with placebo. The pooled (green diamond) and individual effect sizes for all RCTs included were expressed as random-effect odds ratio (OR) and 95% confidence intervals (CI).