Efficacy and safety of semaglutide in non-alcoholic fatty liver disease

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. The prevalence and disease burden of NAFLD are projected to exponentially increase resulting in significant healthcare expenditures and lower health-related quality of life. To date, there are no approved pharmacotherapies for NAFLD or non-alcoholic steatohepatitis (NASH). Semaglutide has glycemic and weight loss benefits that may be advantageous for patients with NAFLD.

Aim: To investigate the efficacy and safety of semaglutide in patients with NAFLD.

Methods: MEDLINE, CENTRAL, and EMBASE were searched from inception to May 1, 2023, to identify eligible randomized controlled trials (RCTs). Meta-analysis was performed using random effects model expressing continuous outcomes as mean differences (MD) or standardized MDs (SMD), and dichotomous outcomes as odds ratios (OR) with 95% confidence intervals (CI). Statistical heterogeneity was assessed using the Cochran's Q test and I² statistic.

Results: Three RCTs involving 458 patients were included. Semaglutide increased the likelihood of NASH resolution (OR: 3.18, 95%CI: 1.70, 5.95; P < 0.001), improvement in steatosis (OR: 2.83, 95%CI: 1.19, 6.71; P = 0.03), lobular inflammation (OR: 1.81, 95%CI: 1.11, 2.96; P = 0.02), and hepatocellular ballooning (OR: 2.92, 95%CI: 1.83, 4.65; P < 0.001), but not fibrosis stage (OR: 0.71, 95%CI: 0.15, 3.41; P = 0.67). Radiologically, semaglutide reduced liver stiffness (SMD: -0.48, 95%CI: -0.86, -0.11; P = 0.01) and steatosis (MD: -4.96%, 95%CI: -9.92, 0.01; P = 0.05). It also reduced alanine aminotransferase (MD: -14.06 U/L, 95%CI: -22.06, -6.07; P < 0.001) and aspartate aminotransferase (MD: -11.44 U/L, 95%CI: -17.23, -5.65; P < 0.001). Semaglutide led to improved cardiometabolic outcomes, including decreased HgA1c (MD: -0.77%, 95%CI: -1.18, -0.37; P < 0.001) and weight loss (MD: -6.53 kg, 95%CI: -11.21, -1.85; P = 0.006), but increased the occurrence of GI-related side effects (OR: 3.72, 95%CI: 1.68, 8.23; P = 0.001). Overall risk of serious adverse events was similar compared to placebo (OR: 1.40, 95%CI: 0.75, 2.62; P < 0.29).

Conclusion: Semaglutide is effective in the treatment of NAFLD while maintaining a well-tolerated safety profile. Future studies are required to evaluate its effects on fibrosis regression and different phases of NAFLD.

Keywords: Fatty liver; Metabolic-associated fatty liver; Non-alcoholic fatty liver disease; Semaglutide.

Figure 1

PRISMA flow diagram of study selection. WHO: World health organization.

Figure 2

Effect of semaglutide on histologic parameters. A: Resolution of non-alcoholic steatohepatitis (NASH) with no worsening of liver fibrosis; B: Improvement in liver fibrosis stage without worsening of NASH; C: Improvement in steatosis; D: Improvement in lobular inflammation; E: Improvement in hepatocellular ballooning. 95%CI: 95% confidence intervals.

Figure 3

Effect of semaglutide on radiologic parameters. A: Liver stiffness assessed by magnetic resonance enterography or Fibroscan; B: Liver steatosis assessed by MRI proton density fat fraction. 95%CI: 95% confidence intervals.

Figure 4

Effect of semaglutide on liver enzymes. A: Alanine aminotransferase; B: Aspartate aminotransferase. 95%CI: 95% confidence intervals.

Figure 5

Effect of semaglutide on cardiometabolic parameters. A: Body weight; B: HgA1c in patients with type 2 diabetes (T2DM) vs without T2DM. 95%CI: 95% confidence intervals.

Figure 6

Adverse events with semaglutide. A: Gastrointestinal related side effects; B: Serious adverse events. 95%CI: 95% confidence intervals.