Published online Oct 7, 2023. doi: 10.3748/wjg.v29.i37.5327
Peer-review started: June 28, 2023
First decision: August 15, 2023
Revised: August 23, 2023
Accepted: September 12, 2023
Article in press: September 12, 2023
Published online: October 7, 2023
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).
Several randomized clinical trials have demonstrated the beneficial effects of semaglutide in patients with NAFLD. Prior systematic review with meta-analysis assessing the impact of semaglutide did not report histological outcomes and were not focused on a NAFLD specific population.
This study aimed to review the efficacy and safety of semaglutide, focusing on patients with NAFLD, in order to more specifically reflect the NAFLD population and expand the current understanding of semaglutide in NAFLD.
MEDLINE, CENTRAL, EMBASE, and grey literature sources were searched from inception to May 1, 2023, to identify eligible randomized controlled trials (RCTs) using a predefined search strategy. Predetermined outcomes were extracted, and quality assessment was performed using the Cochrane risk-of-bias 2 tool and GRADE framework. 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 I2statistic.
A total of 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 ALT (MD: -14.06 U/L, 95%CI: -22.06, -6.07; P < 0.001) and AST (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).
Semaglutide demonstrated significant histologic improvements, with a higher likelihood of NASH resolution and improved NAS components, but it did not significantly improve fibrosis stage compared to placebo. Furthermore, semaglutide resulted in radiologic improvements in liver stiffness and steatosis, liver enzymes, as well as cardiometabolic effects on body weight and HgA1c, while maintaining a well-tolerated safety profile.
Additional RCTs with larger sample sizes and longer durations are required to characterize the effects of semaglutide on fibrosis regression and its role in the different phases of NAFLD.