The effect of GLP-1 receptor agonists on liver health in participants living with overweight/obesity: a systematic review and meta-analysis.

Problem

Overweight and obesity are associated with various metabolic disturbances, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which pose significant health risks. Glucagon-like peptide-1 receptor agonists (GLP-1RA), known for their effects on glucose metabolism, are novel anti-obesity medications, but their efficacy in treating NAFLD is unclear. This study aims to systematically review and conduct a meta-analysis to evaluate the impact of GLP-1RA on hepatic health in participants living with overweight or obesity.

Approach

A comprehensive search of electronic databases (Medline, Embase, Scopus, Cochrane, ClinicalTrials.gov) was performed to identify relevant studies published up to November 2023. Randomized controlled trials (RCTs) comparing GLP-1RA to placebo or standard care in adults living with overweight/obesity without type 2 diabetes and that reported on liver parameters were included. Data were extracted, and quality assessment was conducted using RoB2 and GRADE. Pooled mean differences (MD) or Estimated Treatment Ratio (ETR) with 95% CI were calculated using random-effects models.

Findings

The final review incorporated a total of 16 studies with 8296 participants, each investigating one of six distinct glucagon-like peptide-1 receptor agonists (GLP-1 RAs): Liraglutide (n=6), Semaglutide (n=5), Tirzepatide (n=2), Retatrutide (n=1), Dulaglutide (n=1), and Orforglipron (n=1). Out of these, 11 unique studies were selected for inclusion in the meta-analysis. Duration of intervention ranged from 16 weeks to 72 weeks.Compared to control, GLP-1RA significantly reduced Alanine Transaminase (ALT) (MD = -18.55IU/L; 95%CI [-21.01, -16.10]), Aspartate Aminotransferase (AST) (MD = -7.38IU/L; [-8.61, -6.15]), Body Mass Index (BMI) (MD = -3.43kg/m2; [-5.48, -1.37]) and Waist Circumference (WC) (MD = -5.68cm; [-8.09, -3.27]). The subgroup meta-analysis showed differences in efficacy between specific GLP-1RA - Semaglutide appeared more effective than Liraglutide in treating overweight/obesity, with more significant reductions in liver enzymes ALT and AST, BMI, and WC.

Consequences

A significant reduction in ALT levels compared to AST levels is observed in participants treated with GLP-1RA. Sensitivity analysis on GLP-1RA dosages showed Semaglutide has more potent effects than Liraglutide in similar settings, but dose response relations remain unclear due to limited data. Tirzepatide and Retatrutide, dual and triple receptor agonists, show greater efficacy than single GLP-1RAs, but it is unclear if liver benefits are solely due to GLP-1 receptor activation or other mechanisms.This meta-analysis demonstrates that GLP-1RAs significantly improve key liver health parameters (ALT, AST) in participants living with overweight/obesity. These agents may represent a new pharmacotherapy for NAFLD. However, additional large randomized controlled trials in diverse populations are warranted to confirm the efficacy of different GLP-1RAs for treating obesity-associated liver disease.