Comparative efficacy of GLP-1 RA, tirzepatide and SGLT-2 inhibitors in metabolic liver disease: A network meta-analysis

Aim: Metabolic liver disease, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis, is a major cause of chronic liver dysfunction worldwide, creating an urgent need for effective treatments. This systematic literature review (SLR) and network meta-analysis (NMA) systematically reviews and compares the efficacy and safety of glucagon-like peptide-1 receptor agonists, tirzepatide and sodium–glucose co-transporter-2 inhibitors for this condition. The results of the SLR and NMA were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methods: The MEDLINE and EMBASE databases, as well as the Cochrane Central Register of Controlled Trials, were systematically searched for publications from database inception to 9 November 2024. Risk of bias assessment of the included randomized clinical trials was performed using the Cochrane Risk of Bias 2 tool. Effect sizes were synthesized using pairwise and NMAs within a random-effects framework, assessing heterogeneity and estimating treatment rankings via the surface under the cumulative ranking curve. Analyses were performed using R software with the ‘netmeta’ package. Results: Overall, 25 studies involving 2688 participants were included in the analysis. Exenatide and tirzepatide significantly reduced liver fat fraction and liver enzymes vs. placebo, outperforming liraglutide and other agents. Liraglutide and dapagliflozin improved hepatic steatosis by controlled attenuation parameter, whereas empagliflozin reduced proton density fat fraction dose-dependently. Conclusion: This NMA demonstrated that GLP-1 RAs, SGLT-2 inhibitors and tirzepatide significantly improve surrogate markers of NAFLD, with exenatide and tirzepatide showing the greatest efficacy in reducing hepatic steatosis. PROSPERO ID CRD42024609736.