New anti-diabetic agents for the treatment of non-alcoholic fatty liver disease: a systematic review and network meta-analysis of randomized controlled trials

Objectives: This network meta-analysis aims to compare the efficacy and safety of new anti-diabetic medications for the treatment of non-alcoholic fatty liver disease (NAFLD). Materials and methods: March 2022 to identify all randomized controlled trials (RCTs) in NAFLD patients. Outcomes included reductions in intrahepatic steatosis (IHS) and liver enzyme levels. The efficacy and safety of DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and other therapies were indirectly compared using a NMA approach. Unstandardized mean difference (USMD) with 95% confidence intervals (CI) were calculated. Results: 2,252 patients from 31 RCTs were included. "Add-on" GLP-1 agonists with standard of care (SoC) treatment showed significantly reduced IHS compared to SoC alone USMD (95%CI) -3.93% (-6.54%, -1.33%). Surface under the cumulative ranking curve (SUCRA) identified GLP-1 receptor agonists with the highest probability to reduce IHS (SUCRA 88.5%), followed by DPP-4 inhibitors (SUCRA 69.6%) and pioglitazone (SUCRA 62.2%). "Add-on" GLP-1 receptor agonists were also the most effective treatment for reducing liver enzyme levels; AST USMD of -5.04 (-8.46, -1.62), ALT USMD of -9.84 (-16.84, -2.85) and GGT USMD of -15.53 (-22.09, -8.97) compared to SoC alone. However, GLP-1 agonists were most likely to be associated with an adverse event compared to other interventions. Conclusion: GLP-1 agonists may represent the most promising anti-diabetic treatment to reduce hepatic steatosis and liver enzyme activity in T2DM and NAFLD patients. Nevertheless, longer-term studies are required to determine whether this delays progression of liver cirrhosis in patients with NAFLD and T2DM. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021259336.1.