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

Tanawan Kongmalai; Varalak Srinonprasert; Thunyarat Anothaisintawee; Pinkawas Kongmalai; Gareth McKay; John Attia; Ammarin Thakkinstian

doi:10.3389/fendo.2023.1182037

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

Front Endocrinol (Lausanne). 2023 Jun 27:14:1182037. doi: 10.3389/fendo.2023.1182037. eCollection 2023.

Authors

Tanawan Kongmalai¹, Varalak Srinonprasert^{2

3

4}, Thunyarat Anothaisintawee⁵, Pinkawas Kongmalai⁶, Gareth McKay⁷, John Attia⁸, Ammarin Thakkinstian^{4

5}

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
² Siriraj Health Policy Unit, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
³ Division of Geriatric Medicine, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁴ Mahidol University Health Technology Assessment Graduate Program, Mahidol University, Bangkok, Thailand.
⁵ Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
⁶ Department of Orthopaedics, Faculty of Medicine, Srinakharinwirot University, Ongkharak, Nakhon Nayok, Thailand.
⁷ Centre for Public Health, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University, Belfast, Ireland.
⁸ School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia.

Abstract

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: PubMed and Scopus were searched from inception to 27^th 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.

Keywords: DPP-4 inhibitors; GLP-1 agonists; NAFLD; SGLT-2 inhibitors; anti-diabetic medications; diabetes; network meta-analysis; non-alcoholic fatty liver disease.

Publication types

Meta-Analysis
Systematic Review
Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2* / drug therapy
Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use
Glucagon-Like Peptide 1 / therapeutic use
Glucagon-Like Peptide-1 Receptor
Humans
Hypoglycemic Agents / therapeutic use
Network Meta-Analysis
Non-alcoholic Fatty Liver Disease* / chemically induced
Non-alcoholic Fatty Liver Disease* / drug therapy
Randomized Controlled Trials as Topic

Substances

Dipeptidyl-Peptidase IV Inhibitors
Glucagon-Like Peptide-1 Receptor
Hypoglycemic Agents
Glucagon-Like Peptide 1

Grants and funding

This study was funded by the National Research Council of Thailand (NRCT) N42A640323. The study funder had no role in the design or conduct of the study.