Meta-Analysis
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Aug 15, 2023; 14(8): 1289-1300
Published online Aug 15, 2023. doi: 10.4239/wjd.v14.i8.1289
Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma: A systematic review and meta-analysis
Maja Cigrovski Berkovic, Francesco Giovanardi, Anna Mrzljak, Quirino Lai
Maja Cigrovski Berkovic, Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb, Zagreb 10000, Croatia
Francesco Giovanardi, Quirino Lai, General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
Anna Mrzljak, Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb 10000, Croatia
Anna Mrzljak, Department of Medicine, School of Medicine, Zagreb 10000, Croatia
Author contributions: Lai Q and Mrzljak A contributed to the conception and design of the study; Giovanardi F and Lai Q contributed to the acquisition of data; Lai Q and Giovanardi F analyzed and interpreted the data; Mrzljak A and Cigovski Berkovic M drafted the article; Lai Q critically revised the manuscript; and all authors approved the final version.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Maja Cigrovski Berkovic, MD, PhD, Adjunct Associate Professor, Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb, Horvaćanski zavoj 15, Zagreb 10000, Croatia. maja.cigrovskiberkovic@gmail.com
Received: February 27, 2023
Peer-review started: February 27, 2023
First decision: April 11, 2023
Revised: April 24, 2023
Accepted: May 16, 2023
Article in press: May 16, 2023
Published online: August 15, 2023
Processing time: 164 Days and 15.3 Hours
Abstract
BACKGROUND

Hepatocellular carcinoma (HCC) is among the commonest malignancies associated with significant cancer-related death. The identification of chemo-preventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing. Metformin, a first-line agent used in the treatment of type 2 diabetes mellitus (T2DM), has been associated with inhibition of HCC growth.

AIM

To determine whether metformin can prevent adverse events (i.e., death, tumor progression, and recurrence) after any HCC treatment in T2DM patients.

METHODS

A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy. A search of the PubMed and Cochrane Central Register of Con-trolled Trials Databases was conducted.

RESULTS

A total of 13 studies (n = 14886 patients) were included in this review. With regard to the risk of death, a decreased risk was reported in cases receiving metformin, although this decrease was not statistically significant [odds ratio (OR) = 0.89, P = 0.42]. When only patients treated with curative strategies were considered, a more marked correlation between metformin and favorable cases was reported (OR = 0.70, P = 0.068). When analyzing palliative treatment, there was no statistical significance in terms of the correlation between metformin and favorable cases (OR = 0.74, P = 0.66). As for the risks of progressive disease and recurrence, no obvious correlation between metformin use and reduced risk was reported. When sub-analyses were performed for patients from different regions, the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin (OR = 0.69, P = 0.17), but the same was not seen in patients from Western countries (OR = 1.19, P = 0.31).

CONCLUSION

Metformin failed to show a marked impact in preventing adverse effects after HCC treatment. A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death, especially in patients from Eastern regions. Great heterogeneity was reported among the different studies. Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.

Keywords: Hepatocellular carcinoma; Metformin; Type 2 diabetes mellitus; Death; Recurrence; Progression; Treatment

Core Tip: The identification of chemopreventive agents following hepatocellular carcinoma (HCC) treatments with the potential to lower the risk of its adverse course is of paramount relevance. Among them, metformin has been recently examined in this setting. The present systematic review and meta-analysis aim to determine the role of metformin in preventing HCC adverse events (i.e., death, tumor progression, and recurrence). Metformin only showed statistical significance as a protective factor for the risk of death in patients receiving curative therapies for HCC, but failed as a protective agent for progressive disease and recurrence. Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.