Meta-Analysis
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 21, 2024; 30(7): 759-769
Published online Feb 21, 2024. doi: 10.3748/wjg.v30.i7.759
Metformin and pancreatic neuroendocrine tumors: A systematic review and meta-analysis
Maja Cigrovski Berkovic, Alessandro Coppola, Vibor Sesa, Anna Mrzljak, Quirino Lai
Maja Cigrovski Berkovic, Department for Sport and Exercise Medicine, Faculty of Kinesiology University of Zagreb, Zagreb 10000, Croatia
Alessandro Coppola, Department of Surgery, Sapienza University of Rome, Rome 00185, Italy
Vibor Sesa, Anna Mrzljak, Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
Anna Mrzljak, Department of Medicine, School of Medicine, Zagreb 10000, Croatia
Quirino Lai, General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
Author contributions: Lai Q and Cigrovski Berkovic M contributed to the conception and design of the study; Coppola A and Lai Q contributed to the acquisition of data; Lai Q, Coppola A, and Sesa V analyzed and interpreted the data; Mrzljak A and Cigrovski Berkovic M drafted the article; Lai Q critically revised the manuscript; all authors approved the final version.
Conflict-of-interest statement: There is no conflict-of-interest for authors.
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, Assistant Professor, Department for Sport and Exercise Medicine, Faculty of Kinesiology University of Zagreb, Horvacanski zavoj 15, Zagreb 10000, Croatia. maja.cigrovskiberkovic@gmail.com
Received: November 19, 2023
Peer-review started: November 19, 2023
First decision: December 15, 2023
Revised: December 18, 2023
Accepted: January 23, 2024
Article in press: January 23, 2024
Published online: February 21, 2024
Processing time: 93 Days and 20.8 Hours
ARTICLE HIGHLIGHTS
Research background

Advanced pancreatic neuroendocrine tumors (pNETs) are difficult to treat with low overall survival (OS). In pNET development, hyperactivation of PI3K/Akt signaling and activation of the mTOR pathway mediated through insulin-like growth factor-1 have been implicated to play a crucial role in carcinogenesis, thus providing the rationale for metformin use. Moreover, although risk factors for pNET are still inconclusive, type 2 Diabetes mellitus (T2DM) has been described as an essential contributor to tumor development, with a high incidence and prevalence of diabetes seen among pNET patients. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.

Research motivation

Regarding scarce data on pNET treatment and risk factors we wanted to investigate and analyze available data related to diagnostic and prognostic value of T2DM and metformin in association with pNET.

Research objectives

The main aim of this review was to systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNETs.

Research methods

A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), OS and progression-free survival.

Research results

A total of 13 studies (n = 5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with I2 = 0%) confirms the correlation between T2DM and insurgence of pNET (odds ratios = 2.13, 95%CI = 1.56-4.55; P < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment (TFS) in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; P < 0.001). The study heterogeneity was intermediate, with I2 = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.

Research conclusions

T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment (TFS) of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Research perspectives

Future research should further try to identify other risk factors and their influence on pNETs as well as the role of metformin in the diagnosis and prognosis of pNET.