No association between metformin use and survival in patients with pancreatic cancer: An observational cohort study

Frouws, Martine A. MD; Mulder, Babs G. Sibinga BSc; Bastiaannet, Esther PhD; Zanders, Marjolein M.J. MD, PhD; van Herk-Sukel, Myrthe P.P. PhD; de Leede, Eleonora M. MD; Bonsing, Bert A. MD, PhD; Mieog, J. Sven. D. MD, PhD; Van de Velde, Cornelis J.H. MD, PhD; Liefers, Gerrit-Jan MD, PhD

Section Editor(s): Gopichandran., Vijayaprasad

doi: 10.1097/MD.0000000000006229
Research Article: Observational Study

Abstract: Several studies have suggested an association between use of metformin and an increased overall survival in patients diagnosed with pancreatic cancer, however with several important methodological limitations. The aim of the study was to assess the association between overall survival, pancreatic cancer, and metformin use.

A retrospective cohort study of 1111 patients with pancreatic cancer was conducted using data from The Netherlands Comprehensive Cancer Organization (1998–2011). Data were linked to the PHARMO Database Network containing drug-dispensing records from community pharmacies. Patients were classified as metformin user or sulfonylurea derivatives user from the moment of first dispensing until the end of follow up. The difference in overall survival between metformin users and nonusers was assessed, and additionally between metformin users and sulfonylurea derivatives users. Univariable and multivariable parametric survival models were used and use of metformin and sulfonylurea derivatives was included as time-varying covariates.

Of the 1111 patients, 91 patients were excluded because of differences in morphology, 48 patients because of using merely metformin before diagnosis, and 57 metformin-users ever used contemporary sulfonylurea derivatives and were therefore excluded. Lastly, 8 patients with a survival of zero months were excluded. This resulted in 907 patients for the analysis. Overall, 77 users of metformin, 43 users of sulfonylurea derivatives, and 787 nonusers were identified. The adjusted rate ratio for overall survival for metformin users versus nonusers was 0.86 (95% CI: 0.66–1.11; P = 0.25). The difference in overall survival between metformin users and sulfonylurea derivatives users showed an adjusted rate ratio of 0.90 (95% CI: 0.59–1.40; P = 0.67).

No association was found between overall survival, pancreatic cancer, and metformin use. This was in concordance with 2 recently published randomized controlled trials. Future research should focus on the use of adjuvant metformin in other cancer types and the development or repurposing of other drugs for pancreatic cancer.

aDepartment of Surgical Oncology, Leiden University Medical Center, Leiden, The Netherlands, P.O. Box 9600, 2300 RC, The Netherlands

bComprehensive Cancer Organisation The Netherlands, P.O. Box 231, 5600 AE, Eindhoven, The Netherlands

cPHARMO Institute for Drug Outcomes Research, van Deventerlaan 30/40, Utrecht, 3528 AE, The Netherlands.

Correspondence: Martine A. Frouws, Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands (e-mail: M.a.frouws@lumc.nl).

Abbreviations: ATC = anatomical therapeutic chemical, ECR = Eindhoven Cancer Registry, IQR = interquartile range, OGLD = oral glucose-lowering drug, RR = rate ratio, SD = sulfonylurea derivatives.

M.H.S. is an employee of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related health care authorities and for pharmaceutical companies. However, this study was not financially supported by a pharmaceutical company.

The other authors have no conflicts of interest to disclose.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Received November 14, 2016

Received in revised form January 31, 2017

Accepted January 31, 2017

Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.