Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy.

Obiageli Ezewuiro,Olufunmilayo I Olopade,Iris L Romero,Masha Kocherginsky,Gini F Fleming,Tatyana A Grushko,Mohammed Habis,Jessica Hunn,Jean A Hurteau,Kathryn A Mills,Xing Xie

doi:10.1371/journal.pone.0147145

Obiageli Ezewuiro, Olufunmilayo I Olopade + Show 9 more

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https://doi.org/10.1371/journal.pone.0147145

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Abstract

There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.

Highlights

Metformin (N, N dimethybiguanide) is an oral antidiabetic drug in the biguanide class
The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes
Median follow-up for the 108 patients who were still alive at the end of the study (53 at University of Chicago Medical Center (UCMC) and 55 at NorthShore University Health System (NSUHS)) was 37.0 months

Summary

Introduction

Metformin (N, N dimethybiguanide) is an oral antidiabetic drug in the biguanide class. Metformin was approved by the Food and Drug Administration (FDA) for diabetes treatment in 1995, and was later recommended as first line therapy for type II diabetes by the American Diabetes Association [2]. Metformin is commonly used to treat polycystic ovary syndrome, a use not approved by the FDA [3]. A protective effect of metformin against cancer was first suggested in 2005 in a case-control study by Evans et al, who reported that patients with type II diabetes treated with metformin had a reduced risk of cancer [4]. In 2013, a meta-analysis of six observational studies (24,410 patients) found that use of metformin was associated with reduced risk of death due to cancer (OR 0.65, 95% CI 0.53–0.80; P < .0001) [8]. It is hypothesized that metformin’s anti-cancer effects are mediated by systemic effects via decreasing both insulin and glucose and by direct effects on cancer cells through activation of critical signaling pathways, including AMP-activated kinase (AMPK) [9]

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