Association of metformin use with cancer incidence and mortality: A meta-analysis

Abstract

Purpose

To assess the effect of metformin intake on cancer incidence and mortality.

Methods

Original articles in English published until June 15, 2012 were searched for in electronic databases (MEDLINE, ISI Web of Science and EMBASE databases) and relevant reviews were examined. Meta-analysis was applied to calculate the summary relative risk (SRR) and their 95% confidence intervals (95% CI). Sensitivity analysis was conducted to assess the robustness of the pooled estimator. The risk of publication bias was assessed by the Egger regression asymmetry test.

Results

According to the eligibility criteria, 37 studies comprising 1,535,636 participants, were selected in terms of intervention and data of cancer incidence or mortality. Among metformin users compared with non-users, the SRR for overall-cancer incidence was 0.73 (95% CI, 0.64–0.83) and that for mortality was 0.82 (95% CI, 0.76–0.89). The risk reductions for liver, pancreatic, colorectal and breast cancer incidence were 78%, 46%, 23% and 6%, respectively. Also, metformin can reduce the mortality of liver cancer (SRR, 0.23; 95% CI, 0.09–0.60) and breast cancer (SRR, 0.63; 95% CI, 0.40–0.99). No statistically significant association between metformin and prostate cancer incidence was found.

Conclusions

Metformin can reduce the incidence of overall cancer, liver cancer, pancreatic cancer, colorectal cancer and breast cancer as well as the mortality of overall cancer, liver cancer and breast cancer. No beneficial effect on prostate cancer incidence was found for meformin intake in the meta-analysis.

Introduction

Metformin is a widely used drug for the treatment of type 2 diabetes mellitus which effectively decreases circulating levels of glucose and insulin mainly by ameliorating insulin resistance [1]. Recently, metformin has been attracting much attention as a potential anti-cancer agent. One potential mechanism is that metformin can indirectly modify cancer risk by alleviating insulin resistance-associated hyperinsulinemia and hyperglycemia [10], [11], both of which have been implicated in the mechanisms linking diabetes and cancer [12], [13], [14]. In addition, metformin can directly inhibit cancer cells by initiating the pivotal LKB1/AMPK/mTOR axis which regulates energy metabolism and protein synthesis of the cell. Other possible mechanisms could be suppressing tyrosine kinase receptors such as HER1 and HER2 [15], [16], anti-inflammatory effects [17], antioxidant effects [18] and killing of cancer stem cells [19].

A number of epidemiological studies have assessed the association between metformin and cancer risk, but the results were inconsistent. For breast cancer, Ruiter et al. [2], Bosco et al. [4] and He et al. [7] found a 5%, 19% and 53% risk reduction respectively in metformin users while some other studies found no beneficial effect of metformin [21], [22], [23].

In this controversial context, we performed a meta-analysis of currently available relevant epidemiological studies to quantitatively assess the effect of metformin on cancer incidence and mortality.