Metformin and Colorectal Cancer Risk in Diabetic Patients

There has been substantial interest in investigating whether the long-term administration of metformin to diabetic patients leads to a reduction in the incidence of malignancies in general or more specifically colorectal cancer. A number of studies have been published on this field with mixed results (1,2). In this issue of Diabetes Care , Zhang et al. (3) report the results of a meta-analysis of five observational studies including 108,161 patients with type 2 diabetes. As compared with other antidiabetic treatments combined, use of metformin was associated with a lower risk of colorectal cancer (relative risk 0.63 [95% CI 0.47–0.84]). There was no evidence of significant heterogeneity among the included studies or statistical evidence of publication bias. Metformin is the first drug of choice for the management of type 2 diabetes (4,5). It has two main antidiabetic mechanisms of action, both of which have also been implicated as anticarcinogenic mechanisms. Firstly, metformin inhibits hepatic glucose production through an LKB1/AMP-activated protein kinase–mediated mechanism. Metformin-induced initiation of an LKB1-mediated AMP-activated protein kinase–dependent energy stress response has been shown to adversely affect the survival of cancer cell lines (6,7). Secondly, metformin improves insulin sensitivity in peripheral tissues reducing hyperinsulinemia. Insulin resistance and hyperinsulinemia have been associated with increased risk of several types of neoplasm (8,9) and specifically with colorectal cancer (10). These mechanistic pathways provide sufficient rationale for investigating the hypothesis that use of metformin is associated with reduced risk of selected malignancies. It is worth emphasizing that the study by Zhang et al. is a meta-analysis of observational studies and not a meta-analysis of randomized controlled trials. Thus, all the limitations inherent in the original observational studies included in the meta-analysis …