Chemopreventive Effect of Metformin on Gastric Cancer Development.

Although Helicobacter pylori infection is the most important causative factor for gastric cancer (GC), H. pylori eradication alone does not completely eliminate the GC risk. In addition to H. pylori eradication, other risk factors for GC should be identified and targeted. Diabetes mellitus (DM) confers a 20% increased risk of GC, which could be mediated via several biological mechanisms including the stimulation of cell proliferation via hyperinsulinemia and increased insulingrowth factor production, the promotion of angiogenesis, and DNA damage. With a current global prevalence of 9.3% and a predicted rise to 10.2% by 2030, DM could contribute substantially to the burden of GC cases worldwide. Emerging evidence showed that metformin possesses chemopreventive effects via both direct (e.g., adenosine monophosphate-activated protein kinase activation and subsequent inhibition of the mammalian target of rapamycin pathway) and indirect (e.g., modulation of the interaction between tumor cells and their microenvironment and gut microbiota) pathways. A recent meta-analysis of observational studies showed that metformin use was associated with 24% lower GC risk. However, many available observational studies related to metformin effects suffered from biases including the failure to adjust for the H. pylori infection status and serial glycemic control and time-related biases. Future prospective studies addressing these pitfalls are needed.