Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and Confounders

Abstract

Previous meta-analyses have shown that the anti-diabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiological studies. We performed a meta-analysis with a focus on confounders and biases, including BMI, study type, and time related biases. We identified 71 articles published between January 1, 1966 to May 31, 2013 through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in diabetic patients. Overall cancer incidence was reduced by 31% (SRR=0.69, 95%CI: 0.52–0.90), although between-study heterogeneity was considerable (I2=88%). Cancer mortality was reduced by 34% (SRR=0.66, 95%CI: 0.54–0.81; I2=21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR=0.82, 95%CI: 0.70–0.96 with I2=76% and SRR=0.90; 95%CI: 0.89–0.91 with I2=56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in diabetic patients. However the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to non-diabetic populations and to specific organ sites.

Reduced colorectal cancer incidence in type 2 diabetic patients treated with metformin: a meta-analysis

“…In line with the mechanism exploration, the conclusion that metformin is related to the decreased CRC incidence among T2DM patients is also supported by our metaanalysis. Previous meta-analyses mostly supported reduced CRC risk associated with diabetes treated with metformin (Zhang et al 2011;Soranna et al 2012;Gandini et al 2014). The recent metaanalysis performed by Zhang et al (2011), including five studies, suggested a 37% reduction (95% CI: 0.50-0.79) of colon cancer incidence, which was consistent with our results.…”

“…Decensi et al (2010) included three articles in the meta-analysis of colon cancer incidence (Currie et al 2009;Libby et al 2009), which were all included in our study and in addition we also included eight more studies. Metaanalysis for all cancer risk by Gandini et al (2014) also found an Figure 3. Forest plot of colorectal cancer risk estimates for the relationship between use of metformin and CRC incidence among type 2 diabetic mellitus in different regions, study designs, and other anti-diabetes treatments.…”

“…However, other studies did not detect the relationship between metformin treatment and CRC risk among diabetes (Yang et al 2004;Bodmer et al 2012;Cardel et al 2014;Tsilidis et al 2014;Xu et al 2014). Several meta-analyses were conducted to evaluate the relationship, while the tissue still remains controversial (Decensi et al 2010;Zhang et al 2011;Noto et al 2012;Soranna et al 2012;Gandini et al 2014). …”

“…Notably, one study investigated the association between metformin and colorectal adenoma (Chung et al 2008). Gandini et al (2014) performed a new meta-analysis, which shows that metformin may reduce cancer incidence and mortality in patients with diabetes, including the colon cancer. Thereafter, several further studies were conducted to explore the relationship between metformin therapy and CRC risk among T2DM (Tsilidis et al 2014;Xu et al 2014).…”

Metformin: Hype or Hope for Cancer

“…20 Metformin was shown to reduce cancer risk of 31% and cancer mortality of 34% in a recent meta-analysis. 21 In an another recent meta-analysis which included 265 studies, metformin or glitazones were linked with lower incidence of cancer but; oral antidiabetic medications called sulfonylureas, insulin and alpha-glucosidase inhibitors were linked with increased incidence of cancer (RR= 0.86, 0.93 vs 1.20, 1.21, 1.10 respectively). 22 Metformin was approved in Europe in 1958 and in USA in 1995 for use in type 2 diabetes mellitus which is an insulin sensitizer and mainly acts through inhibiting hepatic gluconeogenesis by activating LKB1 (liver kinase B1)/AMP-activated protein kinase (AMPK).…”