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 antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and 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 patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52-0.90], although between-study heterogeneity was considerable (I(2) = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54-0.81; I(2) = 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 I(2) = 76% and SRR, 0.90; 95% CI, 0.89-0.91 with I(2) = 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 patients with diabetes 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 nondiabetic populations and to specific organ sites.

Figure 1. Study flow diagram

Of 750 citations identified, 47 independent studies were included in the analysis.

Figure 2. Forest Plot of the association between metformin and cancer incidence or cancer mortality

Forest plots of risk estimates from observational studies and randomized controlled trials of metformin use and cancer incidence (A) or cancer mortality (B). Black boxes indicate hazard ratios (HRs), and horizontal lines represent 95% confidence intervals (CIs). Black diamonds represent the summary relative risk estimates. The vertical dotted line represents a risk estimate of 1.00.

Figure 3. Forest plots of the association between metformin use and individual site cancer incidence

Forest plots of risk estimates from observational studies and randomized controlled trials of metformin use and breast cancer (A), prostate cancer (B), colon cancer (C), pancreas cancer (D), liver cancer (E), lung cancer (F). Black boxes indicate hazard ratios (HRs), and horizontal lines represent 95% confidence intervals (CIs). Black diamonds represent the summary relative risk estimates. The vertical dotted line represents a risk estimate of 1.00. P for BMI is the p-value for the interaction between BMI-adjusted analysis and unadjusted analysis.