Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis

Abstract

Objective: Oral antidiabetic drugs (including metformin and sulfonylurea) may play a role in the relationship between type 2 diabetes and cancer. To quantify the association between metformin and sulfonylurea and the risk of cancer, we performed a meta-analysis of available studies on the issue.

Materials and methods: We performed a MEDLINE search for observational studies that investigated the risk of all cancers and specific cancer sites in relation to use of metformin and/or sulfonylurea among patients with type 2 diabetes mellitus. Fixed- and random-effect models were fitted to estimate the summary relative risk (RR). Between-study heterogeneity was tested using χ(2) statistics and measured with the I(2) statistic. Publication bias was evaluated using funnel plot and Egger's regression asymmetry test.

Results: Seventeen studies satisfying inclusion criteria and including 37,632 cancers were evaluated after reviewing 401 citations. Use of metformin was associated with significantly decreased RR of all cancers (summary RR 0.61, 95% confidence interval [CI] 0.54-0.70), colorectal cancer (0.64, 95% CI 0.54-0.76), and pancreatic cancer (0.38, 95% CI 0.14-0.91). With the exception of colorectal cancer, significant between-study heterogeneity was observed. Evidence of publication bias for metformin-cancer association was also observed. There was no evidence that metformin affects the risk of breast and prostate cancers, nor that sulfonylurea affects the risk of cancer at any site.

Conclusions: Metformin, but not sulfonylurea, appears to reduce subsequent cancer risk. This has relevant implications in light of the exploding global epidemic of diabetes.

Figure 1.

Flow chart of the selection of studies for inclusion in the meta-analysis.

Figure 2.

Forest plot of study-specific relative risk estimates for any cancer site when comparing use of metformin versus various reference therapies by study design. Squares represent study-specific relative risk estimates (size of the square reflects the study-specific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary relative risk estimates with corresponding 95% CIs; p-values are from testing for heterogeneity across study-specific estimates. Abbreviations: CI, confidence interval; RR, relative risk.

Figure 3.

Forest plot of study-specific relative risk estimates for use of metformin, versus all reference therapies, and specific sites of cancer. Squares represent study-specific relative risk estimates (size of the square reflects the study-specific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary relative risk estimates with corresponding 95% CIs; p-values are from testing for heterogeneity between study-specific estimates. Abbreviations: CI, confidence interval; RR, relative risk.

Figure 4.

Forest plot of study-specific relative risk estimates for any site of cancer when comparing use of sulfonylurea versus all reference therapies. Squares represent study-specific relative risk estimates (size of the square reflects the study-specific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary relative risk estimates with corresponding 95% CIs; p-values are from testing for heterogeneity between study-specific estimates. Abbreviations: CI, confidence interval; RR, relative risk.

Figure 5.

Funnel plot for publication bias in the study investigating cancer risk associated with use of metformin (A) and sulfonylurea (B). Abbreviations: RR, relative risk; SE, standard error.