Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 1;188(10):1794-1800.
doi: 10.1093/aje/kwz157.

Metformin Treatment and Cancer Risk: Cox Regression Analysis, With Time-Dependent Covariates, of 320,000 Persons With Incident Diabetes Mellitus

Free PMC article

Metformin Treatment and Cancer Risk: Cox Regression Analysis, With Time-Dependent Covariates, of 320,000 Persons With Incident Diabetes Mellitus

Rachel Dankner et al. Am J Epidemiol. .
Free PMC article


There is conflicting evidence regarding the association between metformin use and cancer risk in diabetic patients. During 2002-2012, we followed a cohort of 315,890 persons aged 21-87 years with incident diabetes who were insured by the largest health maintenance organization in Israel. We used a discrete form of weighted cumulative metformin exposure to evaluate the association of metformin with cancer incidence. This was implemented in a time-dependent covariate Cox model, adjusting for treatment with other glucose-lowering medications, as well as age, sex, ethnic background, socioeconomic status, smoking (for bladder and lung cancer), and parity (for breast cancer). We excluded from the analysis metformin exposure during the year before cancer diagnosis in order to minimize reverse causation of cancer on changes in medication use. Estimated hazard ratios associated with exposure to 1 defined daily dose of metformin over the previous 2-7 years were 0.98 (95% confidence interval (CI): 0.82, 1.18) for all-sites cancer (excluding prostate and pancreas), 1.05 (95% CI: 0.67, 1.63) for colon cancer, 0.98 (95% CI: 0.49, 1.97) for bladder cancer, 1.02 (95% CI: 0.59, 1.78) for lung cancer, and 0.88 (95% CI: 0.56, 1.39) for female breast cancer. Our results do not support an association between metformin treatment and the incidence of major cancers (excluding prostate and pancreas).

Keywords: bladder cancer; breast cancer; colorectal cancer; diabetes mellitus; lung cancer; metformin; time-varying treatment; weighted cumulative exposure.


Figure 1.
Figure 1.
Percentages of diabetic Israelis at risk of cancer who were using metformin (solid curve) and other glucose-lowering medications (dotted curve), by years since diabetes diagnosis, 2002–2012. For calculation of trajectories, see Table 2 (third plus fourth columns divided by second column for metformin trajectory; sixth plus seventh columns divided by second column for other glucose-lowering medication trajectory).

Similar articles

See all similar articles


    1. Romero R, Erez O, Hüttemann M, et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017;217(3):282–302. - PMC - PubMed
    1. American Diabetes Association 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2018;41(suppl 1):S73–S85. - PubMed
    1. Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–1305. - PMC - PubMed
    1. Wu L, Zhu J, Prokop LJ, et al. Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies. Sci Rep. 2015;5:10147. - PMC - PubMed
    1. Suissa S, Azoulay L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care. 2012;35(12):2665–2673. - PMC - PubMed

Publication types