Metformin Treatment Among men With Diabetes and the Risk of Prostate Cancer

A Population-Based Historical Cohort Study

Laurence S. Freedman; Nirit Agay; Ruth Farmer; Havi Murad; Liraz Olmer; Rachel Dankner


Am J Epidemiol. 2022;191(4):626-635. 

In This Article

Abstract and Introduction


There is conflicting evidence regarding the association between metformin treatment and prostate cancer risk in diabetic men. We investigated this association in a population-based Israeli cohort of 145,617 men aged 21–89 years with incident diabetes who were followed over the period 2002–2012. We implemented a time-dependent covariate Cox model, using weighted cumulative exposure to relate metformin history to prostate cancer risk, adjusting for use of other glucose-lowering medications, age, ethnicity, and socioeconomic status. To adjust for time-varying glucose control variables, we used inverse probability weighting of a marginal structural model. With 666,553 person-years of follow-up, 1,592 men were diagnosed with prostate cancer. Metformin exposure in the previous year was positively associated with prostate cancer risk (per defined daily dose; without adjustment for glucose control, hazard ratio (HR) = 1.53 (95% confidence interval (CI): 1.19, 1.96); with adjustment, HR = 1.42 (95% CI: 1.04, 1.94)). However, exposure during the previous 2–7 years was negatively associated with risk (without adjustment for glucose control, HR = 0.58 (95% CI: 0.37, 0.93); with adjustment, HR = 0.60 (95% CI: 0.33, 1.09)). These positive and negative associations with previous-year and earlier metformin exposure, respectively, need to be confirmed and better understood.


There is conflicting evidence regarding the effect of metformin therapy on prostate cancer risk. Recent meta-analyses[1–3] of observational studies found no clear evidence of a previously hypothesized protective association.[4–7] Nevertheless, analyzing observational study data addressing this question is fraught with pitfalls[8] that, in turn, can influence meta-analysis results, so the question remains open. The high prevalence of diabetes, widespread use of metformin treatment for diabetes, and relatively high incidence of prostate cancer make this question important.

We describe here analysis of a population-based cohort study of patients diagnosed with diabetes, aimed at addressing this question. Important features of our analysis are the use of Cox regression with time-dependent covariates describing metformin treatment history[9] and inverse probability weighting (IPW) of marginal structural models (MSMs).[10] MSM analysis addresses bias arising in Cox regression when a time-varying treatment is modified in response to a time-varying marker—here, hemoglobin A1c (HbA1c) or blood glucose level—that is itself associated with the disease outcome, prostate cancer.