Metformin Treatment Among Men With Diabetes and the Risk of Prostate Cancer: A Population-Based Historical Cohort Study

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.