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

Abstract

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.

Keywords: glucose-lowering medications; inverse probability weighting; marginal structural models; metformin; prostate cancer; time-dependent confounding; type 2 diabetes.

Figure 1

Time frame of a study on metformin treatment among diabetic men and prostate cancer risk, Israel, 2002–2012. A) Calendar time; B) Cox model time frame, months.

Figure 2

Projected prostate-cancer–free proportion of diabetic men in follow-up for 2 treatment regimens: no metformin treatment (“none”) and high-dose (≥0.5 defined daily dose) metformin treatment (“high”), Israel, 2002–2012. Estimates were based on the weighted marginal structural model using the missing-value indicators method and were computed for the age category 70–80 years, the socioeconomic status category “high,” and the ethnicity category “Ashkenazi Jew.” Follow-up extended from 2 years after diabetes diagnosis onward. Time = quarter-years of follow-up starting 2 years after diabetes diagnosis.