The Time Is Ripe for a Randomized Trial of Metformin in Clinically Localized Prostate Cancer

In a population study making excellent use of Ontario’s universal health plan electronic data, Margel et al 1 showed increasing duration of metformin use among diabetic men after a diagnosis of prostate cancer was associated with decreased prostate cancer–specific and all-cause mortality. Prostate cancer–specific mortality decreased by 24% for each additional 6 months of metformin use after diagnosis; use of other antidiabetic medications did not significantly decrease prostate cancer–specific mortality. The authors were thorough in their investigation, performing many sensitivity analyses to attempt to rule out possible biases. As the distribution of clinical characteristics specific to metformin users and nonusers was not provided, it is difficult to assess the possibility of residual confounding; however, the authors appropriately adjusted for many covariates. Also, the specificity of the results for metformin lends further support for causal relation. Interestingly, although postdiagnostic use of metformin was highly significant, the association of cumulative metformin use before prostate cancer diagnosis with prostate cancer death was null. As prostate cancer date of diagnosis is a rather arbitrary point in the progression of the disease, this discrepancy between the impact of pre- and postdiagnostic use is perplexing and warrants further study. Despite these concerns, the authors provide a convincing case for a causal interpretation and for initiating a randomized trial of metformin among men with localized prostate cancer at diagnosis. The potential benefits of metformin could exceed those of existing drug therapies, particularly given its safety profile. Margel et al 1 wisely chose to focus their analysis on prostate cancer mortality. Of course, this is clinically the most important out