Abstract
TO THE EDITOR: Margel et al 1 recently reported on a populationbased retrospective cohort study that used a unique large database to investigate patients with prostate cancer diagnosed with incident diabetes. Increased cumulative duration of metformin exposure after prostate cancer diagnosis was associated with decreases in both all-cause and prostate cancer–specific mortality among men with diabetes. The study showed that prostate cancer–specific mortality even decreased by 24% for each additional 6 months of metformin use after the diagnosis of prostate cancer. Although the approach used in this study did circumvent numerous potential limitations and biases, 2 on the basis of the authors’ conclusions and study design, we have a few comments and requests for clarification. With regard to their statistical analyses, the effects of cumulative duration of exposure to metformin on mortality were assessed by using a Cox proportional hazards model in which drug exposures after prostate cancer diagnosis were modeled as time-dependent covariates. The comparison was not exclusively between users who had different durations of exposure, but also between users and nonusers of the drug. This means that in the time-dependent model, patients not using metformin were included in the analysis as 0 for cumulative use of metformin. Modeling the line for this specific hazard ratio (HR) of cumulative metformin use could be expected to be greatly influenced by events in the nonusers, given that patients using and not using metformin might differ in their previous susceptibility to dying as a result of cancer. As a consequence, these results might be affected by confounding by indication, which could not be avoided by the inclusion of cumulative drug exposure exclusively, as supposed in this analysis. It can be shown algebraically that with the inclusion of an ever-never termformetforminuseinthemodel,theHRofthecumulativeeffectterm
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