Diabetes drug lowers prostate cancer-specific, all-cause mortality

Chicago-In men with diabetes who are diagnosed with prostate cancer, use of metformin reduces both cancer-specific and all-cause mortality, and the treatment benefits increase with increasing cumulative duration of exposure to the drug, according to the results of a retrospective study presented at the American Society of Clinical Oncology annual meeting in Chicago.

The population-based observational cohort study included 3,837 men who were identified from several Ontario health care administrative databases. The patient accrual period extended from 1997 to 2008; eligible patients had to be at least 66 years of age and have incident diabetes followed by a diagnosis of prostate cancer. By the end of follow-up in 2009 (median, 4.64 years), 1,343 men had died (35%), including 291 men (7.6%) from their prostate cancer.

In a multivariate analysis adjusting for multiple confounders associated with metformin exposure and the mortality outcomes, the risk of death from prostate cancer was decreased by 24% for each additional 6 months of metformin use. Metformin use also reduced all-cause mortality in a dose-dependent fashion, although the magnitude of the benefit declined steadily over time from 24% for the first 6 months of exposure to 7% during months 24 to 30.

Multiple sensitivity analyses were also performed, and the results were similar, demonstrating that the benefits of metformin for improving both mortality outcomes were robust, reported first author David Margel, MD, a uro-oncology fellow at the University of Toronto.

He suggested the study findings provide support for the role of metformin as antidiabetic treatment in men with prostate cancer and for investigating it as a chemopreventive agent in men with low-risk prostate cancer.

“Metformin is first-line therapy for diabetics. We believe that among men with both diabetes and prostate cancer, it may be used not only to treat diabetes but also improve prostate cancer outcomes. Metformin may also be a useful adjunct to help prevent the metabolic consequences of androgen deprivation therapy in men with advanced disease on a hormone regimen,” said Dr. Margel, who worked on the study with Neil E. Fleshner, MD, MPH, and colleagues.

“Most importantly, however, we believe our study sets proof of concept for a phase III prospective, randomized trial investigating metformin for chemoprevention in men with low-risk prostate cancer choosing active surveillance. This trial is funded, and we hope to start accruing patients later this year.”

Anticancer mechanism questioned

Dr. Margel believes that analyses of blood and tissue samples collected from participants in the randomized controlled study may help elucidate the anticancer mechanism of action of metformin. Current hypotheses suggest the benefit may be an indirect consequence of metformin’s lowering of insulin levels or it may be the result of direct activation of the enzyme AMPK, which is involved in cellular energy homeostasis.

“Past studies examining an association between metformin use and prostate cancer have generally yielded negative results, but they looked for an effect on incident cancer development. If metformin is acting to deprive existing cancer cells of the energy they need to survive, it might be expected to limit cancer progression rather than cancer initiation,” Dr. Margel said.

“With that idea in mind, our study was designed to evaluate the association of cumulative metformin use and mortality outcomes among diabetic men with prostate cancer.”UT

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