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Metformin to Treat Cancer: Misstep in Translational Research from Observational Studies.

Metformin is a drug that has been used since the 1950s as first-line treatment for type 2 diabetes and that is currently being studied as a cancer treatment. The quest into metformin as a potential treatment for cancer began in 2005 with an observational case–control study from Scotland that reported a reduction in the incidence of cancer with metformin use (odds ratio 0.77; 95% confidence interval [CI]: 0.64, 0.92). This “Research Pointers” publication, which advanced the hypothesis that metformin could lower the incidence of cancer in patients with diabetes, was particularly notable because of the well-documented elevated risk of several cancers in patients with diabetes. The study generated considerable excitement in the oncology community and spawned a keen interest in investigating metformin as an agent for cancer prevention and treatment in patients with or without diabetes. As a result, in the 10-year period following the initial hypothesis-generating publication, several observational studies have been conducted in various healthcare databases to verify this hypothesis. This efficient and rapid pharmacoepidemiologic approach of exploiting existing healthcare databases to assess the real-world effects of medications, including identifying new indications for older drugs, is now popular and widespread. Most of these observational studies reported beneficial effects of metformin, showing reductions in cancer incidence and improved prognosis associated with metformin use, thus “confirming” the 2005 study results. In addition, several metaanalyses of these observational studies have contributed to reinforce these findings. These confirmatory observational studies were thus rapidly followed by the launch of randomized controlled trials to assess the efficacy of metformin as a treatment for several cancers. In this commentary, I submit that this quest into metformin as a treatment for cancer is a likely instance of serious missteps in translational research, with currently running randomized trials motivated by observational studies that have sufficiently serious biases to question their conclusions. This metformin–cancer example should not be construed as a questioning of the importance of otherwise rigorous observational studies in the armamentarium of clinical research. With this example, I also raise the issue of challenges in interpreting data from multiple randomized trials prompted by flawed observational data.