Hype versus hope: metformin and vitamin D as anticancer agents

There has been increasing interest in the use of metformin and vitamin D to reduce cancer risk and improve outcomes. Metformin, an oral antidiabetic drug, improves insulin resistance and has been associated with reduced cancer incidence and cancer mortality. Low levels of vitamin D have also been associated with increased cancer risk, mainly in retrospective studies, and it has been suggested that vitamin D supplementation might play a role in cancer prevention. Preclinical data provide a biologic rationale for these associations; however, the human data arise predominantly from observational studies and caution is needed in their translation into clinical practice. This is because of the recognized limitations of observational studies, such as time-related survival biases, selection and referral biases, short follow-up, and the presence of confounding factors that can lead to spurious or inaccurate findings. Combined examination of associations with cancer risk and outcome (occurring when exposure in a population that does not yet have cancer is analyzed in relation to cancer death) may yield results that are difficult to interpret. Finally, associations across all cancers may differ from those in specific cancer types. These shortcomings can be overcome in properly designed and adequately powered prospective randomized trials; however, such trials are both expensive and time consuming. We review the literature examining the associations of metformin and vitamin D with cancer, discussing weakness and strengths and making recommendations for further research and clinical practice.