A Pharmacist’s Perspective on Metformin Use and Cancer Outcomes

Having grown into the diabetes gold standard treatment, metformin trails an unsurpassed legacy of inexpensive safety and efficacy. This fact remains unaltered by the anecdotal risk of lactic acidosis, history of a feared and deadly outcome inherited from its medicinally engineered counterpart, phenformin. Upon this soon to be centennial of metformin’s published evidence (1922-2022), the mechanisms and interplays of its beneficial effects, noticed rather recently by the oncology community, are yet to be fully elucidated. With a 1 in 2 lifetime chance of developing cancer among the sons and daughters of the obesity pandemic, metformin’s unintended benefits in cancer have reached a rather difficult to ignore moment in time: a serendipitous ‘‘metformin age’’ for clinical oncology. Despite dramatic societal need for a safe, effective, and inexpensive cancer drug, naysayers, driven by myriads of confounders pledging proven shortcomings in any retrospective studies reporting a cancer-related benefit in metformin users, convincingly promote the evidence of our inability to indicate who may benefit or suffer most from metformin treatment. Facing continued inconsistency in understanding its benefits in cancer, metformin stars in the clinical trials arena as the first antitumor agent tested simultaneously by the greatest number of clinical trials in cancer history: 102 in North America, 61 in Europe, and 50 throughout the rest of the world over the last 5 years alone. Awaiting for the answer to the question ‘‘to be or not to be’’ treated with metformin if diagnosed with cancer, not less than 70 clinical trials enrolling patients with cancer of various origins to receive or not metformin over weeks or years were actively recruiting as of August 25, 2014, according to clinicaltrials.gov. Nearly all studies (65 of 70) excluded individuals with type 2 diabetes, the main population ever shown to have had improved cancer outcomes from metformin treatment. Investigating metformin as cancer treatment (56 of 70) or as a preventative therapy (6 of 70), a quarter of these studies were early phase clinical trials (0 or I), over two-thirds of them reporting to enroll less than 100 patients, a quite unexpected design approach in light of the established safety profile of metformin. Interestingly, with a wealth of already published evidence linking obesity and type 2 diabetes physiology to cancer, the most wanted biguanide on Earth remains underutilized in millions of prediabetes or undiagnosed patients with diabetes spurring forward the obesity pandemic into a diabetes pandemic and potentially further into a cancer pandemic in the coming decades. The graying of America suggests that metformin utilization may increase regardless of the latest clinical trials’ teachings. So, one may humbly point then that whether or not a patient with cancer could benefit from metformin is less a matter of newly discovered science but rather a matter of evaluating whether the respective patient with cancer already has an indication for receiving metformin or not. Instances of impaired insulin sensitivity—as implied by the combined evidence of glucose tolerance testing, hemoglobin A1c, insulin, C-peptide, cholesterol or C-reactive protein levels—would warrant overall clinical benefit from addition of metformin in likely any patient with cancer, assuming no contraindication noted for the drug. Of outmost importance, the utilization of metformin in patients with cancer for treatment of old or newly diagnosed type 2 diabetes, as denoted by the above-mentioned measures of insulin resistance, is already supported by nearly a century of research evidence and represents on-label utilization under existing approval of the Food and Drug Administration. Why then wait, my colleagues, why then wait?