Metformin in the prevention and treatment of colorectal cancer

Background. Obesity and diabetes mellitus significantly increase the risk of colorectal cancer (CRC) and negatively affect the survival of these patients. Colorectal cancer and diabetes mellitus share common pathophysiological mechanisms, such as hyperglycemia, hyperinsulinemia, insulin resistance, and chronic inflammation. Metformin is the most commonly used drug for the treatment of type 2 diabetes mellitus (T2DM) worldwide. In addition to its hypoglycemic effect, metformin has anti-tumor effects, which has stimulated interest in researching metformin as a potential method of preventing CRC and slowing its progression. Purpose – to highlight the results of studies of the chemopreventive and therapeutic effects of metformin in colorectal cancer patients. Materials and methods. Data searches for the review were conducted using PubMed, Scopus, Google Scholar, and ClinicalTrials.gov databases. Research data published in 2014–2024 were analyzed and systematized. Results. Epidemiologic studies of recent decades have shown that patients with T2DM taking metformin have a lower risk of colorectal adenomas and CRC developing and a better prognosis. There is some evidence of a protective role of the drug in patients without diabetes. It was found that the risk of developing CRC depends on the dose and duration of metformin use. Use of metformin is associated with improved survival of patients with both early stages of CRC and metastatic disease. However, some publications have not proven a relationship between metformin use and the risk of CRC and survival of these patients, which requires an analysis of the reasons for these discrepancies. The experience of using metformin in combination with chemotherapy, chemoradiotherapy, and immunotherapy in patients with CRC is currently limited to a small number of studies with small patient samples. A moderate improvement in antitumor efficacy was observed with the combination of metformin with 5-fluorouracil and irinotecan in patients with refractory metastatic CRC. Recent studies have shown promising antitumor activity of the combination of metformin with polychemotherapy in CRC treatment. In patients with locally advanced rectal cancer with diabetes mellitus, the degree of tumor regression and reduction of lymph node lesion after neoadjuvant concurrent chemoradiotherapy was higher in the group receiving metformin than in the group of patients not using this drug. Similar results were obtained in patients without diabetes. The increase in antitumor activity in the combination of metformin with immune checkpoint blockers observed in preclinical studies, was not confirmed in patients with stage IV microsatellite stable CRC. Conclusions. Observational studies and meta-analyses have demonstrated a reduction in CRC incidence and mortality among people receiving metformin. The drug has also been shown to be beneficial for diabetic patients with rectal cancer undergoing neoadjuvant chemoradiotherapy. Patients receiving the combination treatment had better pathologic responses compared to patients who did not take the drug. At the same time, studies of the combined use of metformin with chemotherapeutic drugs are limited mainly to small single-arm trials. Randomized clinical trials with large numbers of CRC patients are needed to confirm the therapeutic efficacy of metformin in combination with standard anticancer treatment.