SUMMARY: The American Cancer Society estimates that in 2024, 2,001,140 new cancer cases will be diagnosed, and 611,720 cancer deaths are projected to occur in the United States. The Center for Disease Control and Prevention recommends healthy eating habits, limiting alcohol consumption and skin protection for cancer prevention, screening tests for breast, cervical, colorectal and lung cancer for early detection, as well as HPV and Hepatitis B vaccination to lower the risk of cervical and liver cancer respectively.
Metformin is one of the most commonly prescribed agents for Type 2 diabetes worldwide. Metformin is a synthetic guanidine derived compound. Numerous epidemiological studies have shown that Type 2 diabetes patients receiving Metformin had a decreased risk of the occurrence of various types of cancers, compared to those taking other antidiabetic agents. Numerous meta-analyses have also confirmed that Metformin reduces cancer incidence by 30-50%. These findings in addition to the safety and cost-effectiveness of Metformin have generated a lot of interest in the research community. Metformin exhibited promising anticancer effects in preclinical studies by inducing cell cycle arrest at different stages of cell division depending on the cancer type, promoting cell death, suppressing cancer cell migration, invasion and metastasis, as well as deregulating cancer metabolism. Further Metformin enhanced sensitivity to radiotherapy, chemotherapy, and immunotherapy.
There has been renewed interest in the anticancer mechanisms of Metformin and it has been reported to mimic significant metabolic effects of caloric restriction at both cellular and systemic levels. It has been postulated that Metformin induces a direct effect on cancer cells, independent of blood glucose and insulin levels, and indirect effect thru systemic metabolic changes depending on blood glucose and insulin levels. The primary site at which Metformin exerts its anticancer activity is the mitochondria. Metformin inhibits mitochondrial complex I and triggers energy depletion, which activates AMPK (Adenosine Monophosphate-activated Protein Kinase ) and inhibits mTOR, limiting cancer growth. Additionally, metformin also exerts anticancer effects that are independent of AMPK but rather dependent on Rag GTPases or REDD1.
To date, there has been no comprehensive review of the literature assessing the relationship between Metformin and cancer risk. The researchers therefore conducted a comprehensive systematic review of literature and meta-analysis, to investigate the association between Metformin or any of its analogs use, and cancer risk, and specific cancer type when possible. From an initial pool of more than 6,000 articles, identified in PubMed/MEDLINE, Embase, Cochrane Library, Web of Science, and Scopus from inception through March 7, 2023, 166 studies with cancer incidence information were included in the meta-analysis. Majority of these studies took place in populations with Type 2 diabetes. This analysis was then stratified by cancer type and study type. The authors decided not to provide a summary analysis for specific cancer types because of the heterogeneity between studies due to different study designs, as this analysis included many case-control studies, some prospective cohort studies and some retrospective cohort studies.
This analysis showed a reduced risk for overall cancer in case-control studies (RR=0.55) and in prospective cohort studies (RR = 0.65). Metformin use was associated with reduced risk of gastrointestinal cancer (RR = 0.79), urologic cancer (RR = 0.88) and hematologic malignancies (RR = 0.87). The most striking association was observed for gastrointestinal cancer risk, which showed a risk reduction of 21%.
It was concluded that Metformin may be associated with a decreased risk of many cancer types, and there appears a striking association between Metformin and reduced risk for gastrointestinal cancers. The researchers added that additional studies in populations without diabetes are needed to better understand the utility of Metformin in cancer prevention.
Association of metformin use and cancer incidence: a systematic review and meta-analysis. O’Connor L, Bailey-Whyte M, Bhattacharya M, et al. JNCI:Journal of the National Cancer Institute, djae021, https://doi.org/10.1093/jnci/djae021. 30 January 2024.
