Metformin and cancer risk

Metformin is considered the first line option for people with type 2 diabetes requiring tablet treatment. A number of observational studies have shown that metformin carries a substantially lower risk of several types of cancer as compared with other standard glucose-lowering therapies. Metformin has the potential to lower cancer risk via its overall effect of reducing hyperinsulinemia and insulin resistance, or via more specific effects mediated by inhibition of AMP kinase including indirect effects upon growth or tumor suppressor signaling. In vitro studies support an action of metformin via these mechanisms, and it is currently in clinical trial as an adjuvant to standard anti-cancer therapies for breast and prostate cancer.

Background

Several lines of evidence suggest that metformin has the potential to reduce cancer risk. Its overal effect is to reduce hyperinsulinemia and insulin resistance, and this may in itself contribute to a reduction in the risk of tumor development. The drug does however trigger a number of more specific molecular interactions which make it of particular interest for the prevention and/or treatment of cancer.

Biologic evidence

The cellular mechanism of action of metformin is to decrease insulin resistance by activating AMP-activated protein kinase, which enhances insulin-mediated glucose uptake into the cell (i.e. its intended glucose-lowering action). In addition to this indirect insulin-sparing effect, metformin may also directly inhibit tumour growth. Activation of AMPK also results in downstream suppression of signaling through mTOR, a central cell growth controller, and increased concentrations of LKB1, a potent tumour suppressor which inhibits cell division and the production of molecules required for cell growth. Thus, the observed antiproliferative effects of metformin may derive from both direct or indirect effects on insulin resistance and circulating insulin levels[1][2][3][4][5][6].

Epidemiologic Evidence

Numerous observational studies have confirmed a decreased risk of cancer or cancer mortality associated with metformin use[7][8]. The reduced risk of cancer and cancer mortality observed in these observational studies has been consistently in the range of 15-30%, and is corroborated by the UKPDS metformin study, where a 29% reduction in cancer mortality was observed, although this was not statistically significant given the relatively small sample size. Cumulative exposure to metformin has also been shown to be associated with a further reduction in the risk of cancer or cancer mortality. Importantly, the findings of reduced cancer risk with metformin have been consistent regardless of whether weight or BMI were controlled for in statistical analyses[9].

Metformin and Breast Cancer

There has been particular interest in the effects of metformin on breast cancer outcomes. Epidemiologic studies have similarly observed 15-40% reductions in the risk of breast cancer with metformin use, particularly among peri- or post-menopausal women with type 2 diabetes[10]. One study found that long-term use of metformin (>5 years duration) was associated with a 56% decreased risk of breast cancer[11].

There is also evidence supporting the role of metformin in reducing insulin levels among non-diabetic hyperinsulinemic women with early stage breast cancer. These observational findings, combined with the experimental evidence of the beneficial effects of metformin on breast cancer cell lines in vitro[12] add to the evidence supporting a potential role for metformin in breast cancer chemoprevention. Several ongoing trials are exploring metformin as an adjuvant or neoadjuvant therapy for women with breast cancer, and these can be found in ClinicalTrials.gov.

Importantly, metformin is believed to induce inhibitory effects on estrogen receptor (ER)-positive and ER-negative breast cancer cells, thus, suggesting a comprehensive therapeutic benefit for the drug[13]. Recent “window-of-opportunity” studies suggests that short-term pre-operative course of metformin as neoadjuvant therapy for non-diabetic breast cancer patients is well tolerated, and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects[14].

Metformin and Prostate Cancer

There are few epidemiologic studies that have focused specifically on metformin use and prostate cancer incidence or mortality, and the results thus far have been inconclusive. Three studies found a decreased risk of prostate cancer associated with metformin use[15][16]. However, it is important to note that, independent of any potential moderating effects of metformin, type 2 diabetes is already associated with a decreased risk of prostate cancer. Therefore, confounding by indication may have played a role in these findings, since these studies were not designed to differentiate between the effects of metformin from that of the underlying disease. Two other studies have observed no effect of metformin on the risk of prostate cancer and a non-significant increased risk of prostate cancer (RR: 1.23, 95%CI: 0.99-1.52) associated with metformin use. As with breast cancer, several ongoing trials for metformin and prostate cancer are registered at ClinicalTrials.gov.

References

  1. ^ Schneider MB et al. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 2001;120:1263-70

  2. ^ Zakikhani M et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006;66:10269-73.

  3. ^ Anisimov VN et al. Effct of metformin on life span and on the development of spontaneous mammary tumours in HER-2/neu transgenic mice. Exp Gerontol 2005;40:685-93.

  4. ^ Buzzai M et al. Systematic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumour cell growth. Cancer Res 2007;67:6745-52.

  5. ^ Wong AK et al. AMP-activated protein kinase pathway: a potential therapeutic target in cardio metabolic disease. Clin Sci (Lond) 2009;116:607-20.

  6. ^ Wang W et al. AMP-activated protein kinase and cancer. Acta Physiol 2009;196:55-63.

  7. ^ Decensi A et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res 2010;3:1451-61.

  8. ^ Bodmer M et al. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol 2012;107:620-6.

  9. ^ Libby G et al: New users of metformin are at low risk of incident cancer: A cohort study among people with type 2 diabetes. Diabetes Care 2009;32:1620-5.

  10. ^ Bosco JL et al. Metformin and incident breast cancer among diabetic women: a population-based case-control study in Denmark. Cancer Epidemiol Biomarkers Prev 2011;20:101-11.

  11. ^ Bodmer M et al. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 2010;33:1304-8.

  12. ^ Jung JW et al. Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoSOne 2011;6:e28068.

  13. ^ Bayraktar S et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer 2012;118:1202-11.

  14. ^ Hadad S et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat 2011;128:783-94

  15. ^ Murtola TJ et al. Antidiabetic medication and prostate cancer risk: a population-based case-control study. Am J Epidemiol 2008;168:925-31.

  16. ^ Azoulay L et al. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev 2011;20:337-44.

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