Background: Endometrial cancer incidence and mortality is increasing due to rising obesity rates, an ageing population and a preponderance of cardiovascular deaths. Novel treatments are required for women who are unfit for or who decline surgery, to reduce the risk of disease recurrence and improve survival. Laboratory work and small uncontrolled window studies suggest that metformin reduces endometrial cancer proliferation through inhibition of the PI3K-Akt-mTOR pathway and selectively targets cancer stem cells responsible for metastasis and disease recurrence in breast and ovarian cancer. Methods: i) The clinical efficacy of metformin was tested in a double-blind, placebo-controlled, randomised trial. Expression of Ki-67 and markers of the PI3K-Akt-mTOR and insulin signalling pathway were compared prior to and following treatment. ii) Cell lines were used to characterise endometrial cancer stem cells and to investigate the effect of metformin on these cells in the context of a model of obesity associated endometrial cancer. iii) The true prevalence of cardiovascular risk factors in women with endometrial cancer was compared with the general population and the impact of universal screening and treatment of modifiable risk factors on 10-year cardiovascular disease risk determined. Results: Standard diabetic doses of metformin for 1-5 weeks prior to surgery did not result in an overall reduction in endometrial cancer proliferation when tested in a methodologically robust randomised controlled trial. BMI significantly influenced response to treatment (p=0.05); non-obese women had a non-significant decrease in Ki-67 expression of 8.3% (95%CI -18.70 to +2.09) following metformin exposure, whilst no effect was seen in obese women (mean difference in post-treatment Ki-67 +5.50%, 95%CI -8.31 to +13.81). This difference was unrelated to serum drug levels. Metformin had no effect on the PI3K-Akt-mTOR pathway and insulin signalling when pre- and post-treatment endometrial biopsies were directly compared. Metformin reduced the number and activity of endometrial cancer stem cells, characterised by high ALDH activity and CD133 positivity, and decreased the expression of cancer stem cell genes at a lower concentration than that required to affect overall cell proliferation in vitro. This effect was, however, abolished in the presence of adipocyte-conditioned media. Women with newly diagnosed endometrial cancer had a 1.4-fold increased 10-year cardiovascular disease risk, as measured by QRISK2 score, compared with the general population due to higher levels of unrecognised and undertreated risk factors. Screening and treatment of these risk factors could reduce an individualâs absolute risk by 1.82%, requiring 55 women with endometrial cancer to be treated to prevent one cardiovascular event compared with 145 women in the general population. Conclusions: Obese women appear to be resistant to the anti-tumour effects of metformin as a consequence of adipocyte secreted mediators. Metformin has a specific and selective effect on endometrial cancer stem cells in a cell line model; its effect on these cells in vivo should be examined. The increased risk of cardiovascular disease in women with a history of endometrial cancer may be improved by metformin treatment; the effect of long term therapy on overall and cardiovascular specific survival should be examined in a randomised controlled trial.