Exploring the Role of SGLT2 Inhibitors in Cancer: Mechanisms of Action and Therapeutic Opportunities

Cancer cells utilize larger amounts of glucose than their normal counterparts, and the expression of GLUT transporters is a known diagnostic target and a prognostic factor for many cancers. Recent evidence has shown that sodium-glucose transporters are also expressed in different types of cancer, and SGLT2 has raised particular interest because of the current availability of anti-diabetic drugs that block SGLT2 in the kidney, which could be readily re-purposed for the treatment of cancer. The aim of this article is to perform a narrative review of the existing literature and a critical appraisal of the evidence for a role of SGLT2 inhibitors for the treatment and prevention of cancer. SGLT2 inhibitors block Na-dependent glucose uptake in the proximal kidney tubules, leading to glycosuria and the improvement of blood glucose levels and insulin sensitivity in diabetic patients. They also have a series of systemic effects, including reduced blood pressure, weight loss, and reduced inflammation, which also make them effective for heart failure and kidney disease. Epidemiological evidence in diabetic patients suggests that individuals treated with SGLT2 inhibitors may have a lower incidence and better outcomes of cancer. These studies are confirmed by pre-clinical evidence of an effect of SGLT2 inhibitors against cancer in xenograft and genetically engineered models, as well as by in vitro mechanistic studies. The action of SGLT2 inhibitors in cancer can be mediated by the direct inhibition of glucose uptake in cancer cells, as well as by systemic effects. In conclusion, there is evidence suggesting a potential role of SGLT2 inhibitors against different types of cancer. The most convincing evidence exists for lung and breast adenocarcinomas, hepatocellular carcinoma, and pancreatic cancer. Several ongoing clinical trials will provide more information on the efficacy of SGLT2 inhibitors against cancer.