Repurposing SGLT2 Inhibitors Beyond Diabetes: Emerging Roles in Cancer Prevention and Therapy.

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were originally developed as glucose-lowering agents for the management of type 2 diabetes mellitus. Nevertheless, accumulating evidence suggests that their therapeutic potential extends far beyond glycemic control, with emerging roles in cardiovascular and renal protection and, more recently, cancer prevention and therapy. This chapter explores the expanding landscape of SGLT2 inhibitors in oncology, highlighting the molecular mechanisms, preclinical evidence, and evolving clinical implications associated with their anticancer properties. Preclinical studies have demonstrated functional SGLT2 expression in several malignancies, including renal, pancreatic, prostate, liver, and breast cancers, where enhanced glucose uptake supports tumor growth and metabolic adaptation. By inhibiting glucose transport and altering cellular energy metabolism, SGLT2 inhibitors may suppress tumor proliferation, induce apoptosis, and reduce metastatic potential. Additionally, these agents  display indirect anticancer effects through modulation of insulin resistance, reduction of chronic inflammation, attenuation of oxidative stress, and alteration of the tumor microenvironment. Emerging studies also suggest synergistic interactions between SGLT2 inhibitors and established anticancer therapies, including chemotherapy, immunotherapy, and targeted agents. Despite promising experimental findings, clinical evidence remains limited, and several challenges persist regarding optimal patient selection, tumor specificity, dosing strategies, and long-term safety in oncology settings. Furthermore, concerns of adverse effects such as ketoacidosis, genitourinary infections, and volume depletion warrant careful evaluation in cancer population. This review critically examines current knowledge regarding the mechanistic basis and translational potential of SGLT2 inhibitors as adjunctive or repurposed anticancer therapies. By incorporating findings from metabolic research, experimental oncology, and early clinical investigations, this chapter aims to provide a comprehensive overview of how SGLT2 inhibition may represent a novel and promising therapeutic avenue in precision cancer medicine.