Sodium–glucose cotransporter 2 inhibitors in breast cancer patients on endocrine therapy: a targeted strategy to mitigate long-term cardiometabolic risk

BACKGROUND: Hormone receptor-positive breast cancer (HR+ BC) represents the most common breast cancer subtype and is increasingly characterized by long-term survivorship complicated by substantial cardiometabolic and cardiovascular morbidity. Endocrine therapies, including aromatase inhibitors, selective estrogen receptor modulators and degraders, and ovarian suppression, remain central to disease control but promote metabolic dysfunction, vascular injury, and systemic inflammation, thereby increasing cardiovascular disease (CVD) risk and potentially contributing to endocrine resistance. These alterations are also associated with adverse changes in adipose tissue distribution, increased visceral fat accumulation, and dysregulated lipid metabolism, further amplifying cardiometabolic risk. Consequently, CVD has emerged as a leading cause of non-cancer mortality among breast cancer survivor. METHODS: We performed a comprehensive narrative review of mechanistic, preclinical, and clinical evidence evaluating the cardiometabolic and oncologic effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the context of breast cancer and cardio-oncology. Literature from experimental models, observational and real-world studies was synthesized to delineate the biological pathways through which SGLT2i may influence cardiovascular risk, metabolic health, and endocrine therapy resistance in HR + BC. MAIN BODY: SGLT2 inhibitors, originally developed as glucose-lowering agents, confer robust cardiovascular and renal protection that extends beyond glycemic control. Emerging evidence indicates that SGLT2i modulate key biological pathways relevant to HR+ BC survivorship, including insulin-IGF-1 signaling, PI3K-Akt-mTOR and AMPK pathways, adipose tissue inflammation, hepatic steatosis, endothelial dysfunction, myocardial energetics, and systemic inflammatory tone. In addition, SGLT2i promote favorable adipose tissue remodeling, with preferential reduction in visceral adiposity and improvement in adipokine profiles, and induce lipid metabolism reprogramming characterized by enhanced fatty acid oxidation and reduced hepatic lipogenesis, contributing to improved cardiometabolic homeostasis. Observational and propensity-matched studies in oncology populations associate SGLT2i use with reduced incidence of heart failure, attenuation of cancer therapy-related cardiac dysfunction, and improved cardiovascular outcomes, including in breast cancer survivors exposed to cardiotoxic therapies. Beyond cardiovascular protection, converging data suggest that SGLT2i may indirectly mitigate or delay resistance to endocrine therapy by suppressing hyperinsulinemia-driven growth signaling, remodeling adipokine and inflammatory networks, and altering tumor-host metabolic interactions. CONCLUSION: SGLT2 inhibition represents a promising systems-level strategy at the intersection of cardio-oncology, metabolism, and endocrine resistance in HR+ breast cancer. By simultaneously targeting glucose homeostasis, adipose tissue dysfunction, and lipid metabolism, SGLT2i may improve both cardiovascular outcomes and long-term cancer control. Dedicated prospective trials are urgently needed to define their clinical role in breast cancer survivorship and precision cardio-oncology.