SGLT2 Inhibitors in Cancer Patients: A Comprehensive Review of Clinical, Biochemical, and Therapeutic Implications in Cardio-Oncology

Abstract

Patients with active cancer and cancer survivors are at a markedly increased risk for developing cardiovascular comorbidities, including heart failure, coronary artery disease, and renal dysfunction, which are often compounded by the cardiotoxic effects of cancer therapies. This heightened cardiovascular vulnerability underscores the urgent need for effective, safe, and evidence-based cardioprotective strategies to reduce both cardiovascular morbidity and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), a class of drugs originally developed for the treatment of type 2 diabetes, have demonstrated significant cardiovascular and renal benefits in high-risk populations, independent of glycemic control. Among the currently available SGLT2i, such as empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin, there is growing evidence supporting their role in reducing major adverse cardiovascular events (MACEs), hospitalization for heart failure, and the progression of chronic kidney disease. Recent preclinical and clinical data suggest that SGLT2is exert cardioprotective effects through multiple mechanisms, including the modulation of inflammasome activity, specifically by reducing NLRP3 inflammasome activation and MyD88-dependent signaling, which are critical drivers of cardiac inflammation and fibrosis. Moreover, SGLT2is have been shown to enhance mitochondrial viability in cardiac cells, promoting improved cellular energy metabolism and function, thus mitigating cardiotoxicity. This narrative review critically evaluates the emerging evidence on the cardiorenal protective mechanisms of SGLT2is, with a particular focus on their potential role in cardio-oncology. We explore the common pathophysiological pathways between cardiovascular dysfunction and cancer, the molecular rationale for the use of SGLT2is in cancer patients, and the potential benefits in both primary and secondary prevention of cardiovascular toxicity related to oncological treatments. The aim is to propose a therapeutic paradigm utilizing SGLT2is to reduce cardiovascular mortality, MACE, and the burden of cardiotoxicity in high-risk oncology patients, fostering an integrated approach to cardio-oncology care.

Keywords: SGLT2; cancer; cardioprotection; cardiotoxicity; inflammation; metabolism; pathology.

Figure 1

Overall illustration of SGLT2i-related cardiorenal benefits. SGLT2is increase glucose urinary excretion, improve tubule-glomerular feedback and mesangial expansion. Moreover, SGLT2is are able to reduce podocyte lipotoxicity through the inhibition of mTORC-1 pathways in podocytes and reduce inflammation and fibrosis in Bowman capsule through the inhibition of MCP-1, KIM-1, and IL-6. Beneficial renal properties reduce glucose metabolism and increase small chain fatty acid (SCFA) levels systemically and in myocardial tissue. The SCFA metabolism increases LKB-1/pAMPK signaling in myocardial cells that reduces NLRP-3 and MyD-88 pathways. The inhibition of NLP-3 and MyD88 reduces NF-kB/pro-inflammatory cytokine and chemokine pathways, resulting in autophagy and an improvement of mitochondrial functions in myocardial tissue. ⬆: increase; ⬇: decrease.

Figure 2

SGLT2is exert direct and indirect cardiac benefits, resulting in enhanced ejection fraction and mitochondrial viability of cardiomyocytes. SGLT2is reduce systemic levels of several cytokines, including IL-1α, IL-1β, IL-2, IL-4, IL-6, IL17-α, IFN-γ, TNF-α, G-CSF, and GM-CSF levels and hs-CRP, and reduce plasma levels of MDA and 4-HNA (lipid peroxidation products), free fatty acids, and MMP-3 levels, improving cardiac health. Moreover, SGLT2is reduce white adipose tissue content and increase brown adipose tissue, rich in M2-polarized macrophages with an-ti-inflammatory properties and anti-obesogenic activity. Switching WAT to BAT induced by SGLT2is reduces several cardiovascular risk factors, including obesity, metabolic syndrome, in-sulin resistance, type-2 diabetes mellitus (T2DM), visceral obesity, and non-alcoholic fatty liver disease (NAFLD).

Figure 3

Chronology of SGLT2 inhibitor revolution in cardiology.

Figure 4

Proposed molecular mechanisms underlying the cardioprotective effects of SGLT2 inhibitors against anticancer-therapy-induced cardiotoxicity. Antineoplastic agents like anthracyclines increase intracellular Ca²⁺ concentrations, leading to mitochondrial dysfunction and elevated reactive oxygen species (ROS) production. ROS accumulation induces lipid peroxidation products (MDA and 4-HNA) and activates MyD-88 and the NLRP3 inflammasome, culminating in nuclear factor-kappa B (NF-κB) activation and transcription of pro-inflammatory cytokines (IL-1β, IL-6, and IL-8). These processes contribute to maladaptive myocardial inflammation and remodeling. SGLT2 inhibitors attenuate intracellular Na⁺ and Ca²⁺ overload, reduce oxidative stress, and inhibit MyD-88/NLRP3-mediated inflammatory pathways. Furthermore, SGLT2is activate AMPK (pAMPK), which enhances mitochondrial viability and suppresses NF-κB signaling. The combined effect is a reduction in pro-inflammatory cytokine release and oxidative injury, promoting cardiomyocyte survival and limiting cancer-therapy-related cardiac dysfunction. ⬆: increase; ⬇: decrease.