FROM BENCH TO BEDSIDE: INVESTIGATING SGLT2 INHIBITORS AS A NOVEL STRATEGY AGAINST CHEMOTHERAPY-INDUCED CARDIOMYOPATHY

Abstract

Therapeutic Area

Pharmacologic Therapy

Background

Anthracyclines are essential components of chemotherapeutic regimens for a broad spectrum of malignancies, yet their utility is constrained by cumulative, dose-dependent cardiotoxicity, often culminating in non-ischemic cardiomyopathy and heart failure. The pathogenesis involves oxidative stress, mitochondrial dysfunction, and topoisomerase IIβ–mediated DNA damage in cardiomyocytes. While ACE inhibitors and angiotensin receptor blockers (ARBs) have demonstrated modest cardioprotective effects, the efficacy of newer heart failure therapies remains underexplored. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, endorsed as Class I therapy for heart failure with reduced ejection fraction (HFrEF) per 2022 AHA/ACC/HFSA guidelines, have shown robust cardioprotective effects in large cardiovascular outcomes trials. However, their potential to prevent or attenuate anthracycline-induced cardiotoxicity has not been systematically evaluated. This study aimed to assess preclinical and clinical evidence supporting their use in anthracycline-exposed populations.

Methods

A systematic review was conducted in accordance with PRISMA 2020 guidelines. Comprehensive searches of major medical databases and clinical trial registries were performed through March 2025. Eligible studies investigated SGLT2 inhibitors, beta-blockers, or ACE inhibitors in adult patients receiving anthracycline-based chemotherapy or in animal models replicating this exposure. Primary outcomes included changes in left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), and incidence of heart failure. Studies involving pre-existing heart failure or non-anthracyclinerelated cardiotoxicity were excluded.

Results

Preclinical studies (n=4) consistently demonstrated that SGLT2 inhibitors mitigated cardiomyocyte injury, fibrosis, and oxidative stress, preserving cardiac function in anthracycline-exposed models. In one study, LVEF was significantly higher in animals treated with SGLT2 inhibitors (61.3% ± 11%) versus controls (49.2% ± 8%, p = 0.007). Additional studies corroborated reduced histopathological damage and improved myocardial performance. No clinical trials to date have specifically assessed SGLT2 inhibitors in oncology populations. Nevertheless, major cardiovascular trials (e.g., EMPA-REG OUTCOME, DECLARE-TIMI 58) have demonstrated substantial reductions in heart failure events among non-cancer cohorts. In contrast, ACE inhibitors and beta-blockers have shown variable efficacy during chemotherapy, with inconsistent findings across studies.

Conclusions

SGLT2 inhibitors exhibit consistent cardioprotective effects in preclinical models of anthracycline cardiotoxicity and possess well-established efficacy in broader cardiovascular populations. These findings underscore the critical need for prospective trials evaluating their safety and therapeutic potential in cardio-oncology, with implications for reshaping current preventive strategies.