From bench to bedside: investigating SGLT2 inhibitors as a novel strategy against chemotherapy-induced cardiomyopathy.

Abstract

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 co-transporter-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 by PRISMA 2020 guidelines. Comprehensive searches of major medical databases and clinical trial registries were performed through March 2025. Eligible studies investigated SGLT2 inhibitors, β-blockers, or ACE inhibitors in adult patients receiving anthracycline-based chemotherapy or in animal models replicating this exposure. Primary outcomes included changes in LVEF, GLS, and incidence of heart failure. Studies involving pre-existing heart failure or non-anthracycline-related 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%) vs. 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 β-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.

Systematic review registration: PROSPERO [1056661].