BACKGROUND: Anthracycline-induced cardiotoxicity (AIC) is characterized by a disruption in myocardial metabolism. OBJECTIVES: The authors used a large animal model to test sodium-glucose cotransporter inhibitor therapy to prevent AIC. METHODS: Female large white pigs (n = 36) were used to identify the most translational AIC regimen: 6 triweekly intravenous doxorubicin injections (1.8 mg/kg each). Another group of 32 pigs were randomized (1:1:2) to doxorubicin plus empagliflozin 20 mg, doxorubicin plus empagliflozin 10 mg, or doxorubicin control. Pigs were serially examined using multiparametric cardiac magnetic resonance and magnetic resonance spectroscopy. At the end of the 21-week follow-up period, blood samples were obtained to measure myocardial metabolic substrate extraction, and the left ventricle was harvested and processed for analysis using metabolomics, transmission electron microscopy, mitochondrial respirometry, and histopathology. RESULTS: Final left ventricular ejection fraction (LVEF), the prespecified primary outcome, was significantly higher in pigs receiving 20 mg empagliflozin than in the doxorubicin control group (median 57.5% [Q1-Q3: 55.5%-60.3%] vs 47.0% [Q1-Q3: 40.8%-47.8%]
P = 0.027). Final LVEF in pigs receiving 10 mg empagliflozin was 51% (Q1-Q3: 46.5%-55.5%
P = 0.020 vs 20 mg empagliflozin). The incidence of AIC events was 0%, 50%, and 72% in the empagliflozin 20 mg, empagliflozin 10 mg, and doxorubicin control groups, respectively. Empagliflozin 20 mg treatment resulted in enhanced ketone body consumption by the myocardium, preserved magnetic resonance spectroscopy-measured cardiac energetics, and improved mitochondrial structure and function on transmission electron microscopy and respirometry. These changes were more modest with the 10-mg empagliflozin dose. CONCLUSIONS: Sodium-glucose cotransporter-2 inhibitor therapy with empagliflozin exerts a dose-dependent cardioprotective effect against AIC. The improved LVEF was accompanied by enhanced ketone body consumption, improved cardiac energetics, and preserved mitochondrial structure and function.