Empagliflozin and intermittent fasting as a strategy to mitigate anthracycline-induced cardiotoxicity

Empagliflozin (EMPA) has shown cardioprotective potential by enhancing myocardial energy availability, a mechanism also observed with intermittent fasting strategies, such as time-restricted feeding (TRF). Given the cardiotoxicity of anthracyclines as Doxorubicin (Dox), integrating pharmacological and nonpharmacological interventions is of growing interest in cardio-oncology. This study assessed EMPA, alone or with TRF, in mitigating Dox-induced cardiovascular damage using both an experimental model and a clinical case. Rats were assigned to control, Dox, Dox + EMPA, Dox + TRF, or Dox + EMPA + TRF groups. Treatments included Dox (12 mg/kg), EMPA (10 mg/kg), and TRF (16 h/8 h), for four weeks. In the clinical case, a cancer patient undergoing Dox therapy received EMPA (10 mg/day) followed by TRF for three months. Cardiovascular parameters were measured. In animals, Dox significantly increased systolic, diastolic, and mean arterial pressures, mitigated by EMPA or TRF individually, with no additive effect when combined. EMPA partially normalized Dox-induced P wave and QRS alterations, while EMPA, TRF, or both reduced QTc prolongation. Histology showed Dox-induced myocardial remodeling and inflammation, which were attenuated by all treatments, restoring cardiomyocyte occupancy, reducing extracellular matrix expansion, and decreasing inflammatory infiltrate. All co-treatments prevented Dox-related leukopenia, normalizing leukocyte counts. Mechanistically, EMPA and TRF modulated Dox-induced inflammation in distinct ways: both (alone or combined) lowered TNF, TRF alone produced the strongest IL-1β suppression, the combined treatment increased IL-10 and TGF-β significantly. Clinically, the patient experienced weight loss, stable blood pressure, and cardiovascular stability although a rise in troponin levels. In conclusion, individual EMPA and TRF may help mitigate Dox-induced cardiotoxicity in certain contexts, though further clinical studies are needed to confirm their safety.