Background: Doxorubicin and Trastuzumab (DOX+TRZ) are two of the most commonly used anti-cancer medications for treating women with breast cancer. Although these two drugs enhance overall survival rates in women with breast cancer, they are associated with an increased risk of cardiotoxicity. As a novel anti-diabetic medication, various randomized controlled trials have demonstrated that sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as Empagliflozin (EMPA), reduce the risk of hospitalizations and mortality due to heart failure in patients with and without diabetes. However, little is known about the potential effects of SGLT2 inhibitors in treating DOX+TRZ mediated cardiotoxicity.
METHODS AND RESULTS: For the 6-week study, a total of 50 C57Bl/6 female mice were randomly assigned to receive weekly treatment with saline or DOX+TRZ intraperitoneally for 3 weeks to establish a chronic in vivo murine model of chemotherapy induced cardiotoxicity. Mice were treated with Perindopril (PER) (3 mg/kg), EMPA (10 mg/kg) or EMPA+PER orally for an additional 3 weeks for a total of 6 weeks. Echocardiography was performed on a weekly basis and at the end of week 6, the mice were euthanized for histological analysis. In mice treated with DOX+TRZ, the left ventricular ejection fraction (LVEF) decreased from 74±4% at baseline to 37±6% at week 6. Mice treated with either PER, EMPA, or EMPA+PER via oral gavage demonstrated an improvement in LVEF of 62±4%, 63±3%, and 64±4%, respectively (p < 0.05) (Figure 1). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX+TRZ treated mice. Oral gavage with EMPA and EMPA+PER, however, improved myofibril integrity at week 6 in mice receiving DOX+TRZ.
Conclusion: EMPA was equivalent to PER in improving cardiovascular remodeling in a chronic in vivo model of DOX+TRZ mediated cardiotoxicity.
