341 - IS EMPAGLIFLOZIN EQUIVALENT AND/OR SYNERGISTIC WITH ACE INHIBITION IN THE PREVENTION OF CHEMOTHERAPY MEDIATED CARDIOTOXICITY?

Background: Breast cancer is a major public health concern in Canada. Doxorubicin and Trastuzumab (DOX+TRZ) are two of the most common anti-cancer drugs used in the treatment of breast cancer. While these two anti-cancer drugs improve overall survival in women with breast cancer, they increase the risk of developing heart failure. As a novel anti-diabetic medication, several randomized controlled trials have demonstrated that sodium-glucose co-transporter 2 (SGLT2) inhibitors, including Empagliflozin (EMPA), reduce the risk of heart failure associated hospitalization and mortality in patients with and without diabetes. Little is known, however, about whether SGLT2 inhibitors are cardioprotective in the setting of chemotherapy mediated cardiotoxicity.

METHODS AND RESULTS: In a chronic in vivo murine model of chemotherapy mediated cardiotoxicity, a total of 75 C57BL/6 female mice received prophylactic treatment with Perindopril (PER) (3 mg/kg), EMPA (10 mg/kg), or EMPA+PER orally for a total of 3 weeks as a run-in period prior to weekly administration of DOX+TRZ (8mg/kg and 3mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Serial echocardiography was performed on a weekly basis and at the end of week 6, cardiac tissue was collected for histological and biochemical analyses. In mice treated with DOX+TRZ, the left ventricular ejection fraction (LVEF) decreased from 75±3% at baseline to 41±4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 57±3%, 66±3%, and 68±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. Prophylactic administration with PER, EMPA, or EMPA+PER, however, improved myofibril integrity at week 6 in mice receiving DOX+TRZ.


Conclusion: In a chronic in vivo murine model of DOX+TRZ induced cardiotoxicity, the prophylactic administration of EMPA or EMPA+PER was superior to PER alone in preventing adverse cardiovascular remodeling.