Evaluation of the Possible Safety and Efficacy of Dapagliflozin in the Prophylaxis of Doxorubicin-Induced Cardiotoxicity

Breast cancer is the most common type of cancer in women and the first cause of cancer death among them. In Egypt, it represents 33%of female cancer cases and more than 22,000 new cases are diagnosed each year. This is expected to rise exponentially over the next years given the enlarging population and changes in the population pyramid.

The Early Breast Cancer "Trialists" Collaborative Group (EBCTCG) reported that the inclusion of anthracyclines as doxorubicin in the management of breast cancer improved absolute survival by approximately 3% at 5 years and 4% at 10 years. Therefore, anthracyclines remain the cornerstone of treatment for breast cancer patients.

Despite its effectiveness, doxorubicin is associated with cumulative, dose-dependent, and potential cardiotoxicity.

Although the main mechanism of doxorubicin-induced cardiotoxicity has not been fully known, there are several mechanisms proposed for cardiac injury including oxidative stress, free radical generation, and apoptosis are most widely reported. Other mechanisms are also involved such as impaired mitochondrial function, perturbation in iron regulatory protein, disruption of Ca2+ homeostasis, autophagy, and the release of nitric oxide and inflammatory mediators.

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is a class of glucose-lowering agents and is used to treat patients with type 2 diabetes. Besides reducing glucose reabsorption, DAPA has shown protective effects on cardiovascular diseases. The cardioprotective effects of DAPA have been demonstrated in patients with diabetic cardiomyopathy, heart failure (HF) with preserved ejection fraction (EF), and HF with reduced EF. SGLT2 inhibitors exert their cardioprotective effect by increasing energy metabolism, mitochondrial biogenesis, autophagy, and ketone bodies while decreasing endoplasmic reticulum (ER) stress, ferroptosis, oxidative stress, and inflammation.

In a recent animal study, DAPA protected against doxorubicin-induced cardiotoxicity by reducing ER stress, as evidenced by the decreased expression of the ER-related proteins including glucose-regulated protein 78, protein kinase R-like endoplasmic reticulum kinase and transcription factor 4.

Doxorubicin administration have been shown to increase HF incidence, HF admissions, and the development of cardiomyopathy which is defined by a decline in left ventricle ejection fraction and these outcomes were attenuated by SGLT2 inhibitors.

It is known that doxorubicin increases the circulating level of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and cardiac Troponin T (cTnT) which DAPA significantly reduced in a recent animal study.

Inclusion criteria

• Age ≥18 years old.
• Chemo-naïve patients with biopsy confirmed diagnosis of breast cancer and with stage I-III breast cancer according to the American Joint Committee on Cancer (TNM staging system of breast cancer).
• Patients intended to receive at least 4 cycles of doxorubicin or more.
• Patients with performance status <2 according to Eastern Cooperative Oncology Group (ECOG) score.
• Echocardiographic LVEF ≥55%.
• Adequate baseline hematologic values (absolute neutrophilic count ≥ 1.5 ×109/L, platelet count ≥ 90 × 109/L and hemoglobin level ≥ 10 g/dl).
• Patients with adequate liver function and adequate renal function.
• Signed informed consent to participate in the study.

Exclusion criteria

• Age <18 years old and >65 years old.
• Patients with prior exposure to anthracyclines within the last 6 months.
• Patients with evidence of metastasis at initial assessment.
• Treatment with any SGLT-2 inhibitors for 6 months prior to the screening.
• Patients taking any other cardioprotective medications.
• Pregnancy and breast feeding.
• Alcohol abuse.
• History of heart failure or LVEF <50%.
• Presence of any cardiac-related conditions such as angina pectoris, valvular disease, uncontrolled systemic hypertension, coronary heart disease, and cardiac surgery within the last 3 months.
• Patients with type 1 diabetes mellitus or diabetic ketoacidosis, history of stroke, and patients with severe renal impairment with GFR <25ml/min/1.73m2 . - Patients taking gatifloxacin as it causes major drug interaction with dapagliflozin.