Cardioprotective Effect of Empagliflozin in Breast Cancer Patients

Empgliflozin Cardioprotective Effect

Empagliflozin, Cardioprotection, Dox Cardiotoxicity

Background: Doxorubicin (DOX) remains a cornerstone in adjuvant and neoadjuvant therapy for breast cancer, but its utility is hindered by dose-dependent cardiotoxicity. Both SGLT2 inhibitors (Empagliflozin) and Biguanides (Metformin) have demonstrated off-target cardioprotective and metabolic properties in preclinical and clinical settings. Objective: To compare the cardioprotective efficacy, safety, and metabolic/oncologic outcomes of Empagliflozin versus Metformin in non-diabetic or controlled-diabetic women with breast cancer undergoing doxorubicin-based chemotherapy. Design: Prospective, 3-arm, open-label (or double-blind), randomized controlled clinical trial (RCT). Duration: 18 months

Background & Rationale Anthracyclines, primarily Doxorubicin, induce cardiotoxicity through reactive oxygen species (ROS) accumulation, topoisomerase II-beta inhibition, mitochondrial dysfunction, and cardiomyocyte apoptosis. * Empagliflozin (SGLT2 inhibitor): Reduces oxidative stress, attenuates cardiac inflammation, improves myocardial energy bioenergetics, and prevents adverse left ventricular remodeling independently of glycemic status. * Metformin (AMPK activator): Restores autophagic flux, preserves mitochondrial membrane potential, reduces ROS production, and exhibits anti-tumor proliferation effects. * Gaps in Knowledge: While both drugs individually show promise against anthracycline-induced cardiotoxicity (AIC), direct head-to-head clinical trials comparing an SGLT2i versus Metformin during active anthracycline treatment are lacking. 3\. Study Hypothesis * Primary Hypothesis: Prophylactic administration of Empagliflozin or Metformin significantly attenuates the subclinical decline in Left Ventricular Ejection Fraction (LVEF) and Global Longitudinal Strain (GLS) compared to standard care in women receiving doxorubicin. * Secondary Hypothesis: Empagliflozin demonstrates superior reduction in cardiac biomarker elevation (hs-cTnI, NT-proBNP) and microvascular strain compared to Metformin. 4\. Study Objectives Primary Objective To compare the changes in left ventricular systolic function (measured via baseline to 6-month Echocardiographic GLS and LVEF) among the Empagliflozin group, Metformin group, and Control group. Secondary Objectives 1. Evaluate subclinical myocardial injury via serum biomarkers: High-sensitivity Cardiac Troponin I (hs-cTnI) and N-terminal pro-B-type Natriuretic Peptide (NT-proBNP). 2. Monitor metabolic profiles (fasting blood glucose, HbA1c, and lipid profile). 3. Evaluate patient-reported outcomes (Karnofsky Performance Scale / Minnesota Living with Heart Failure Questionnaire). 4. Compare the safety profile, chemotherapy completion rates, and short-term oncologic response (pathological Complete Response in neoadjuvant settings). 5. Methodology & Study Design 5.1 Study Settings and Design * Design: Prospective, randomized, parallel-group, active-controlled trial. * Setting: Tanta Oncology Hospital / Cardio-Oncology Center. 5.2 Participant Eligibility Criteria Inclusion Criteria: 1. Adult females (≥18 years) with histologically confirmed breast cancer. 2. Scheduled to receive doxorubicin-based chemotherapy regimens (e.g., AC regimen: Doxorubicin + Cyclophosphamide every 2 or 3 weeks for 4 cycles). 3. Baseline LVEF ≥ 55 on transthoracic echocardiography with normal baseline GLS. 4. Estimated Glomerular Filtration Rate (eGFR) \< 45 mL/min/1.73 m2 5. Written informed consent provided. Exclusion Criteria: 1. Prior exposure to anthracyclines, mediastinal radiation, or anti-HER2 therapy. 2. Pre-existing heart failure, coronary artery disease, or LVEF $\< 55\\%$. 3. Uncontrolled Type 2 Diabetes Mellitus (HbA1c $\> 8.5\\%$) or Type 1 Diabetes Mellitus. 4. Severe renal impairmet (eGFR \< 45 mL/min/1.73 m2) or hepatic dysfunction. 5. History of recurrent Urinary Tract Infections (UTIs), genital mycotic infections, or ketoacidosis (for Empagliflozin safety). 6. Hypersensitivity to Empagliflozin or Metformin.

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