Cardioprotective Effect of Empagliflozin in Breast Cancer Patients

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.