The goal of this randomized, double-blind, placebo-controlled clinical trial is to determine whether dapagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, can help prevent anthracycline-induced cardiotoxicity caused by anthracycline chemotherapy in adult women with breast cancer receiving (neo)adjuvant treatment.
The main questions the study aims to answer are:
i) Does dapagliflozin reduce the decline in left ventricular function (measured by LVEF, GLS, and myocardial work) during and after anthracycline therapy? ii) Does dapagliflozin lessen the deteriorating effect of chemotherapy on endothelial function and arterial stiffness? iii) Does dapagliflozin effect levels of cardiac injury and inflammation biomarkers (e.g., hs-troponin T, NT-proBNP, ST-2, GDF-15, galectin-3, IL-6, MPO)?
Researchers will compare dapagliflozin 10 mg daily with placebo to see whether those receiving dapagliflozin experience less heart and vascular impairment during treatment.
Participants will:
* Take either dapagliflozin or placebo once daily during anthracycline chemotherapy. * Undergo heart and vascular ultrasound, and a 6-minute walk test before chemotherapy and again at 24 and 52 weeks. * Provide blood samples before, during and after chemotherapy to measure cardiac biomarkers. * Complete multiple questionnaires on quality of life.
Adults ≥18 years.
Histologically confirmed breast cancer with planned (neo)adjuvant anthracycline-based chemotherapy (4 cycles of epirubicin + cyclophosphamide or doxorubicin + cyclophosphamide).
Eligible to start dapagliflozin or placebo prior to or at initiation of chemotherapy.
Able to perform baseline echocardiography, vascular ultrasound (FMD and carotid stiffness), 6-minute walk test, and biomarker sampling.
Known heart failure (any prior diagnosis of HF).
Clinically significant valvular heart disease.
Prior exposure to chemotherapy or radiotherapy to the left chest.
Type 1 diabetes mellitus.
Parallel
Dapagliflozin 10 mg
DrugForgixa® 10 mg daily
Placebo
DrugLactose tablet daily
Change in Global Longitudinal Strain (GLS)
Global Longitudinal Strain (GLS), measured using speckle-tracking echocardiography in three apical views, will be used to quantify subclinical left ventricular systolic dysfunction. The primary endpoint is the change in GLS from baseline to 24 and 52 weeks. A relative worsening of \>15% is considered clinically meaningful.
Change in Flow-Mediated Dilation (FMD) of the Brachial Artery
Endothelial function will be assessed by ultrasound measurement of flow-mediated dilation (FMD) of the brachial artery after forearm cuff occlusion. The endpoint is the absolute change in FMD (%) from baseline to 24 weeks. A reduction \>2 absolute percentage points will be considered clinically meaningful. FMD will also be measured at 52 weeks to characterize the sustained effect of dapagliflozin on endothelial function compared with placebo.
Change in Cardiovascular and Inflammatory Biomarkers
Serum concentrations of high-sensitivity cardiac troponin, NT-proBNP, ST-2, GDF-15, galectin-3, interleukin-6, and myeloperoxidase will be measured at predefined time points. The endpoint is the change in biomarker levels from baseline to 24 weeks, analyzed as absolute and/or relative change. Biomarkers will also be assessed at 52 weeks to evaluate longer-term effects of dapagliflozin on myocardial injury, hemodynamic stress, remodeling, and inflammation compared with placebo.
Change in Health-Related Quality of Life (EQ-5D Index Score)
Quality of life will be assessed using the EQ-5D questionnaire (5-dimension index score). The endpoint is the change in EQ-5D index score from baseline to 24 weeks. Higher scores indicate better health status. The questionnaire will also be administered at 52 weeks to evaluate longer-term effects of dapagliflozin versus placebo on patient-reported quality of life.
Change in Left Ventricular Ejection Fraction (LVEF)
LVEF will be measured by transthoracic echocardiography using the modified biplane Simpson method from apical 4- and 2-chamber views. The endpoint is the absolute change in LVEF (%) from baseline to 24 weeks. A decrease ≥10 percentage points or a drop below 53% will be considered clinically relevant. LVEF will also be assessed at 52 weeks to evaluate longer-term effects of dapagliflozin versus placebo on left ventricular systolic function.
Change in Carotid Arterial Stiffness (Pulse Wave Velocity and Stiffness Index β)
Arterial stiffness will be evaluated by ultrasound-based assessment of carotid pulse wave velocity (PWV) and stiffness index β using dedicated software. The endpoint is the absolute change in carotid PWV (m/s) and stiffness index β from baseline to 24 weeks. An increase in PWV ≥1 m/s will be considered clinically relevant. Measurements will be repeated at 52 weeks to assess persistent vascular effects of dapagliflozin versus placebo.
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