Sodium-glucose Transporter Type 2 Inhibition in Anthracycline-related Cardiotoxicity

Cardiac dysfunction is a major complication of cancer drug therapies, affecting approximately 10% of patients treated with anthracyclines. It has the worst prognosis of all cardiomyopathies and is currently thought to be a consequence of an energetic based mitochondrial dysfunction. This energy deficit could potentially be ameliorated by the putative cardiometabolic benefits of sodium-glucose transporter type 2 inhibition. In pilot data from patients with breast cancer, the investigators have demonstrated that cardiac magnetic resonance spectroscopy can identify and quantify the myocardial energetic deficit associated with anthracycline therapy. The purpose of this study is to determine whether sodium-glucose transporter type 2 inhibition has the potential to reverse the myocardial energetic deficit associated with anthracycline toxicity.

Inclusion criteria

• Patients with breast cancer between 18-70 years of age.
• Patients with low to medium cardiovascular risk.
• Patients scheduled for adjuvant or neo-adjuvant anthracycline therapy.
• Patients who are able to give written informed consent to take part in the study.
• Patients who can read and understand English.

The current thresholds for defining cardiovascular risk for patients undergoing anthracycline chemotherapy are as follows: normal resting 12-lead electrocardiogram, plasma cardiac troponin I concentration < 99th centile, serum brain natriuretic peptide concentration <35 pg/mL or serum N-terminal pro-brain natriuretic peptide concentration <125 pg/mL, left ventricular ejection fraction >55%, global longitudinal strain >-18% and healthy life-style (normal body-mass index, non-smoker). Low cardiovascular risk will allow for the presence of one abnormal life-style factor (body-mass index indicating obesity (>30 kg/m2), current smoker or significant smoking history), or presence of only one of the following in the clinical history: hypertension, stage 1-2 chronic kidney disease, age 65-79 years, borderline left ventricular ejection fraction (50-54%) or elevated cardiac biomarkers. Medium cardiovascular risk will permit the combination of any 2-4 of the lifestyle or clinical history variables indicated above.

Exclusion criteria

• Patients with a known intolerance of dapagliflozin
• Patients with high cardiovascular risk as specified by the most recent cardio-oncology guidelines.
• Patients with significant renal impairment (estimated glomerular filtration rate <45 mL/min/1.73 m2).
• Patients with a previous cancer diagnosis.
• Patients with known type 1 or 2 diabetes mellitus. We will not actively screen for diabetes. This is not done in clinical practice and there have been no issues.
• Patients with a contraindication to magnetic resonance imaging.
• Patients with prior exposure to anthracyclines.
• Patients who cannot read and understand English.
• Patients who are pregnant