Anthracycline-based chemotherapy is the standard treatment for several common cancer
types, including breast cancer, lymphoma and sarcoma. However, within 12 months, up to
20% of the 1,000,000 patients worldwide treated with anthracyclines each year have a
significant reduction in left ventricular ejection fraction (LVEF), leading to a three to
six-fold higher rates of incident heart failure. Once established, anthracycline-induced
heart failure carries a poor prognosis with a 2-year survival of only 40%.
Consistent data have established that sodium-glucose transport protein 2 (SGLT2)
inhibitors reduce incident heart failure in patients without cancer. There is biological
plausibility and animal data to support the hypothesis central to this proposal that
SGLT2 will reduce anthracycline-induced cardiotoxicity (AIC). Anthracyclines increase
inflammatory cytokines, increase cell death, increase myocardial fibrosis leading to a
decrease in the LVEF. In animal and cellular models, SGLT2 inhibitors reduce inflammatory
cytokines, increase cell viability, reduce myocardial fibrosis and prevent the decline in
LVEF with anthracyclines. There are no preliminary clinical data testing whether SGLT2
inhibitors are cardioprotective during treatment with anthracyclines among patients with
breast cancer.
We propose a single-center randomized double-blind placebo-controlled trial, in 80
patients, who will be randomized 1:1 to dapagliflozin 10mg/daily or placebo to determine
whether dapagliflozin started prior to anthracyclines reduces AIC in patients breast
cancer. The endpoint AIC will be defined as a 6% difference in the change in LVEF between
groups within the first 9 months after the start of therapy. LVEF will be measured using
the gold-standard, cardiac magnetic resonance (CMR), performed in an established core
clinical trials laboratory by expert researchers.
Participants will be recruited over 2 years from a large volume academic oncology
network. Myocardial fibrosis is a key intermediary that occurs prior to the development
of LV dysfunction. CMR is the gold-standard imaging technique for fibrosis; therefore, to
test whether the sub-acute development of myocardial fibrosis can predict the late
occurrence of AIC and whether dapagliflozin reduces myocardial fibrosis, we also propose
measuring the extent of fibrosis at baseline and 9 months.
We hypothesize that dapagliflozin will attenuate the anthracycline-induced increase in
myocardial fibrosis. Secondary and exploratory outcomes will include significant changes
in myocardial perfusion assessed by stress CMR, flow-mediated vasodilatation assessed by
ultrasound, exercise capacity assessed by cardiopulmonary exercise test, and biomarkers.
If successful, this study will show that dapagliflozin started prior to anthracyclines
will preserve the LVEF and will attenuate the anthracycline-induced cardiovascular
toxicity.