Anthracyclines, such as doxorubicin, are effective anticancer agents but may cause dose-dependent cardiac injury, including early changes in left ventricular function and cardiac biomarkers. Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor with established cardiovascular benefits in heart failure and potential cardioprotective effects beyond glucose lowering, including modulation of oxidative stress, inflammation, myocardial energetics and fibrotic remodeling.

This randomized, double-blind, placebo-controlled phase 2 trial evaluated whether dapagliflozin attenuates early anthracycline-associated cardiac functional and biomarker changes in adults receiving anthracycline-based chemotherapy. A total of 94 participants were randomized in a 1:1 ratio to receive dapagliflozin 10 mg orally once daily plus standard anthracycline-based chemotherapy or matching placebo plus standard anthracycline-based chemotherapy for 4 months. Ninety participants completed the 4-month follow-up and were included in complete-case analyses.

The primary echocardiographic outcome was change in left ventricular function from baseline to 4 months. Left ventricular systolic function was assessed using left ventricular ejection fraction (LVEF) as the principal systolic measure. Transmitral E/A ratio was analyzed as an exploratory filling index because it was consistently available across participants. Tissue Doppler indices and comprehensive diastolic dysfunction grading were not consistently available and were therefore not used for formal diastolic grading in the final analysis.

Secondary outcomes included cardiac troponin I, NT-proBNP, galectin-3, CA 15-3, renal and hepatic function parameters, and adverse events. Echocardiography and laboratory biomarkers were assessed at baseline and 4 months, while adverse events were monitored continuously throughout the study period.

Chemotherapy-induced cardiotoxicity is an important concern in cancer care, particularly among patients receiving anthracycline-based chemotherapy. Anthracycline-associated myocardial injury may involve oxidative stress, mitochondrial dysfunction, inflammation, cardiomyocyte injury and myocardial remodeling. Sodium-glucose cotransporter-2 inhibitors have demonstrated cardiovascular benefits in heart failure and may also influence biological pathways relevant to anthracycline-associated cardiac injury.

This randomized, double-blind, placebo-controlled phase 2 trial was designed to evaluate the potential cardioprotective effects of dapagliflozin in adult cancer patients receiving anthracycline-based chemotherapy.

The study was conducted at Azadi Oncology Center, Duhok, Iraq, affiliated with Hawler Medical University and the Duhok General Health Directorate. The center is now known as Omed Oncology Hospital. All participants were recruited at this single site.

A total of 94 participants were randomized in a 1:1 ratio. Forty-seven participants were allocated to dapagliflozin 10 mg orally once daily plus standard anthracycline-based chemotherapy, and 47 participants were allocated to matching placebo plus standard anthracycline-based chemotherapy. Study treatment was continued for 4 months. Four participants withdrew consent during follow-up, leaving 45 participants in each group with complete baseline and 4-month follow-up data for complete-case analyses.

The primary echocardiographic outcome was change in left ventricular function from baseline to 4 months. Left ventricular systolic function was assessed using change in LVEF as the principal systolic measure. The diastolic component was assessed using transmitral E/A ratio, which was consistently available across participants and was analyzed as an exploratory filling index. Tissue Doppler indices and comprehensive ASE/EACVI-based diastolic dysfunction grading were not consistently available and were therefore not used for formal diastolic grading in the final analysis.

Secondary outcomes included changes in cardiac troponin I, NT-proBNP, galectin-3, CA 15-3, renal function parameters, hepatic function parameters and adverse events. Echocardiography and laboratory biomarkers were assessed at baseline and 4 months. Adverse events were monitored throughout the 4-month treatment and follow-up period and graded according to CTCAE criteria where applicable.

Comparative analyses were performed using change-from-baseline values. Between-group differences in continuous outcomes were assessed using independent-samples t-tests or Mann-Whitney U tests according to data distribution. Categorical variables were compared using chi-square or Fisher's exact tests where appropriate. The primary analysis was performed as a complete-case analysis among participants with available baseline and 4-month follow-up data. No imputation was used for the primary analysis.

The study was approved by the Hawler Medical University Ethics Committee and the Duhok General Health Directorate. Written informed consent was obtained from all participants before enrollment.

Inclusion Criteria:

• Histologically confirmed breast cancer (or other cancers as relevant to the study).
• Age 18-70 years.
• Planned treatment with anthracycline-based chemotherapy
• Normal kidney function, defined as serum creatinine 0.6-1.2 mg/dL.
• Normal liver function, defined as ALT and AST 10-40 U/L.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Willingness to participate and provide written informed consent.

Exclusion Criteria:

• History of symptomatic heart failure (NYHA class III-IV) or prior anthracycline-related cardiac dysfunction.
• Previous use of Dapagliflozin.
• Pregnancy or breastfeeding.
• Severe renal impairment (eGFR < 30 mL/min/1.73m²).
• Uncontrolled diabetes mellitus (HbA1c > 9%).
• Active or recurrent urinary tract infections (UTIs) within the last 6 months.
• Known hypersensitivity to Dapagliflozin or related compounds.
• Concurrent participation in another clinical trial investigating cardioprotective agents.

At this time, individual participant data (IPD) will not be shared publicly. The data will be kept confidential to ensure participant privacy and comply with ethical and regulatory requirements, including those related to informed consent and data protection. Access to the data may be considered for future collaborations under strict ethical guidelines and approval from the relevant oversight bodies.

Participants were randomized using a computer-generated block randomization sequence. Allocation concealment was maintained using sequentially numbered, sealed treatment containers prepared before participant enrollment. Dapagliflozin and placebo tablets were matched in appearance, packaging, and labeling. Participants, care providers, investigators, and outcome assessors were blinded to treatment allocation.