Dapagliflozin for Prevention of Chemotherapy-Induced Cardiotoxicity: a Randomized Controlled Trial

Brief Summary

Background \& Rationale Anthracyclines, such as doxorubicin, and trastuzumab (Herceptin) are widely used in cancer treatment but are associated with cardiotoxicity, which can lead to left ventricular dysfunction, heart failure, and long-term cardiovascular complications. Anthracycline-induced cardiotoxicity is primarily dose-dependent and often irreversible, resulting from oxidative stress, mitochondrial damage, and apoptosis of cardiomyocytes. In contrast, trastuzumab-induced cardiotoxicity is typically not dose-dependent and is often reversible, occurring due to HER2 receptor blockade in cardiac tissue, impairing myocardial repair mechanisms. The combination of anthracyclines and trastuzumab significantly increases the risk of cardiac dysfunction, necessitating effective cardioprotective strategies.

Dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor (SGLT2i), is approved for type 2 diabetes mellitus and heart failure with reduced ejection fraction (HFrEF) but has demonstrated cardioprotective benefits beyond glucose control. It exerts beneficial effects through reducing oxidative stress, inflammation, and myocardial fibrosis, making it a promising candidate for mitigating chemotherapy-induced cardiotoxicity. This study aims to evaluate Dapagliflozin's potential role in preventing cardiotoxicity associated with anthracycline and/or trastuzumab-based chemotherapy.

Study Design

This randomized, double-blind, placebo-controlled trial will enroll 100 cancer patients receiving anthracycline and/or trastuzumab-based chemotherapy. Participants will be randomly assigned in a 1:1 ratio to one of two groups:

Control Group (n=50): Standard anthracycline-based and/or trastuzumab-based chemotherapy + placebo Intervention Group (n=50): Standard anthracycline-based and/or trastuzumab-based chemotherapy + Dapagliflozin

Objectives \& Outcomes

Primary Outcome:

Change in Left Ventricular Ejection Fraction (LVEF) measured by echocardiography over a 4-month follow-up period.

Secondary Outcomes:

* Serum cardiac biomarkers: Serum Troponin I, Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), and Serum Galectin-3.
* Renal function markers: Serum Creatinine and Blood Urea Nitrogen (BUN).
* Cancer progression marker: Serum Carbohydrate Antigen 15-3 (CA 15-3).
* Incidence of Major Adverse Cardiovascular Events (MACE), including heart failure, myocardial infarction, and arrhythmias.
* Assessment of chemotherapy-related and Dapagliflozin-related adverse effects, including hypoglycemia, hypotension, electrolyte imbalances, and renal function changes.

Patient Follow-Up \& Safety Monitoring Patients will be closely monitored throughout the study with scheduled assessments at baseline, during chemotherapy, and at the 4-month follow-up.

* Cardiac function will be assessed using echocardiography and serum cardiac biomarkers.
* Renal function and metabolic status will be evaluated to ensure Dapagliflozin safety.
* Adverse events will be classified according to the Common Terminology Criteria for Adverse Events (CTCAE).

Significance of the Study By investigating Dapagliflozin's potential role in preventing anthracycline- and/or trastuzumab-induced cardiotoxicity, this study may provide a novel cardioprotective strategy for cancer patients. If successful, this intervention could improve cardiac outcomes, maintain chemotherapy efficacy, and enhance long-term quality of life.

Detailed Description

Background and Rationale Chemotherapy-induced cardiotoxicity is a significant concern in cancer treatment, particularly with anthracyclines (e.g., doxorubicin) and HER2-targeted therapies like trastuzumab (Herceptin). These agents, while highly effective in treating malignancies, are associated with dose-dependent or reversible cardiac dysfunction, respectively, potentially leading to heart failure, arrhythmias, and long-term cardiovascular complications.

Anthracycline-induced cardiotoxicity is often irreversible, resulting from oxidative stress, mitochondrial dysfunction, and direct cardiomyocyte apoptosis.

Trastuzumab-induced cardiotoxicity is not dose-dependent and is often reversible, primarily occurring due to HER2 receptor blockade in cardiac tissue, impairing myocardial repair mechanisms.

The risk is highest when anthracyclines and trastuzumab are used sequentially, as seen in standard treatment protocols for HER2-positive breast cancer.

Dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor (SGLT2i), is primarily used for type 2 diabetes mellitus and heart failure with reduced ejection fraction (HFrEF). However, emerging evidence suggests cardioprotective properties independent of glucose control, including:

Reduction of oxidative stress and myocardial fibrosis Improvement of mitochondrial efficiency and myocardial metabolism Reduction in systemic and myocardial inflammation Modulation of sodium and calcium handling in cardiomyocytes Given these mechanisms, Dapagliflozin may provide a protective effect against chemotherapy-induced cardiotoxicity, preserving cardiac function without compromising cancer treatment efficacy.

Study Design and Methodology This is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the cardioprotective effects of Dapagliflozin in cancer patients undergoing anthracycline and/or trastuzumab-based chemotherapy.

Study Sites

Primary Location: Azadi Oncology Center affiliated with Hawler Medical University and the Duhok General Health Directorate .

Multicenter Design: This study may extend to additional oncology centers if necessary to achieve enrollment targets.

Study Population

Target Enrollment: 100 participants receiving anthracycline-based and/or trastuzumab-based chemotherapy.

Randomization Ratio: 1:1 (50 patients in each group). Intervention and Control Groups

Control Group (n = 50): Standard chemotherapy + placebo. Dapagliflozin Group (n = 50): Standard chemotherapy + Dapagliflozin (10 mg/day, oral) for four chemotherapy cycles.

Follow-up Period

Duration: 4 months from initiation of chemotherapy. Assessment Intervals: Baseline, during each chemotherapy cycle, and at study completion.

Primary and Secondary Study Endpoints Primary Endpoint

Change in Left Ventricular Ejection Fraction (LVEF) from baseline to post-treatment, measured by echocardiography.

Secondary Endpoints

Cardiac Biomarkers: Serum Troponin I, Serum NT-proBNP, Serum Galectin-3. Cancer Progression: Serum CA 15-3 as a marker of tumor burden. Renal Function: Serum Creatinine, Blood Urea Nitrogen (BUN), estimated glomerular filtration rate (eGFR).

Adverse Events: Incidence of chemotherapy-related and Dapagliflozin-related adverse effects, graded using Common Terminology Criteria for Adverse Events (CTCAE).

Safety and Monitoring Plan Cardiotoxicity Surveillance

Echocardiography: Baseline, mid-treatment, and end of study. Biomarkers: Serial assessment of Troponin I, NT-proBNP, and Galectin-3. Electrocardiogram (ECG): To detect subclinical arrhythmias and QT prolongation. Monitoring for Dapagliflozin-Related Adverse Events

Hypoglycemia, hypotension, and dehydration risks will be evaluated. Renal function will be closely monitored to assess potential nephrotoxicity. Urinary tract infections (UTIs) and ketoacidosis screening will be conducted. Statistical Analysis Plan Sample Size Calculation

A total of 100 patients (50 per group) provides 80% power to detect a significant difference in LVEF decline, assuming an estimated effect size of 10% reduction in cardiotoxicity rates with Dapagliflozin.

Planned Statistical Methods

Descriptive statistics for baseline demographic and clinical characteristics. Comparative analysis using paired t-tests, Wilcoxon signed-rank tests (for non-parametric data), and ANOVA for repeated measures.

Multivariate regression models to control for confounding variables, such as age, baseline cardiac function, and chemotherapy regimen.

Kaplan-Meier survival analysis (if applicable) to evaluate the time-to-event for major adverse cardiac events.

Handling of Missing Data

Multiple imputation techniques will be used to address missing data, ensuring robustness of findings.

Ethical Considerations and Compliance Ethical Approval: The study will adhere to the guidelines of Hawler Medical University's Ethics Committee and the General Directorate of Health.

Informed Consent: Written informed consent will be obtained from all participants before enrollment.

Confidentiality: Patient data will be de-identified and stored securely, ensuring compliance with Good Clinical Practice (GCP) and international research ethics standards.

Ongoing Safety Monitoring: An independent Data and Safety Monitoring Board (DSMB) will oversee interim analyses and evaluate safety data.

Potential Impact and Future Directions

If Dapagliflozin proves effective in mitigating chemotherapy-induced cardiotoxicity, this study could:

Introduce SGLT2 inhibitors as a cardioprotective strategy in cancer patients receiving cardiotoxic chemotherapy.

Improve clinical decision-making for oncologists and cardiologists in managing high-risk patients.

Open pathways for further research into cardioprotective agents beyond traditional heart failure medications.

This study represents a significant advancement in cardio-oncology by integrating a widely available, well-tolerated drug into chemotherapy regimens to potentially improve patient survival and quality of life.

Eligibility Criteria:
Inclusion Criteria:

* Histologically confirmed breast cancer (or other cancers as relevant to the study).
* Age 18-70 years.
* Planned treatment with anthracycline-based and/or trastuzumab-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.