Anthracycline- and HER2-induced cardiotoxicity: mechanisms, current strategies, and the emerging role of dapagliflozin as a targeted cardioprotective agent
Hakar Abdulkareem Saeed, Nidhal Abdulkader Mohammed Ali, Ramadhan T. Othman
Abstract
Chemotherapy-induced cardiotoxicity (CIC) is a well-recognized and potentially severe complication of cancer treatment, particularly with anthracyclines and HER2-targeted therapies. As cancer survival improves, long-term cardiovascular outcomes have become increasingly important, yet current preventive strategies-such as dose reduction, dexrazoxane, neurohormonal blockers, and statins-offer only limited protection and are underutilized in routine clinical practice. There is a growing need for novel interventions that are safe, effective, and mechanistically targeted. Dapagliflozin, a SGLT2 inhibitor initially developed for type 2 diabetes, has demonstrated substantial cardioprotective effects in patients with heart failure, regardless of glycemic status. Its mechanisms-including improved cardiac metabolism, mitochondrial preservation, anti-inflammatory and antioxidant effects, and inhibition of fibrosis-align closely with the known pathways of chemotherapy-induced myocardial injury. Preclinical models have shown that dapagliflozin can preserve left ventricular function, reduce biomarker elevation, and prevent structural remodeling in hearts exposed to doxorubicin. Building on this evidence, a randomized, double-blind, placebo-controlled clinical trial (NCT06888505) is currently underway to evaluate dapagliflozin in cancer patients receiving anthracycline-based chemotherapy, with or without trastuzumab. The study incorporates serial biomarker assessments and cardiac function monitoring to assess its preventive potential.Dapagliflozin represents a promising therapeutic candidate in cardio-oncology. Its pleiotropic cardioprotective effects, oral route of administration, and established safety profile make it a strong contender for integration into future preventive strategies aimed at reducing the cardiovascular burden of cancer therapy.