Greco A, Quagliariello V, Rizzo G, Tedeschi A, Schirinzi S, Turco A, Galiazzo M, Acquaro M, De Amicis M, Klersy C, Ghio S, Perrone L, Paccone A, Uccello G, Canale M L, Oliva S, Guerra F, De Luca L, Maurea N, Scelsi L
Cardiology Division, Fondazione Policlinico San Matteo, IRCCS, Pavia, Italy.
Cardiology Division, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Napoli, Italy.
Cardiooncology. 2025 Sep 1;11(1):79. doi: 10.1186/s40959-025-00368-9.
SGLT2i exerts several cardiometabolic benefits in heart failure with reduced and preserved ejection fraction through the systemic reduction of insulin, visceral fat, chemokines and growth factors involved in cardiovascular diseases. Anthracyclines are considered the principal culprit drugs behind chemotherapy-induced cardiotoxicity. The pathognomonic manifestation of anthracycline-induced cardiotoxicity is a hypokinetic cardiomyopathy progressively leading to heart failure. Anthracycline-induced cardiotoxicity is still a significant problem that compromises the quality of life and overall survival of breast cancer (BC) patients. Sequential therapy regimen of anthracyclines and HER-2 blocking agents is associated to higher risk of cardiotoxicity compared to monotherapy regimen. Recent studies in preclinical models of anthracycline-induced cardiotoxicity concluded that SGLT2i are able to prevent ejection fraction reduction and myocardial inflammation and fibrosis. A very recent retrospective study indicates that SGLT2i were associated with lower rate of cardiac events among patients with cancer and T2DM who were treated with anthracyclines. These data support the conducting of a randomized clinical trial testing Dapagliflozin in patients with breast cancer treated with anthracyclines+/- trastuzumab.
To evaluate the cardioprotective effects of the SGLT2 inhibitor Dapagliflozin in chemotherapy-naive patients with stage I-III breast cancer undergoing anthracycline-based treatment with or without trastuzumab, by assessing its ability to reduce the incidence of cardiotoxicity and improve systemic cardiometabolic markers.
Chemotherapy-naive patients (18-70 years) scheduled for antracycline +/- trastuzumab treatment in the [neo-]adjuvant setting for stage I-III breast cancer, will be randomized using a web-based system stratified by the use of trastuzumab to follow a chemotherapy regimen plus Dapagliflozin [10 mg/die] [active group] or chemotherapy regimen plus standard of care [control group]. During follow up period, if a patient develops asymptomatic or symptomatic systolic disfunction will be treated according to good clinical practice. From randomization, to the third, sixth, twelfth and eighteenth months, echocardiographic and cardiological visits will be performed associated to blood analysis for quantification of cardiotoxicity biomarkers (NT-pro-BNP, hsTNI), CKD-EPI eGFR and systemic inflammation (hsCRP, chemokines, cytokines and growth factors).
The study is ongoing. Results will be published when the study is completed.
The PROTECT trial is the first randomized clinical study designed to evaluate whether Dapagliflozin can reduce anthracycline- and/or trastuzumab-associated cardiotoxicity in patients with early-stage breast cancer. Beyond its established cardiometabolic effects, this trial will also provide insight into the systemic anti-inflammatory and metabolic benefits of SGLT2 inhibition in the oncology setting. Findings from this study may pave the way for novel cardio-oncology strategies aimed at improving both cardiac outcomes and quality of life in cancer patients.
ClinicalTrials.gov NCT06341842 [EudraCT Number 2022-003377-28]. Registered on 19 March 2024.
钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）通过系统性降低胰岛素、内脏脂肪、参与心血管疾病的趋化因子和生长因子，对射血分数降低和保留的心力衰竭患者产生多种心脏代谢益处。蒽环类药物被认为是化疗诱导心脏毒性的主要罪魁祸首。蒽环类药物诱导心脏毒性的典型表现是运动减弱型心肌病，逐渐导致心力衰竭。蒽环类药物诱导的心脏毒性仍然是一个严重问题，会影响乳腺癌（BC）患者的生活质量和总体生存率。与单一疗法相比，蒽环类药物和HER-2阻断剂的序贯治疗方案与更高的心脏毒性风险相关。最近在蒽环类药物诱导心脏毒性的临床前模型中的研究得出结论，SGLT2i能够预防射血分数降低以及心肌炎症和纤维化。一项非常新的回顾性研究表明，在接受蒽环类药物治疗的癌症和2型糖尿病患者中，SGLT2i与较低的心脏事件发生率相关。这些数据支持开展一项随机临床试验，测试达格列净在接受蒽环类药物+/-曲妥珠单抗治疗的乳腺癌患者中的效果。
通过评估SGLT2抑制剂达格列净降低心脏毒性发生率和改善全身心脏代谢标志物的能力，评价其在未接受过化疗、处于I-III期乳腺癌且正在接受含或不含曲妥珠单抗的蒽环类药物治疗患者中的心脏保护作用。
计划在I-III期乳腺癌的[新]辅助治疗中接受蒽环类药物+/-曲妥珠单抗治疗的未接受过化疗的患者（18-70岁），将使用基于网络的系统进行随机分组，根据是否使用曲妥珠单抗进行分层，以遵循化疗方案加用达格列净[10毫克/天][治疗组]或化疗方案加用标准治疗[对照组]。在随访期间，如果患者出现无症状或有症状的收缩功能障碍，将按照良好临床实践进行治疗。从随机分组开始，在第三个月、第六个月、第十二个月和第十八个月，进行超声心动图和心脏检查，并进行血液分析，以量化心脏毒性生物标志物（N末端脑钠肽前体、高敏肌钙蛋白I）、慢性肾脏病流行病学合作组估算肾小球滤过率（CKD-EPI eGFR）和全身炎症（高敏C反应蛋白、趋化因子、细胞因子和生长因子）。
研究正在进行中。研究完成后将公布结果。
PROTECT试验是第一项旨在评估达格列净是否能降低早期乳腺癌患者蒽环类药物和/或曲妥珠单抗相关心脏毒性的随机临床研究。除了其已确定的心脏代谢作用外，该试验还将深入了解SGLT2抑制在肿瘤学环境中的全身抗炎和代谢益处。这项研究的结果可能为旨在改善癌症患者心脏结局和生活质量的新型心脏肿瘤学策略铺平道路。
ClinicalTrials.gov NCT06341842[欧洲临床试验数据库编号2022-003377-28]。于2024年3月19日注册。
