Sodium-glucose Transporter Type 2 Inhibition in Anthracycline-related Cardiotoxicity

Официальное название

Sodium-glucose Transporter Type 2 Inhibition in Anthracycline-related Cardiotoxicity - SPRINT

Обзор

Cardiotoxicity is heart damage that arises from certain drugs, such as those used for cancer treatment and develops in approximately 10% of patients with breast cancer who are treated with anthracyclines. It has been suggested that sodium-glucose transporter-2 (SGLT2) inhibitors may reduce the damage to the heart caused by anthracycline chemotherapy. The investigators wish to determine whether dapagliflozin (SGLT2 inhibitor) taken daily during chemotherapy will reduce the rate of cardiotoxicity.

Подробное описание

Cardiac dysfunction is a major complication of cancer drug therapies, affecting approximately 10% of patients treated with anthracyclines. It has the worst prognosis of all cardiomyopathies and is currently thought to be a consequence of an energetic based mitochondrial dysfunction. This energy deficit could potentially be ameliorated by the putative cardiometabolic benefits of sodium-glucose transporter type 2 inhibition. In pilot data from patients with breast cancer, the investigators have demonstrated that cardiac magnetic resonance spectroscopy can identify and quantify the myocardial energetic deficit associated with anthracycline therapy. The purpose of this study is to determine whether sodium-glucose transporter type 2 inhibition has the potential to reverse the myocardial energetic deficit associated with anthracycline toxicity.

Вмешательства

• Препарат Sodium-glucose transport-2 (SGLT-2) inhibitors
  Dapagliflozin 10mg in addition to standard clinical care
• Другое Standard medical treatment
  Standard clinical care

Первичные конечные точки

• Cardiac energetics [Срок оценки: From enrolment to the end of treatment at the end of approximately 22 weeks]

Вторичные конечные точки (1)

• Myocardial Ca2+ influx [Срок оценки: From enrolment to the end of treatment at the end of approximately 22 weeks]

Критерии участия

Критерии включения

• Patients with breast cancer between 18-70 years of age.
• Patients with low to medium cardiovascular risk.
• Patients scheduled for adjuvant or neo-adjuvant anthracycline therapy.
• Patients who are able to give written informed consent to take part in the study.
• Patients who can read and understand English.

The current thresholds for defining cardiovascular risk for patients undergoing anthracycline chemotherapy are as follows: normal resting 12-lead electrocardiogram, plasma cardiac troponin I concentration < 99th centile, serum brain natriuretic peptide concentration <35 pg/mL or serum N-terminal pro-brain natriuretic peptide concentration <125 pg/mL, left ventricular ejection fraction >55%, global longitudinal strain >-18% and healthy life-style (normal body-mass index, non-smoker). Low cardiovascular risk will allow for the presence of one abnormal life-style factor (body-mass index indicating obesity (>30 kg/m2), current smoker or significant smoking history), or presence of only one of the following in the clinical history: hypertension, stage 1-2 chronic kidney disease, age 65-79 years, borderline left ventricular ejection fraction (50-54%) or elevated cardiac biomarkers. Medium cardiovascular risk will permit the combination of any 2-4 of the lifestyle or clinical history variables indicated above.

Критерии исключения

• Patients with a known intolerance of dapagliflozin
• Patients with high cardiovascular risk as specified by the most recent cardio-oncology guidelines.
• Patients with significant renal impairment (estimated glomerular filtration rate <45 mL/min/1.73 m2).
• Patients with a previous cancer diagnosis.
• Patients with known type 1 or 2 diabetes mellitus. We will not actively screen for diabetes. This is not done in clinical practice and there have been no issues.
• Patients with a contraindication to magnetic resonance imaging.
• Patients with prior exposure to anthracyclines.
• Patients who cannot read and understand English.
• Patients who are pregnant

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Великобритания · 2 центра

• Cardiac Research Office, Aberdeen Royal Infirmary — Aberdeen
• University of Aberdeen — Aberdeen

Публикации

• Baris VO, Dincsoy AB, Gedikli E, Zirh S, Muftuoglu S, Erdem A. Empagliflozin Significantly Prevents the Doxorubicin-induced Acute Cardiotoxicity via Non-antioxidant Pathways. Cardiovasc Toxicol. 2021 Sep;21(9):747-758. doi: 10.1007/s12012-021-09665-y. Epub 2021 Jun 5. PMID 34089496
• Maejima Y. SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function. Front Cardiovasc Med. 2020 Jan 8;6:186. doi: 10.3389/fcvm.2019.00186. eCollection 2019. PMID 31970162
• Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, Flores E, Garcia-Ropero A, Sanz J, Hajjar RJ, Fuster V, Badimon JJ. Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics. J Am Coll Cardiol. 2019 Apr 23;73(15):1931-1944. doi: 10.1016/j.jacc.2019.01.056. PMID 30999996
• Selvaraj S, Fu Z, Jones P, Kwee LC, Windsor SL, Ilkayeva O, Newgard CB, Margulies KB, Husain M, Inzucchi SE, McGuire DK, Pitt B, Scirica BM, Lanfear DE, Nassif ME, Javaheri A, Mentz RJ, Kosiborod MN, Shah SH; DEFINE-HF Investigators. Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF. Circulation. 2022 Sep 13;146(11):808-818. doi: 10.11 PMID 35603596
• Gaborit B, Ancel P, Abdullah AE, Maurice F, Abdesselam I, Calen A, Soghomonian A, Houssays M, Varlet I, Eisinger M, Lasbleiz A, Peiretti F, Bornet CE, Lefur Y, Pini L, Rapacchi S, Bernard M, Resseguier N, Darmon P, Kober F, Dutour A. Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study. Cardiovasc Diabetol. 2021 Mar 1;20(1):57. doi: 10.1186/ PMID 33648515
• Thirunavukarasu S, Jex N, Chowdhary A, Hassan IU, Straw S, Craven TP, Gorecka M, Broadbent D, Swoboda P, Witte KK, Cubbon RM, Xue H, Kellman P, Greenwood JP, Plein S, Levelt E. Empagliflozin Treatment Is Associated With Improvements in Cardiac Energetics and Function and Reductions in Myocardial Cellular Volume in Patients With Type 2 Diabetes. Diabetes. 2021 Dec;70(12):2810-2822. doi: 10.2337/db2 PMID 34610982
• Maslov MY, Chacko VP, Hirsch GA, Akki A, Leppo MK, Steenbergen C, Weiss RG. Reduced in vivo high-energy phosphates precede adriamycin-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol. 2010 Aug;299(2):H332-7. doi: 10.1152/ajpheart.00727.2009. Epub 2010 May 21. PMID 20495142
• Govender J, Loos B, Marais E, Engelbrecht AM. Mitochondrial catastrophe during doxorubicin-induced cardiotoxicity: a review of the protective role of melatonin. J Pineal Res. 2014 Nov;57(4):367-80. doi: 10.1111/jpi.12176. Epub 2014 Oct 18. PMID 25230823

Идентификаторы

NCT: NCT07070765 · 3-033-23

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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