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

Summary

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.

Timeline

Start

2025-12-12

Primary completion

2028-10-31

Completion

2028-10-31

Publications

• Background 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.
• Background 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.
• Background 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.
• Background 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: 10.1161/CIRCULATIONAHA.122.060402. Epub 2022 May 23.
• Background 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/s12933-021-01237-2.
• Background 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/db21-0270. Epub 2021 Oct 5.
• Background 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.
• Background 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.
• Background Koleini N, Kardami E. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget. 2017 Jul 11;8(28):46663-46680. doi: 10.18632/oncotarget.16944.
• Background Goormaghtigh E, Chatelain P, Caspers J, Ruysschaert JM. Evidence of a complex between adriamycin derivatives and cardiolipin: possible role in cardiotoxicity. Biochem Pharmacol. 1980 Nov 1;29(21):3003-10. doi: 10.1016/0006-2952(80)90050-7. No abstract available.
• Background Heck SL, Mecinaj A, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, Gravdehaug B, Rosjo H, Steine K, Geisler J, Gulati G, Omland T. Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2x2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol. Circulation. 2021 Jun 22;143(25):2431-2440. doi: 10.1161/CIRCULATIONAHA.121.054698. Epub 2021 May 16.
• Background Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol. 2007 Oct 9;50(15):1435-41. doi: 10.1016/j.jacc.2007.06.037. Epub 2007 Sep 24.
• Background Lyon AR, Lopez-Fernandez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, Boriani G, Cardinale D, Cordoba R, Cosyns B, Cutter DJ, de Azambuja E, de Boer RA, Dent SF, Farmakis D, Gevaert SA, Gorog DA, Herrmann J, Lenihan D, Moslehi J, Moura B, Salinger SS, Stephens R, Suter TM, Szmit S, Tamargo J, Thavendiranathan P, Tocchetti CG, van der Meer P, van der Pal HJH; ESC Scientific Document Group. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022 Nov 1;43(41):4229-4361. doi: 10.1093/eurheartj/ehac244. No abstract available.
• Background Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000 Apr 13;342(15):1077-84. doi: 10.1056/NEJM200004133421502.
• Background Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GYH, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM; ESC Scientific Document Group. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016 Sep 21;37(36):2768-2801. doi: 10.1093/eurheartj/ehw211. Epub 2016 Aug 26. No abstract available.

Drugs

Indications