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

NCT07070765 | Recruiting

• 1 other identifier: 3-033-23
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Breast Cancer

Keywords

breast cancer; chemotherapy; anthracycline; sodium-glucose transporter type 2 inhibition

Outcome Measures

Primary Outcomes (1)

• Cardiac energetics

  In vivo myocardial phosphocreatine/gamma-adenosine triphosphate (PCr/yATP) ratio by cardiac 31P cardiac magnetic resonance spectroscopy

  From enrolment to the end of treatment at the end of approximately 22 weeks

Secondary Outcomes (1)

• Myocardial Ca2+ influx

  From enrolment to the end of treatment at the end of approximately 22 weeks

Study Arms (2)

Sodium-glucose transporter type 2 inhibition treatment arm

ACTIVE COMPARATOR

Sodium-glucose transporter type 2 inhibition plus standard clinical care for the duration of chemotherapy treatment

Drug: Sodium-glucose transport-2 (SGLT-2) inhibitors

Standard clinical care placebo treatment arm

PLACEBO COMPARATOR

Standard clinical care for the duration of chemotherapy treatment

Other: Standard medical treatment

Interventions

Sodium-glucose transport-2 (SGLT-2) inhibitors DRUG

Dapagliflozin 10mg in addition to standard clinical care

Also known as: Dapagliflozin 10mg in addition to standard clinical care

Sodium-glucose transporter type 2 inhibition treatment arm

Standard medical treatment OTHER

Standard clinical care

Also known as: Standard clinical care

Standard clinical care placebo treatment arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Aberdeen: lead
• NHS Grampian: collaborator

Study Sites (2)

Cardiac Research Office, Aberdeen Royal Infirmary

Aberdeen, Aberdeenshire, AB25 2ZD, United Kingdom

RECRUITING

University of Aberdeen

Aberdeen, AB25 2ZD, United Kingdom

RECRUITING

Related Publications (15)

• 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 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.

  PMID: 31970162 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.

  PMID: 30999996 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.

  PMID: 35603596 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.

  PMID: 33648515 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.

  PMID: 34610982 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.

  PMID: 20495142 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.

  PMID: 25230823 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.

  PMID: 28445146 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.

  PMID: 7458950 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.

  PMID: 33993702 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.

  PMID: 17919562 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.

  PMID: 36017568 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.

  PMID: 10760308 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. Erratum In: Eur Heart J. 2018 Mar 7;39(10):839. doi: 10.1093/eurheartj/ehw562.

  PMID: 27567406 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Sodium-Glucose Transporter 2; dapagliflozin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sodium-Glucose Transport Proteins; Symporters; Ion Pumps; Membrane Transport Proteins; Carrier Proteins; Proteins; Amino Acids, Peptides, and Proteins; Monosaccharide Transport Proteins; Solute Carrier Proteins; Membrane Proteins

Study Officials

• Dana Dawson, MPhil

  University of Aberdeen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sylvia Kamya, MBChB

CONTACT

+441224559573; sylvia.kamya@nhs.scot

Amelia Rudd, PhD

CONTACT

+441224559573; a.e.rudd@abdn.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2025
• First Posted: July 17, 2025
• Study Start: December 12, 2025
• Primary Completion (Estimated): October 31, 2028
• Study Completion (Estimated): October 31, 2028
• Last Updated: April 30, 2026

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)