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

NCT ID: NCT07070765

Last Updated: 2025-07-23

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Clinical Phase

NA

Total Enrollment

70 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-11-01

Study Completion Date

2028-10-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Breast Cancer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Study Groups

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Sodium-glucose transporter type 2 inhibition treatment arm

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

Group Type ACTIVE_COMPARATOR

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

Intervention Type DRUG

Dapagliflozin 10mg in addition to standard clinical care

Standard clinical care placebo treatment arm

Standard clinical care for the duration of chemotherapy treatment

Group Type PLACEBO_COMPARATOR

Standard medical treatment

Intervention Type OTHER

Standard clinical care

Interventions

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

Dapagliflozin 10mg in addition to standard clinical care

Intervention Type DRUG

Standard medical treatment

Standard clinical care

Intervention Type OTHER

Other Intervention Names

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Dapagliflozin 10mg in addition to standard clinical care Standard clinical care

Eligibility Criteria

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Inclusion Criteria

* 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.

Exclusion Criteria

* 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
Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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NHS Grampian

OTHER_GOV

Sponsor Role collaborator

University of Aberdeen

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Dana Dawson, MPhil

Role: PRINCIPAL_INVESTIGATOR

University of Aberdeen

Locations

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University of Aberdeen

Aberdeen, , United Kingdom

Site Status

Countries

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United Kingdom

Central Contacts

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Sylvia Kamya, MBChB

Role: CONTACT

+441224559573

Amelia Rudd, PhD

Role: CONTACT

+441224559573

Facility Contacts

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Sylvia Kamya, MBChB

Role: primary

+441224559573

Amelia Rudd, PhD

Role: backup

References

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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.

Reference Type BACKGROUND
PMID: 34089496 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 31970162 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 30999996 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 35603596 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 33648515 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 34610982 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20495142 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25230823 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 28445146 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 7458950 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 33993702 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17919562 (View on PubMed)

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.

Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
PMID: 10760308 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 27567406 (View on PubMed)

Other Identifiers

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3-033-23

Identifier Type: -

Identifier Source: org_study_id

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