The Effect of Dapagliflozin on Exercise and Cardiac Functional Status of Patients After Fontan Procedure

Overview

While the Fontan operation improves survival for patients with a functional single ventricle, complications like heart failure remain prevalent during follow-up, causing frequent hospitalizations and reduced quality of life. Currently, there are no evidence-based heart failure therapies or guidelines for patients with Fontan palliation. There is growing interest in using sodium-glucose cotransporter 2 inhibitors (SGLT2i) to optimize cardiac conditions in this group. SGLT2i's observed benefits relate to protective effects on cardiac energy metabolism, renal function, sympathetic activation, inflammation, oxidative stress, erythropoiesis, and vascular function. Therefore, SGLT2i may represent a new therapeutic agent to improve exercise capacity and ventricular function in patients with Fontan circulation. This prospective, open-label, single-arm clinical trial investigates the FDA-approved drug dapagliflozin. An open-label design is utilized due to the relatively small cohort of patients with complex underlying hearts. The trial will be conducted at Hong Kong Children's Hospital (the sole pediatric cardiology center in Hong Kong) and Queen Mary Hospital (the largest tertiary referral center for adult congenital heart patients). The total study duration is 2 years. Subjects will participate for 3 months, receiving oral dapagliflozin 10mg once daily. The primary endpoint is VO2 max (maximum rate of oxygen consumption) during cardiopulmonary exercise testing at 3 months. Secondary assessments include questionnaires, history taking, physical examinations, 12-lead electrocardiogram, blood tests, echocardiography, bioelectrical impedance analysis, and urine pregnancy tests. If the hypothesis holds true, clinical translation of this project will: i) Improve long-term outcomes and quality-of-life for Fontan patients, reducing the healthcare burden from repeated heart failure hospitalizations; ii) Revolutionize the management of Fontan-associated heart failure by introducing SGLT2i as a novel, evidence-based therapy locally and globally; iii) Pave the way for multicenter international trials evaluating SGLT2i in the Fontan population and broader congenital heart diseases.

Detailed description

Eligible patients with Fontan circulation who meet all predefined inclusion and exclusion criteria will be recruited from Queen Mary Hospital and Hong Kong Children's Hospital in Hong Kong. Prospective candidates will undergo a screening interview conducted by the research staff. During this interview, the objectives of the clinical trial, the required procedures, and any potential risks will be comprehensively explained. Prior to formal enrollment and the initiation of any study-specific procedures, written informed consent will be legally obtained from the patient or their designated legal guardian.

The study protocol involves a series of scheduled clinical assessments, beginning with a baseline evaluation at Visit 1. During this initial visit, patients will undergo a comprehensive medical history review and a physical examination. Baseline vital signs, including blood pressure, pulse rate, and resting oxygen saturation via pulse oximetry, will be recorded. Routine cardiovascular evaluations will include standard 12-lead electrocardiography. Unless performed within the preceding three months, a comprehensive laboratory panel will be drawn; this includes a complete blood count, renal and liver function tests, calcium and phosphate levels, N-terminal pro b-type natriuretic peptide (NT-proBNP), hemoglobin A1c, fasting glucose, and a lipid profile. Additionally, a urine pregnancy test will be administered to all women of childbearing potential. To establish baseline patient-reported outcomes, participants will complete either the Kansas City Cardiomyopathy Questionnaire (KCCQ) or the Paediatric Quality of Life Inventory (PedsQL).

Specialized cardiovascular diagnostics and subsequent follow-up evaluations will be conducted at Visit 1 (Week 4 ± 1) and Visit 3 (Week 12 ± 1). At the Week 12 follow-up visit, patients will complete a re-administration of the KCCQ or PedsQL questionnaires. During both specified visits, patients will undergo cardiopulmonary exercise testing (CPX) under the direct supervision of a cardiologist. This testing is designed to evaluate critical functional parameters, including peak oxygen consumption (VO₂), total functional capacity measured in metabolic equivalents (METs), oxygen pulse as a surrogate for stroke volume, the anaerobic threshold (VO₂ AT), and ventilatory efficiency (VE/VO₂).

In conjunction with the exercise testing, comprehensive echocardiography will be performed by an independent echocardiographer at Visit 1 and Visit 3, though the baseline scan may be waived if a comprehensive assessment is available from the preceding three years. The echocardiographic analysis will utilize color Doppler flow imaging for the semi-quantitative assessment of systemic atrioventricular (AV) valve regurgitation severity. Conventional pulsed-wave Doppler will be employed to measure early and late diastolic AV valve inflow velocities, allowing for the calculation of the AV systolic-to-diastolic ratio based on the regurgitant jet, which serves as a clinical correlate for ventricular end-diastolic pressure. Furthermore, pulsed-wave tissue Doppler imaging (TDI) will be conducted in the apical four-chamber view. By positioning the sample volume at the lateral AV annulus, researchers will record systolic, early diastolic, and late diastolic velocities to calculate the TDI-based myocardial performance index (MPI). Finally, speckle-tracking echocardiography (STE) will be applied to accurately quantify the systolic and diastolic myocardial deformation, or strain, of the single ventricle.

Interventions

• Drug Dapagliflozin (5-10 mg daily) - SGLT2 Inhibitor Therapy
  Subjects in SGLT2 inhibitor Group will take dapagliflozin 5-10mg once daily orally from Visit 1 (Week 1) to Visit 3 (Week 12 ± 1)

Primary outcome measures

• Maximal oxygen uptake (VO2 max) on cardiopulmonary exercise (CPX) at 3 months [Time frame: At Visit 3 (3 months)]

Secondary outcome measures (12)

• Metabolic equivalents (METs) on cardiopulmonary test (CPX) [Time frame: At Visit 3 (3 months)]
• Oxygen pulse on cardiopulmonary exercise (CPX) at 3 months [Time frame: At Visit 3 (3 months)]
• Anaerobic threshold (VO2 AT) on cardiopulmonary exercise (CPX) at 3 months [Time frame: At Visit 3 (3 months)]
• Ventilatory equivalent for oxygen (VE/VO2) on cardiopulmonary exercise (CPX) at 3 months [Time frame: At Visit 3 (3 months)]
• Cardiac biomarkers level [Time frame: At Visit 3 (3 months)]
• Systemic ventricular function [Time frame: At Visit 3 (3 months)]
• Systemic ventricle dimension [Time frame: At Visit 3 (3 months)]
• Atrioventricular valve regurgitation [Time frame: At Visit 3 (3 months)]
• Kansas City Cardiomyopathy Questionnaire (KCCQ) score [Time frame: At Visit 3 (3 months)]
• Paediatric Quality of Life (PedsQL) [Time frame: At Visit 3 (3 months)]
• Time to first occurrence of clinical events [Time frame: At Visit 3 (3 months)]
• Occurrence of adverse events [Time frame: At Visit 3 (3 months)]

Eligibility criteria

Inclusion criteria

• Patients with a functional single ventricle and who have undergone Fontan procedure
• Adolescents aged ≥ 12 years with body weight ≥30kg and adults

Exclusion criteria

• Planned cardiac and/or non-cardiac surgery in 3 months
• Arrhythmias requiring change in therapy in recent 6 months
• Intervention procedure within 6 months prior to enrollment
• Documented structural abnormalities of the Fontan circulation
• Chronic kidney disease stages 4 to 5
• Inability to perform cardiopulmonary test
• Recent use of SGLT2 inhibitors within 6 months
• Known hypersensitivity to SGLT2 inhibitors
• History of diabetic ketoacidosis
• Recent symptomatic hypoglycaemia within 6 months
• Insulin dependent diabetes mellitus
• History of perineum infection
• Recent urinary tract infection within 6 months
• Recent genital infection within 6 months
• Other known contraindications to SGLT2 inhibitor
• Pregnancy or breast feeding

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Hong Kong · 2 centers

• Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital — Hong Kong
• Queen Mary Hospital — Hong Kong

Publications

• Fernandes SM, McElhinney DB, Khairy P, Graham DA, Landzberg MJ, Rhodes J. Serial cardiopulmonary exercise testing in patients with previous Fontan surgery. Pediatr Cardiol. 2010 Feb;31(2):175-80. doi: 10.1007/s00246-009-9580-5. PMID 19915891
• Nunez J, Palau P, Dominguez E, Mollar A, Nunez E, Ramon JM, Minana G, Santas E, Facila L, Gorriz JL, Sanchis J, Bayes-Genis A. Early effects of empagliflozin on exercise tolerance in patients with heart failure: A pilot study. Clin Cardiol. 2018 Apr;41(4):476-480. doi: 10.1002/clc.22899. Epub 2018 Apr 17. PMID 29663436
• Chen K, Nie Z, Shi R, Yu D, Wang Q, Shao F, Wu G, Wu Z, Chen T, Li C. Time to Benefit of Sodium-Glucose Cotransporter-2 Inhibitors Among Patients With Heart Failure. JAMA Netw Open. 2023 Aug 1;6(8):e2330754. doi: 10.1001/jamanetworkopen.2023.30754. PMID 37615988
• McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O PMID 31535829
• Pascual ES, Zurita MB, Sebastian JD, Silva LG, Peinado AA, Aguado FG. Comparison of Myocardial Deformation by Speckle-Tracking Echocardiography and Cardiac Magnetic Resonance in Patients with Fontan Circulation: Diagnostic Algorithm. J Cardiovasc Echogr. 2021 Jul-Sep;31(3):144-150. doi: 10.4103/jcecho.jcecho_126_20. Epub 2021 Oct 26. PMID 34900549
• Grattan M, Mertens L, Grosse-Wortmann L, Friedberg MK, Cifra B, Dragulescu A. Ventricular Torsion in Young Patients With Single-Ventricle Anatomy. J Am Soc Echocardiogr. 2018 Dec;31(12):1288-1296. doi: 10.1016/j.echo.2018.07.018. Epub 2018 Oct 17. PMID 30340887
• Bellsham-Revell HR, Tibby SM, Bell AJ, Miller OI, Razavi R, Greil GF, Simpson JM. Tissue Doppler time intervals and derived indices in hypoplastic left heart syndrome. Eur Heart J Cardiovasc Imaging. 2012 May;13(5):400-7. doi: 10.1093/ejechocard/jer271. Epub 2011 Dec 8. PMID 22157969
• Cordina R, Ministeri M, Babu-Narayan SV, Ladouceur M, Celermajer DS, Gatzoulis MA, Uebing A, Li W. Evaluation of the relationship between ventricular end-diastolic pressure and echocardiographic measures of diastolic function in adults with a Fontan circulation. Int J Cardiol. 2018 May 15;259:71-75. doi: 10.1016/j.ijcard.2018.02.045. Epub 2018 Feb 12. PMID 29472024

Identifiers

NCT: NCT07482943 · DAPA01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗