Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced or Mildly Reduced Ejection Fraction

Study Overview
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Brief Summary
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Gliflozins have demonstrated a beneficial effect in terms of incident heart failure and related events in patients with or without diabetes. The clinical trial ICARD is an exploratory study that aims to evaluate the cardiometabolic mechanistic effects on the myocardium of dapagliflozin in heart failure with reduced ejection fraction. Deep phenotyping of cardiac and vascular function will be performed using MRI. Myocardial tissue characterization will be based on MRI and FDG-PET for glucose metabolism assessment. Liver steatosis and fibrosis will simultaneously be assessed.

Detailed Description
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Open-label, non-controlled clinical trial (Jardé 1) to assess the cardiovascular and metabolic effects of once-daily dapagliflozin 10 mg during 6 months in patients with heart failure and reduced ejection fraction. Eligibility of patients addressed to the Department of Cardiology (Prof R. Isnard, Pitié-Salpêtrière Hospital, Paris, France) will be investigated at V0: inclusion and exclusion criteria will be checked and informed consent will be signed. Up to twenty one days after V0, patients will come to the VMRI visit (VMRI) for the cardiac and liver gadolinium-injected MRI and AGE Reader (VRMI) and to the baseline visit (V1). Pregnancy will be ruled out in women of childbearing potential with blood beta-HCG. A blood test (including metabolomics and lipidomics) and FDG-PET MRI including Glucose Tolerance Test (GTT) will be performed. Dapagliflozin 10 mg once daily during six months will be prescribed. Fifteen to twenty-one days after treatment initiation, a safety visit (V2) will take place in order to verify the tolerance. A pre-final visit (V3) will be organized after a total of 23 weeks (± 1 week) of treatment. Pregnancy will be ruled out in women of childbearing potential with blood beta-HCG. A blood test (including metabolomics and lipidomics), ECG, trans-thoracic echocardiography (TTE), cardiac and liver MRI and AGE Reader will be performed. After 24 weeks of treatment (6-month treatment), patients will come to the end of study visit (V4), to undergo the final FDG-PET MRI including Glucose Tolerance Test (GTT).

Official Title
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Cardiometabolic Effects of Dapagliflozin in Heart Failure With Reduced or Mildly Reduced Ejection Fraction: an Exploratory Study

Conditions
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Heart Failure, Reduced Ejection Fraction

Intervention / Treatment
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* Drug: Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years NYHA functional class II-IV. Previous hospitalization for heart failure anytime or NT-proBNP >125 pg/ml in the previous 12 months Left ventricular ejection fraction ≤ 50% measured at least 1 time in transthoracic echocardiography in the last 12 months Treated by optimal medical therapy (ACE-I or angiotensin receptor blocker or sacubitril-valsartan, and betablockers, and mineralocorticoid receptor antagonist and furosemide) unless such use was contraindicated or previously associated with side-effects leading to drug discontinuation. No change in drugs dosages in the last month. Able to give written informed consent If female of childbearing potential, have a negative serum pregnancy test Use of a validated method of birth control until the end of the study (men and women) Affiliation to a social security regime Exclusion Criteria: Hypersensitivity to dapagliflozin or to any of the excipients Current treatment with gliflozine Cardiac rhythm disorder including atrial fibrillation > 100 bpm Significant valvular heart disease including mitral or aortic regurgitation > II/IV Hospitalisation for heart failure or unplanned visit for worsening heart failure in the last month Recent (last 3 months) or planned coronary revascularization Acute coronary syndrome, stroke, or transient ischemic attack in the last 3 months Body mass-index > 40 kg/m2 Uncontrolled type 2 diabetes (Hb1AC > 9%) or type 1 diabetes Genetic diabetes (Maturity Onset Diabetes of the Young, MODY) Current treatment for cancer, cardiotoxic cancer treatment in the last year Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones in the last 6 weeks Active infectious diseases Hypovolemia or dehydration, severe hypokalaemia, or severe hyponatremia Contraindication to MRI or to contrast agents used Estimated glomerular filtration rate (eGFR) < 30 ml per minute per 1.73 m2 of body-surface area (according to the Modification of Diet in Renal Disease criteria) Patient on AME (state medical aid) Pregnant or breast-feeding female Current participation in another interventional study or being in the exclusion period at the end of a previous study Patient protected by law (guardianship, tutelage measure, deprived of liberty)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Dapagliflozin is taken orally, once daily at the dosage of 10 mg during 6 months. | Drug: Dapagliflozin<br>* Dapagliflozin (Forxiga) is a very potent selective and reversible inhibitor of SGLT2.<br>* Other names: Forxiga;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate changes in left ventricular (LV) extracellular mass index (ECMi) measured by MRI, induced by once-daily dapagliflozin 10mg during 6 months in patients with heart failure and reduced ejection fraction | MRI measurement of changes in left ventricular extracellular mass index (ECMI) after a 6-month once-daily dapagliflozin 10 mg regimen | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate myocardial morphology | MRI measurement of change: Left and right ventricular volumes and Left atrial volumes | 6 months | 
| To evaluate myocardial morphology | MRI measurement of change: LV mass | 6 months | 
| Left ventricular ejection fraction as a biomarker of myocardial function | MRI measurement of change of left ventricular ejection fraction | 6 months | 
| Right ventricular ejection fraction as a biomarker of myocardial function | MRI measurement of change of right ventricular ejection fraction | 6 months | 
| Left atrial ejection fraction as a biomarker of myocardial function | MRI measurement of change of left atrial ejection fraction | 6 months | 
| Peak global longitudinal strain as a biomarker of myocardial function | MRI measurement of change of peak global LV longitudinal strain | 6 months | 
| Peak radial strain as a biomarker of myocardial function | MRI measurement of change of peak radial LV strain | 6 months | 
| Peak circumferential strain as a biomarker of myocardial function | MRI measurement of change of peak circumferential LV strain | 6 months | 
| Peak circumferential strain as a biomarker of left atrial function | MRI measurement of change of peak circumferential LA strain (reservoir) | 6 months | 
| Peak circumferential strain as a biomarker of left atrial function | MRI measurement of change of peak circumferential LA strain (booster) | 6 months | 
| LV myocardial dense fibrosis (late gadolinium enhancement) as a biomarker of fibrosis | MRI measurement of change of LV myocardial dense fibrosis (late gadolinium enhancement mass) | 6 months | 
| Intracellular mass index (ICMi) as a biomarker of fibrosis | MRI measurement of change of intracellular mass index (ICMi) | 6 months | 
| Extracellular mass index (ECMi) as a biomarker of fibrosis | MRI measurement of change of extracellular mass index (ECMi) | 6 months | 
| To evaluate adipose tissue | MRI measurement of change: epicardial adipose tissue (EAT) and steatosis (triglyceride fraction) | 6 months | 
| To evaluate myocardial steatosis | 1H-MR spectromscopy measurement of modifications of relative myocardial triglyceride content. | 6 months | 
| To evaluate glucose metabolism | 18FDG-PET-MRI measurement of change with glucose uptake analysis | 6 months | 
| Effects of dapagliflozin therapy on the proximal aorta | High resolution cine aortic MRI measurement of ascending aortic areas | 6 months | 
| Effects of dapagliflozin therapy on the proximal aorta | High resolution cine aortic MRI measurement of descending aortic areas | 6 months | 
| Effects of dapagliflozin therapy on the proximal aorta | High resolution cine aortic MRI measurement of ascending aortic distensibility | 6 months | 
| Effects of dapagliflozin therapy on the proximal aorta | High resolution cine aortic MRI measurement of descending aortic distensibility | 6 months | 
| Effects of dapagliflozin therapy on the proximal aorta | High resolution cine aortic MRI measurement of aortic arch pulse wave velocity (PWV) | 6 months | 
| To evaluate the evolution of body composition in multimodality imaging | MRI measurement of change in abdominal subcutaneous and visceral fat using the ATQUA method on DIXON MRI images | 6 months | 
| To evaluate the changes in fasting glucagon | Blood measurement change in glucagon | 6 months | 
| To evaluate the changes in fasting β-hydroxybutyrate | Blood measurement change in β-hydroxybutyrate | 6 months | 
| To evaluate the changes in fasting glycerol | Blood measurement change in glycerol | 6 months | 
| To evaluate the changes in free fatty acid (FFA) | Blood measurement change in free fatty acid (FFA) | 6 months | 
| To evaluate the changes in fasting glycemia | Blood measurement change in glycemia | 6 months | 
| To evaluate the subcutaneous tissue Advanced end-Glycation Products (AGE) | Measurement of the value of AGE on AGE reader | 6 months | 
| Evaluation of pathophysiological changes at the molecular level (metabolite profiling) | Blood measurement of targeted metabolites by LC-MS (Liquid chromatography coupled to mass spectrometry) and by GC-MS (Gas chromatography coupled to mass spectrometry) | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, HFrEF, myocardial function, fibrosis, metabolism