Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure

Study Overview
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Brief Summary
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The hypothesis is that the SGLT-2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure, and if the hypothesis is proven, that this mechanism contributes to the beneficial effects found in EMPA-REG Outcome trial potentially via exerting beneficial effects on the vascular structure and function of the micro- and macrocirculation.

Detailed Description
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SGLT-2 inhibitors such as empagliflozin inhibit the SGLT-2 transport in the proximal tubular cells of the kidney, thereby causing glucosuria to approximately 100 g per day (and sometimes even more). The SGLT-2 inhibition does not only cause glucosuria but also natriuresis, since with each molecule of glucose one molecule of sodium is inhibited to be reabsorbed. Indeed, during the first week SGLT-2 inhibition causes clinically detectable natriuresis but its effect in the long run is not yet illustrated. Of course, a new sodium balance will be achieved after a certain time (otherwise the human body would be completely salt depleted), but total sodium content could be different. With new innovative magnetic resonance imaging (MRI) technology we are able to assess tissue sodium content in the skin and muscle, and observed that sodium content is significantly increased with aging, severe hypertension or hyperaldosteronism. Furthermore, skin sodium content assessed by MRI was closely related to left ventricular mass (r=0.559, p<0.0001, N=89) independently of age, gender, body mass index, and 24 h ambulatory blood pressure (β=0.343, p=0.001, N=89) 11. Using this technology, our first yet unpublished data (clinicaltrials.gov: NCT02383238) indicate that SGLT-2 inhibition decreases sodium content in the skin in patients with diabetes. Finally, we observed previously that in patients with acute chronic heart failure skin sodium content decreased from 43.5 mmol/l to 32.2 mmol/l after diuretic therapy. Thus, the present study aims at analyzing changes in total and tissue sodium content after SGLT-2 inhibition with empagliflozin. In parallel, sodium intake and excretion and central systolic and pulse pressure as well as other vascular parameters will be assessed. In face of the upcoming studies with empagliflozin conducted in patients with reduced and preserved ejection fraction (two large-scale, prospective, doubleblind, placebo controlled studies planned by Boehringer Ingelheim as the sponsor), we thought that we focus on patients with chronic heart failure irrespective diabetic status. The hypothesis is that the SGLT-2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure, and if the hypothesis is proven, that this mechanism contributes to the beneficial effects found in EMPA-REG Outcome trial potentially via exerting beneficial effects on the vascular structure and function of the micro- and macrocirculation.

Official Title
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Randomized, Double-blind, Placebo Controlled, Parallel-group, Prospective Clinical Study to Analyse the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Drug: Empagliflozin 10mg
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 - 85 years Male and Female patients (females of child bearing potential must be using adequate contraceptive precautions) CHF (symptoms and/or sign of CHF, ejection fraction < 40% (HfrEF) 14 or symptoms and/or signs of CHF, ejection fraction 40-49 % and NT-pro BNP > 125 pg/ml, and at least one structural abnormality of left atrium or ventricle (HFmEF) 14 in stable conditions. Females of childbearing potential or within two years of the menopause must have a negative urine pregnancy test at screening visit. Informed consent has to be given in written form. Exclusion Criteria: Any other form of diabetes mellitus than type 2 diabetes mellitus Use of insulin or any SGLT-2 inhibitor within the past 10 weeks prior to the screening visit (visit 1). Patients with more than two blood glucose lowering medications Uncontrolled diabetes (fasting plasma glucose ≥ 240 mg/dl, HbA1c ≥ 10%) Any history of stroke, transient ischemic attack, instable angina pectoris, or myocardial infarction within the last 6 months prior to study inclusion Estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m² (following the inclusion criteria of EMPA-REG OUTCOME study 1-3) Chronic heart failure NYHA stage IV Use of loop diuretics above furosemide > 80 mg/day, or torasemide >40 mg/day, or piretanide > 6 mg/day Implanted pacemakers or defibrillators Any other relevant clinical contraindication of MRI examination Uncontrolled arterial hypertension (i.e. ≥ 180/110 mmHg) Severe disorders of the gastrointestinal tract or other diseases which interfere with the pharmacodynamics and pharmacokinetics of study drugs Significant laboratory abnormalities such as Serum Glutamate-Oxaloacetate-Transaminase (SGOT) or Serum Glutamate-Pyruvate-Transaminase (SGPT) levels more than 3 x above the upper limit of normal range

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase II, randomized (2:1), prospective, double-blind, placebo controlled, parallel-group, single center study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Oral Tablet<br>Patients will be randomized to empagliflozin 10 mg orally once daily or one placebo tablet orally once daily. | Drug: Placebo Oral Tablet<br>* Each patient, after the run-in/wash-out phase, will be randomly assigned in a doubleblind fashion to one of the two treatment sequences according to a randomisation list. and provided by the sponsor.<br>* Other names: PLACEBO;|
| Active Comparator: Empagliflozin<br>Patients will be randomized to empagliflozin 10 mg orally once daily or one placebo tablet orally once daily. | Drug: Empagliflozin 10mg<br>* Each patient, after the run-in/wash-out phase, will be randomly assigned in a doubleblind fashion to one of the two treatment sequences according to a randomisation list. and provided by the sponsor.<br>* Other names: EMPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin sodium content | Skin sodium content (23Na-MRI) assessed at the lower leg | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle sodium content | Sodium content of muscles | 14 weeks | 
| Water content of skin and muscle | Water content (1H) of skin and muscle | 14 weeks | 
| Sodium excretion | Sodium excretion as assessed by sodium creatinine ratio in spot urine | 14 weeks | 
| 24-hour urine sodium excretion | 24-hour urine sodium excretion | 14 weeks | 
| Vascular stiffness Parameter (central systolic pressure) | Vascular stiffness Parameter under resting conditions and ambulatory conditions and their association to change in tissue sodium content | 14 weeks | 
| Flow mediated vasodilation | Flow mediated vasodilation (FMD) as measured by semiautomated ultrasound system | 14 weeks | 
| N-terminal prohormone of brain natriuretic peptide | N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP) to assess their relation to change in tissue sodium content | 14 weeks | 
| Body weight | Measurement of body weight in kg | 14 weeks | 
| HbA1c | Diabetic control (e.g. fasting glucose, glycosylated hemoglobin [HbA1c]) | 14 weeks | 
| ABPM | 24-hour ambulatory blood pressure (ABP) | 14 weeks | 
| Visual analogue scale for dyspnea | Visual analogue scale for dyspnea to assess their relation to change in tissue sodium Content. | 14 weeks | 
| Body constitution | Body constitution (fluid status based on three compartment model lean body mass, adipose tissue mass and overhydration) | 14 weeks | 
| Vascular stiffness Parameter (Pulse pressure) | Vascular stiffness Parameter under resting conditions and ambulatory conditions and their association to change in tissue sodium content | 14 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SGLT-2 inhibitor, Chronic heart failure, tissue sodium,