Clinical trial NCT03128528: Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Heart Failure
Keywords: SGLT-2 inhibitor, Chronic heart failure, tissue sodium,
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
First posted: 2017-04-25
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase II, randomized (2:1), prospective, double-blind, placebo controlled, parallel-group, single center study.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Skin sodium content
timeFrame: 14 weeks
Secondary outcomes:
measure: Muscle sodium content
timeFrame: 14 weeks
measure: Water content of skin and muscle
timeFrame: 14 weeks
measure: Sodium excretion
timeFrame: 14 weeks
measure: 24-hour urine sodium excretion
timeFrame: 14 weeks
measure: Vascular stiffness Parameter (central systolic pressure)
timeFrame: 14 weeks
measure: Flow mediated vasodilation
timeFrame: 14 weeks
measure: N-terminal prohormone of brain natriuretic peptide
timeFrame: 14 weeks
measure: Body weight
timeFrame: 14 weeks
measure: HbA1c
timeFrame: 14 weeks
measure: ABPM
timeFrame: 14 weeks
measure: Visual analogue scale for dyspnea
timeFrame: 14 weeks
measure: Body constitution
timeFrame: 14 weeks
measure: Vascular stiffness Parameter (Pulse pressure)
timeFrame: 14 weeks
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: Clinical Research Center, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg
Study officials:
affiliation: Universitätsklinikum Erlangen
name: Roland E Schmieder, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Striepe K, Jumar A, Ott C, Karg MV, Schneider MP, Kannenkeril D, Schmieder RE. Effects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus. Circulation. 2017 Sep 19;136(12):1167-1169. doi: 10.1161/CIRCULATIONAHA.117.029529. No abstract available.
citation: Kolwelter J, Kannenkeril D, Linz P, Jung S, Nagel AM, Bosch A, Ott C, Bramlage P, Noh L, Schiffer M, Uder M, Achenbach S, Schmieder RE. The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial. Clin Res Cardiol. 2023 Jan;112(1):134-144. doi: 10.1007/s00392-022-02119-7. Epub 2022 Oct 26.
citation: Pietschner R, Kolwelter J, Bosch A, Striepe K, Jung S, Kannenkeril D, Ott C, Schiffer M, Achenbach S, Schmieder RE. Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure. Cardiovasc Diabetol. 2021 Nov 9;20(1):219. doi: 10.1186/s12933-021-01410-7.