Effects of the SGLT2 Inhibitor Empagliflozin in Patients With Euvolemic and Hypervolemic Hyponatremia

Study Overview
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Brief Summary
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Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. It is usually classified as hypovolemic, euvolemic or hypervolemic. The most common aetiology of euvolemic hyponatremia is the syndrome of inappropriate antidiuresis (SIAD). Hypervolemic hyponatremia is common in patients with congestive heart failure (CHF) (10-27%) and liver cirrhosis (up to approximately 50%). In SIAD, the regulation of arginine vasopressin (AVP) secretion is impaired which leads to free water retention. In CHF and liver cirrhosis, the effective arterial blood volume is decreased leading to non-osmotic baroreceptor mediated AVP release and consecutive free water retention. Current treatments of euvolemic and hypervolemic hyponatremia, including the most used treatment fluid restriction, are of limited efficacy. Sodium-Glucose-Co-Transporter 2 (SGLT2) inhibitors reduce glucose reabsorption in the proximal tubule, resulting in glucosuria and consecutive osmotic diuresis. A placebo-controlled randomized trial of our group has shown that a short-term, i.e. a 4-days administration of the SGLT2 inhibitor empagliflozin (Jardiance)® in addition to fluid restriction was effective in increasing the serum sodium concentration in 87 patients with SIAD-induced hyponatremia. The effect of empagliflozin (Jardiance)® without additional fluid restriction is however not yet known. Large randomized controlled trials have shown that SGLT2 inhibitors reduced hospitalization for heart failure in patients with, and more recently without type 2 diabetes. No studies have investigated the effect of SGLT2 inhibitors in hypervolemic hyponatremia. To evaluate the effect of empagliflozin (Jardiance)® in eu- and hypervolemic hyponatremia, a randomized placebo-controlled study is needed.

Official Title
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Effects of the SGLT2 Inhibitor Empagliflozin in Patients With Euvolemic and Hypervolemic Hyponatremia - a Multicentric Randomized Double-blind Placebo-controlled Trial (the EMPOWER Study)

Conditions
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Hyponatremia, SIADH, Liver Failure, Kidney Failure

Intervention / Treatment
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* Drug: Empagliflozin 25 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - chronic eu- OR hypervolemic non hyperosmolar (<300 mOsm/kg) hyponatremia (heparin plasma sodium <135 mmol/L on day of inclusion) Exclusion Criteria: known hypersensitivity or allergy to class of drugs or the investigational product, severe symptomatic hyponatremia in need of treatment with 3% NaCl-solution or in need of intensive/intermediate care treatment at time of inclusion clinical hypovolemia Severe reduction of eGFR <20 mL/min/1,73 m2 (KDIGO G4 and G5) or end stage renal disease Chronic liver insufficiency with Child Pugh Score ≥10 or decompensated liver cirrhosis (jaundice, hepatorenal syndrome, encephalopathy, bleeding, …) Hepatic impairment defined as aspartate transaminase (AST) or alanine transaminase (ALT) >3x the upper limit of normal (ULN); or total bilirubin >2x ULN at time of enrolment uncontrolled hypothyroidism uncontrolled adrenal insufficiency systolic blood pressure <90mmHg contraindication for lowering blood pressure diabetes mellitus type 1 or pancreatic diabetes mellitus treatment with SGLT2 inhibitors, lithium chloride, vaptans, demeclocycline or urea on inclusion day severe immunosuppression (leucocytes <2 G/l) peripheral arterial disease stage III-IV of the Fontaine Classification fasting or other reasons preventing medication intake previous enrolment into the current study participation in another intervention study pregnancy, breastfeeding, intention to become pregnant during the course of the study or lack of safe contraception. end of life care

Ages Eligible for Study
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Minimum Age: 18 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: Multicentric prospective randomized double-blind placebo-controlled study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>Empagliflozin (Jardiance)® 25mg per os once daily for 30 days | Drug: Empagliflozin 25 MG<br>* Empagliflozin 25mg per os once daily for 30 days<br>|
| Placebo Comparator: Placebo<br>Placebo (Lactose tablet) per os once daily for 30 days | Drug: Placebo<br>* Placebo per os once daily for 30 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in average daily area under curve (AUC) for serum sodium concentration | Change in average daily AUC for serum sodium concentration | 4 days | 
| Long-term serum sodium change (before/after treatment) | Absolute change in serum sodium concentration from baseline to end of treatment | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact intervention on bodyweight | change of bodyweight | 30 days | 
| Impact intervention on blood pressure | change of blood pressure | 30 days | 
| Course of serum sodium level | Course of serum sodium level | 30 days | 
| Change of plasma osmolality | Change of plasma osmolality | 30 days | 
| Change of urinary osmolality | Change of urinary osmolality | 30 days | 
| Change of plasma urea | Change of plasma urea | 30 days | 
| Change of urinary urea | Change of urinary urea | 30 days | 
| Change of plasma uric acid | Change of plasma uric acid | 30 days | 
| Change of urinary uric acid | Change of urinary uric acid | 30 days | 
| Change of plasma creatinin | Change of plasma creatinin | 30 days | 
| Change of urinary creatinin | Change of urinary creatinin | 30 days | 
| Change of plasma potassium | Change of plasma potassium | 30 days | 
| Change of urinary potassium | Change of urinary potassium | 30 days | 
| Change in plasma copeptin | Change in plasma copeptin | 30 days | 
| Change in plasma aldosterone | Change in plasma aldosterone | 30 days | 
| Change in plasma renin | Change in plasma renin | 30 days | 
| Change in plasma MR-proANP | Change in plasma MR-proANP | 30 days | 
| Change in plasma NT-proBNP | Change in plasma NT-proBNP | 30 days | 
| Change in plasma CTX | Change in plasma CTX | 30 days | 
| Change in plasma P1NP | Change in plasma P1NP | 30 days | 
| Occurence of thirst | Occurence of thirst | 30 days | 
| Occurence of headache | Occurence of headache | 30 days | 
| Occurence of vertigo | Occurence of vertigo | 30 days | 
| Occurence of nausea | Occurence of nausea | 30 days | 
| Change in general well-being | Change in general well-being according to visual analogue scale | 30 days | 
| Change in quality of life | change in quality of life according to EQ-5D-5L questionnaire | 30 days | 
| Change in cognitive impairment | Change in cognitive impairment measured with the MoCa test | 30 days | 
| Change in visual attention | Change in visual attention measured with the trail making test | 30 days | 
| Change in neuromuscular impairment | Change in neuromuscular impairment measured with the timed up and go test | 30 days | 
| Change in grip strength | Change in grip strength measured with a hand dynamometer | 30 days | 
| Occurence of falls | Occurence of falls | 30 days | 
| Occurence of fractures | Occurence of fractures | 30 days | 
| Length of hospital stay | Length of hospital stay | 30 days |