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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Liver Failure; Hyponatremia; Kidney Failure; SIADH
• Intervention / Treatment: Drug: Empagliflozin 25 MG; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 172
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mirjam Christ-Crain, Prof; Phone Number: +41 61 328 70 80; Email: Mirjam.Christ-Crain@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel
    • Contact: Sophie Monnerat, MD; Phone Number: 0041 61 328 76 08; Email: sophie.monnerat@usb.ch
  • Luzern, Switzerland, 6000
    • Recruiting
    • Kantonsspital Luzern
    • Contact: Stefan Fischli, MD; Phone Number: + 41 41 205 51 03; Email: stefan.fischli@luks.ch
  • Vaud
    • Lausanne, Vaud, Switzerland, 1011
      • Recruiting
      • Centre Hospitalier Universitaire Vaudois (CHUV)
      • Contact: Anne Zanchi, MD; Phone Number: +41 21 314 11 11; Email: anne.zanchi@chuv.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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
Length of hospital stay	Length of hospital stay	30 days
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

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Centre Hospitalier Universitaire Vaudois; Luzerner Kantonsspital
• Investigators: Principal Investigator: Julie Refardt, MD, University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2021
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: June 10, 2020
• First Submitted That Met QC Criteria: June 22, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): June 1, 2023
• Last Update Submitted That Met QC Criteria: May 31, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Metabolic Diseases; Kidney Diseases; Urologic Diseases; Liver Diseases; Water-Electrolyte Imbalance; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Liver Failure; Renal Insufficiency; Hyponatremia; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: EMPOWER study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No