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

NCT ID: NCT04447911

Last Updated: 2025-11-17

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 172 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-04
• Study Completion Date: 2027-02-28

Brief Summary

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.

Conditions

Hyponatremia; SIADH; Liver Failure; Kidney Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Empagliflozin

Empagliflozin (Jardiance)® 25mg per os once daily for 30 days

Group Type: EXPERIMENTAL

Empagliflozin 25 MG

Intervention Type: DRUG

Empagliflozin 25mg per os once daily for 30 days

Placebo

Placebo (Lactose tablet) per os once daily for 30 days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo per os once daily for 30 days

Interventions

Empagliflozin 25 MG

Empagliflozin 25mg per os once daily for 30 days

Intervention Type: DRUG

Placebo

Placebo per os once daily for 30 days

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Basel, Switzerland

OTHER

Sponsor Role: lead

Luzerner Kantonsspital

OTHER

Sponsor Role: collaborator

Centre Hospitalier Universitaire Vaudois

OTHER

Sponsor Role: collaborator

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Julie Refardt, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Basel, Switzerland

Locations

University Hospital of Würzburg, med. Poliklinik

Würzburg, , Germany

Site Status: RECRUITING

Erasmus Universität Medisch Centrum Rotterdam, Department of Internal Medicine

Rotterdam, , Netherlands

Site Status: RECRUITING

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Canton of Vaud, Switzerland

Site Status: RECRUITING

University Hospital Basel

Basel, , Switzerland

Site Status: RECRUITING

Spitalzentrum Biel

Biel, , Switzerland

Site Status: RECRUITING

Kantonsspital Luzern

Lucerne, , Switzerland

Site Status: RECRUITING

Countries

Germany; Netherlands; Switzerland

Central Contacts

Mirjam Christ-Crain, Prof

Role: CONTACT

Mirjam.Christ-Crain@usb.ch

+41 61 328 70 80

Facility Contacts

Irina Chifu, MD

Role: primary

Chifu_I@ukw.de

0049 931 201 39227

Angeliqe Savelbert

Role: primary

b.savelberg@erasmusmc.nl

0031 6 5290 5460

Anne Zanchi, MD

Role: primary

anne.zanchi@chuv.ch

+41 21 314 11 11

Sophie Monnerat, MD

Role: primary

sophie.monnerat@usb.ch

0041 61 328 76 08

Nikolaos Drivakos, MD

Role: primary

nikolaos.drivakos@szb.ch

+41 32 324 44 06

Stefan Fischli, MD

Role: primary

stefan.fischli@luks.ch

+ 41 41 205 51 03

Other Identifiers

EMPOWER study

Identifier Type: -

Identifier Source: org_study_id