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

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.


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