Effects of the SGLT2 inhibitor empagliflozin in patients with euvolemic and hypervolemic hyponatremia – a multicentric randomized double-blind placebo-controlled trial - the EMPOWER Study
Description: Background: Hyponatremia is the most common electrolyte disorder in hospitalized patients. While the syndrome of inappropriate antidiuresis (SIAD) is the prevalent cause in euvolemic patients, congestive heart failure (CHF) and liver cirrhosis are the leading causes in hypervolemic patients. 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 with free water retention. Current treatments of euvolemic and hypervolemic hyponatremia are of limited efficacy and new treatment options are needed. Sodium-Glucose-Co-Transporter 2 (SGLT2) inhibitors reduce glucose reabsorption in the proximal tubule, resulting in glucosuria and consecutive osmotic diuresis. We performed two pilot studies in patients with SIAD, one in hospitalized patients and one in outpatients, showing a significant increase in sodium levels upon treatment with SLGT-2 inhibitors in addition to fluid restriction. Several questions remain unanswered before SGLT-2 inhibitors can be used as treatment for eu- and hypervolemic hyponatremia: First, the effect of empagliflozin without additional fluid restriction is not known. Second, no studies have investigated the effect of SGLT2 inhibitors on sodium levels in hypervolemic hyponatremia. Third, the impact of treatment with SGLT-2 inhibitors on clinical signs and symptoms of hyponatremia is unknown. Aim: To investigate whether treatment with empagliflozin 25mg once daily without additional fluid restriction results in a stronger average daily increase in plasma sodium concentration at day 4 and 30 in patients with euvolemic or hypervolemic hyponatremia compared to placebo and whether clinical outcomes can be improved. Primary and secondary endpoints: Primary endpoints: Change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4 and the change in serum sodium from baseline to day 30. Secondary endpoints: Change in neurocognitive functions assessed by the MoCA Test and the Trail Making Test A and B; change in gait stability assessed by the Timed Up and Go Test; change in grip strength measured with a hand dynamometer; course of general well-being rated by patients on a visual analogue scale (VAS); change in quality of life assessed by the EQ-5D-5L questionnaire. Hypothesis: The null hypothesis is that there is no difference in the primary endpoint between patients treated with empagli?ozin and patients treated with placebo. The alternative hypothesis is that the difference in the primary endpoint between the verum and placebo group is not zero. We will perform a two-sided hypothesis test. Design: Multicentric prospective randomized double-blind placebo-controlled study Patient population: Patients =18 years with chronic eu- or hypervolemic hypotonic hyponatremia <135 mmol/L Sample size considerations: 172 patients will be recruited and randomized 1:1 into the placebo (n = 86) or the intervention arm (n = 86) using a computer-generated random number. Randomization will be performed using a minimization algorithm accounting for volume status (euvolemic versus hypervolemic) and hyponatremia severity.Collaborators and setting: Endocrine Units of 4 tertiary care centers in Switzerland (Basel, Lucerne, Lausanne and Olten). The Clinical Trial Unit of the University of Basel will provide logistic and statistical support for the study.Significance: New treatment options in patients with eu- and hypervolemic hyponatremia are needed. If our hypothesis proofs true, empagliflozin provides a new promising treatment option in these patients, without the need for additional fluid restriction.
Amount: CHF 1,018,000
Funding type: research
Funder scheme: Project funding
Start date: 2022-10-01
End date: 2026-09-30
Investigator: Christ-Crain, Mirjam
Institution: University of Basel – BS
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 212282
OpenAlex ID: G7851000997