Effects of the SGLT2-inhibitor Empagliflozin on Patients With SIADH - the SAND Study (SAND)

Syndrome of inappropriate antidiuresis (SIADH) is characterized by an imbalance of antidiuretic vasopressin (AVP) secretion. The impaired AVP regulation leads to water retention and secondary natriuresis and is a common cause for hyponatremia.

The therapeutic options, aside from treating the underlying disease, depend upon the onset and severity of the symptoms and involve usually fluid restriction or hypertonic saline infusion. Alternative therapeutic options are loop diuretics, administration of oral urea or vasopressin receptor antagonists (vaptans). Despite those options, there are a considerable number of patients which do not sufficiently respond, making additional therapy necessary.

Empagliflozin (Jardiance)® is a sodium glucose co-transporter 2 (SGLT2)-inhibitor, which is a new treatment option developed for patients with diabetes mellitus type 2. The SGLT2 is expressed in the proximal tubule and reabsorbs approximately 90 percent of the filtered glucose. The inhibition of SGLT2 results in renal excretion of glucose with subsequent osmotic diuresis. This mechanism could result in a therapeutic effect in patients with hypotonic hyponatremia as in SIADH.

The aim of this study is to evaluate whether empagliflozin (Jardiance)® has an effect on the serum sodium levels of patients with SIADH.

Study Overview

• Status: Completed
• Conditions: SIADH
• Intervention / Treatment: Other: Placebo; Drug: Empagliflozin

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 84 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

- Hyponatremia <130mmol/l due to SIADH

Exclusion Criteria:

• any Treatment for SIADH during >48h before study start
• severe illness with ICU-Admission
• Treatment with 3% sodium Chloride (NaCl) solution
• uncontrolled hypothyroidism
• uncontrolled adrenal insufficiency
• severe renal impairment (GFR <30ml/min), end stage renal disease
• severe hepatic impairment (Child-Pugh class C)
• systolic blood pressure <90mmHg
• Diabetes mellitus type 1
• acute myocardial infarction or chronic venous insufficiency (CVI)
• Treatment with SGLT2 Inhibitor, Lithium Chloride or Urea
• recurrent urinary-/genital tract infections
• contraindication for lowering blood pressure
• severe immunosuppression
• pregnancy or breastfeeding
• palliative 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
Active Comparator: Empagliflozin; Treatment with empagliflozin 25mg once daily for four days	Drug: Empagliflozin
Placebo Comparator: Placebo; Treatment with Placebo once daily for four days	Other: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum sodium	The primary outcome is the change in serum sodium concentration from baseline to day 5, i.e. 4 days after start of treatment with study drug	4 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum sodium	Serum sodium concentration 1 day after start of Treatment with study drug	1 day
Serum sodium	Serum sodium concentration 2 days after start of treatment with study drug	2 days
Serum sodium	Serum sodium concentration at discharge from hospital	between day 1 to day 30
Serum sodium	Serum sodium concentration 30 days after start of treatment with study drug	30 days
Fluid intake	amount of daily fluid intake	4 days
Urinary excretion	amount of daily urinary excretion	4 days
Serum electrolytes	change of serum electrolytes from baseline to day 5	4 days
Urinary electrolytes	Change of Serum electrolytes from baseline to day 5	4 days
Serum osmolality	Change of Serum osmolality from baseline to day 5	4 days
Urine osmolality	Change of urinary osmolality from baseline to day 5	4 days
Serum glucose	Change of Serum glucose from baseline to day 5	4 days
Urinary glucose	Change of urinary Glucose from baseline to day 5	4 days
Copeptin	Change of Copeptin from baseline to day 5	4 days
Aldosterone	Change of Aldosterone from baseline to day 5	4 days
Renin	Change of Renin from baseline to day 5	4 days
atrial natriuretic peptide (ANP)	Change of ANP from baseline to day 5	4 days
Brain-Natriuretic-Peptide (BNP)	Change of BNP from baseline to day 5	4 days
General well-being	course of General well-being from baseline to day 5 as assessed by patient's self-rating score	4 days
General well-being	course of General well-being from baseline to day 30 as assessed by patient's self-rating score	30 days
Symptoms of hyponatremia	course of hyponatremia symptoms from baseline to day 5	4 days
Symptoms of hyponatremia	Course of hyponatremia symptoms from baseline to day 30	30 days
Body weight	Change of Body weight from baseline to day 5	4 days
Blood pressure	Change of blood pressure from baseline to day 5	4 days
Heart rate	Change of heart rate from baseline to day 5	4 days
length of hospital stay	length of hospital stay	30 days
Treatment escalation	rate of Need for Treatment escalation	30 days
ICU Admission rate	rate of Admission to ICU	30 days
Recurrence hyponatremia	recurrence rate hyponatremia	30 days
Hospital readmission rate	rate of readmission	30 days

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Study Director: Mirjam Christ-Crain, Prof., MD, University Hospital, Basel, Switzerland

Publications and helpful links

General Publications

• Nobbenhuis R, Refardt J, Vogt D, Sailer CO, Winzeler B, Christ-Crain M. Can treatment response to SGLT2-inhibitors in syndrome of inappropriate antidiuresis be predicted by copeptin, natriuretic peptides and inflammatory markers? Biomarkers. 2021 Nov;26(7):647-655. doi: 10.1080/1354750X.2021.1970808. Epub 2021 Aug 30.

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2016
• Primary Completion (Actual): December 14, 2018
• Study Completion (Actual): January 14, 2019

Study Registration Dates

• First Submitted: August 17, 2016
• First Submitted That Met QC Criteria: August 17, 2016
• First Posted (Estimate): August 22, 2016

Study Record Updates

• Last Update Posted (Actual): June 13, 2019
• Last Update Submitted That Met QC Criteria: June 12, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Hyponatremia; SGLT2 inhibitor
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Hypothalamic Diseases; Pituitary Diseases; Water-Electrolyte Imbalance; Inappropriate ADH Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: SAND study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No