ERTU-SODIUM: Study on the Effects of Ertugliflozin on Sodium Storage, Interstitial Volume, and Plasma Volume in HFrEF (ERTU-SODIUM)

ERTU-SODIUM: Double-blind, Prospective, Randomized, Crossover, Placebo-control Study on the Effects of the SGLT2 Inhibitor Ertugliflozin on the Regulation of Interstitial Volume, Plasma Volume, Subcutaneous Sodium Storage, and the Functionality of the Subcutaneous Glycosaminoglycan Network in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF)

The overall hypothesis is that treatment with the SGLT2 inhibitor Ertugliflozin induces a differential regulation in interstitial fluid vs plasma volume, with more reduction of the volume from the interstitial fluid than from the circulating plasma volume, which results in Ertugliflozin inducing more potent congestion relief with minimal impact on blood volume and organ perfusion. Ertugliflozin reduces the levels of sodium and water from the skin and the interstitial tissue (which improves tissue congestion).

Study Overview

• Status: Completed
• Conditions: Heart Failure With Reduced Ejection Fraction; Congestion
• Intervention / Treatment: Drug: Ertugliflozin; Drug: Placebo

Detailed Description

The glucosaminoglycan (GAG) network in the subcutaneous interstitium can non-osmotically bind large amounts of sodium. Therefore, the GAG network creates a hypertonic sodium concentration without fluid accumulation. This means that the subcutaneous GAG act as a third compartment that is able to non-osmotically store sodium without inducing congestion, thus serving as buffer in the case of sodium overload.

The researchers hypothesize that the SGLT2 inhibitor Ertugliflozin enhances the functionality of the subcutaneous GAG network. The hypothesis is that Ertugliflozin-induced GAG functionality induces more potent congestion relief (reduction in sodium and water content in the interstitial tissue) with minimal impact on blood volume and organ perfusion.

The research team will perform a randomized clinical trial with a cross-over design. Patients with heart failure with reduced ejection fraction (HFrEF) will be randomized to the SGLT2 inhibitor Ertuglifozin or to placebo. Skin punch biopsy will be performed before treatment and after treatment (one month) to evaluate skin content of water and sodium. At each time point, an oral salt challenge will be performed to investigate the functionality of the GAG network, and whether Ertugliflozin mitigates the degree of tissue and vascular congestion after this oral salt challenge as compared with placebo.

The overall hypothesis is that treatment with the SGLT2 inhibitor Ertugliflozin induces a differential regulation in interstitial fluid vs plasma volume, with more reduction of the volume from the interstitial fluid than from the circulating plasma volume, which results in Ertugliflozin inducing more potent congestion relief with minimal impact on blood volume and organ perfusion. Ertugliflozin reduces the levels of sodium and water from the skin and the interstitial tissue (which improves tissue congestion). This overarching hypothesis causes:

1. in the baseline situation, chronic treatment with Ertugliflozin:

   1.1. will reduce skin/tissue congestion as demonstrated by lower skin water content and lower volume of interstitial-extracellular fluid

   1.2. will reduce skin sodium content due to a mobilization of sodium from the subcutaneous glucosaminoglycan (GAG) network

   1.3. will create a differential regulation of interstitial vs plasmatic volume, with ertugliflozin decreasing tissue congestion (B-lines and dielectric resistance in lungs) better than placebo

   1.4. will only cause a mild reduction in plasma volume with no neurohormonal activation

   1.5. will ameliorate GAG structure: higher GAG levels, higher sulfated (functional) GAG, less expression of enzymes degrading GAG, less GAG degradation products in plasma

2. after an oral salt challenge (sodium overload), previous chronic treatment with Ertugliflozin:

2.1. will improve the sodium buffering capacity of the skin GAG network, meaning ertugliflozin will enhance non-osmotic sodium storage in the skin without causing tissue congestion (edema) or vascular congestion (increase in plasma volume and filling pressures).

2.2. will reduce skin/tissue congestion (as mentioned in 2.1): lower skin water content and interstitial-extracellular fluid volume

2.3. will not cause vascular congestion, will not raise plasma volume or LV filling pressures

In summary, Ertugliflozin will protect HFrEF patients from acute decompensations induced by dietary transgressions by enhancing the skin sodium buffering capacity

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria:

• age >18 years;
• males and females (females of child bearing potential must be using adequate contraceptive precautions)
• diagnosis of heart failure (New York Heart Association [NYHA] functional class II to III);
• Left ventricular ejection fraction <40%;
• stable symptoms and medical therapy within the last month.
• Informed consent has to be given in written form

Exclusion criteria:

• taking SGLT2i in the last month
• acute coronary syndrome or cardiac surgery within the last month;
• estimated glomerular filtration rate <20 ml/kg/min;
• use of continuous parental inotropic agents;
• systolic blood pressure <90 mm Hg;
• LVAD implantation or cardiac transplantation
• pregnant or lactating women; and
• any other medical condition considered unappropriated by a study physician

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ertugliflozin then Placebo; Treatment with Ertugliflozin for one month, washout period for one month, and then with Placebo for one month	Drug: Ertugliflozin; Treatment with Ertugliflozin 5 mg oral once per day for one month; Drug: Placebo; Treatment with matching placebo to ertugliflozin administered orally once daily for a period of one month
Active Comparator: Placebo; Treatment with matching placebo for one month, washout period for one month, and then Ertugliflozin for one month	Drug: Ertugliflozin; Treatment with Ertugliflozin 5 mg oral once per day for one month; Drug: Placebo; Treatment with matching placebo to ertugliflozin administered orally once daily for a period of one month

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the skin water content	Skin water content is measured as total (wet) weight - dry weight, determined after desiccation at 90°C for 24 hours to stable weight	Baseline and One month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in skin sodium content	Skin sodium content will be measured by flame spectrophotometry after dry ashing	Baseline and One month
Change in interstitial Fluid	Interstitial Fluid to measure tissue congestion and will be calculated as Extracellular Volume minus Plasma Volume	Baseline and One month
Change in pulmonary fluid	Pulmonary fluid content to measure tissue congestion and is quantified using remote dielectric sensing with ReDS Vest	Baseline and One month
Change in the number of pulmonary Kerley's B-lines	The number of pulmonary Kerley's B-lines (aka "comets") to measure tissue congestion and will be quantified using lung ultrasound	Baseline and One month
Change in the plasma volume	Plasma volume to measure vascular congestion.	Baseline and One month
Change in vascular congestion	Vascular congestion will be evaluated using VExUS (Volume Evaluation by UltraSound)	Baseline and One month
Change in left ventricular filling pressures	Left ventricular filling pressures to measure vascular and will be evaluated using the echocardiographic parameter E/e' (surrogate of LV filling pressures)	Baseline and One month
Change in plasma concentrations of catecholamines	Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of catecholamines.	Baseline and One month
Change in plasma concentrations of aldosterone	Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of aldosterone.	Baseline and One month
Change in plasma concentrations of plasma renin activity	Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of plasma renin activity	Baseline and One month

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Investigators: Principal Investigator: Carlos G Santos-Gallego, MD, Icanh School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2023
• Primary Completion (Actual): October 27, 2023
• Study Completion (Actual): October 27, 2023

Study Registration Dates

• First Submitted: November 29, 2021
• First Submitted That Met QC Criteria: November 29, 2021
• First Posted (Actual): December 10, 2021

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: SGLT2 inhibitors; sodium; congestion; heart failure with reduced ejection fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; ertugliflozin
• Other Study ID Numbers: PD21-12423

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No