ERTU-SODIUM: Study on the Effects of Ertugliflozin on Sodium Storage, Interstitial Volume, and Plasma Volume in HFrEF
Study Details
Study Description
Brief Summary
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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:
- 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
- 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 Design
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures
- Change in the skin water content [Baseline and One month]
Skin water content is measured as total (wet) weight - dry weight, determined after desiccation at 90°C for 24 hours to stable weight
Secondary Outcome Measures
- Change in skin sodium content [Baseline and One month]
Skin sodium content will be measured by flame spectrophotometry after dry ashing
- Change in interstitial Fluid [Baseline and One month]
Interstitial Fluid to measure tissue congestion and will be calculated as Extracellular Volume minus Plasma Volume
- Change in pulmonary fluid [Baseline and One month]
Pulmonary fluid content to measure tissue congestion and is quantified using remote dielectric sensing with ReDS Vest
- Change in the number of pulmonary Kerley's B-lines [Baseline and One month]
The number of pulmonary Kerley's B-lines (aka "comets") to measure tissue congestion and will be quantified using lung ultrasound
- Change in the plasma volume [Baseline and One month]
Plasma volume to measure vascular congestion.
- Change in vascular congestion [Baseline and One month]
Vascular congestion will be evaluated using VExUS (Volume Evaluation by UltraSound)
- Change in left ventricular filling pressures [Baseline and One month]
Left ventricular filling pressures to measure vascular and will be evaluated using the echocardiographic parameter E/e' (surrogate of LV filling pressures)
- Change in plasma concentrations of catecholamines [Baseline and One month]
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of catecholamines.
- Change in plasma concentrations of aldosterone [Baseline and One month]
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of aldosterone.
- Change in plasma concentrations of plasma renin activity [Baseline and One month]
Neurohormonal activation to measure vascular congestion and will be evaluated using plasma concentrations of plasma renin activity
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Icahn School of Medicine at Mount Sinai | New York | New York | United States | 10029 |
Sponsors and Collaborators
- Icahn School of Medicine at Mount Sinai
Investigators
- Principal Investigator: Carlos G Santos-Gallego, MD, Icanh School of Medicine at Mount Sinai
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PD21-12423