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).

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

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

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

Beginning 9 months and ending 36 months following article publication.