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