Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis

Abstract

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.

Quantitative Systems Pharmacology: An Exemplar Model‐Building Workflow With Applications in Cardiovascular, Metabolic, and Oncology Drug Development

“…We expected that this analysis would improve our understanding of the renal benefits of SGLT2 inhibition but did not anticipate, initially, insight into the protective effects in heart failure. However, this analysis provided, ultimately, mechanistic insights into both, as we have described previously . We continue to use the model to further explore the cardiac effects of SGLT2 inhibition.…”

“…In addition, prospective simulations with the model indicated that SGLT2 inhibition reduces interstitial fluid volume to a greater extent than blood volume—an experimentally testable hypothesis that may explain the positive effects of these drugs on heart failure hospitalization. These results were communicated through both presentations and peer‐reviewed publications . Importantly, this differential volume mechanism lent decision support to development teams weighing the hypothesis that SGLT2 inhibitors would demonstrate clinical benefit in heart failure and slowing renal disease progression, both indications now pursued in several outcomes trials.…”

“…In addition, we found that the inclusion of this mechanism altered the relative removal of fluid from the blood and interstitium in ways that are likely to be beneficial in volume‐overloaded patients at risk for heart failure. For more details, see the primary publications of these results …”

Protective effect of sodium–glucose cotransporter 2 inhibitors in patients with rapid renal function decline, stage G3 or G4 chronic kidney disease and type 2 diabetes

“…The mechanism is not fully understood, but glomerular blood flow could be maintained, rather than increased, by discontinuing diuretics. SGLT2i provides better control of heart congestion by reducing interstitial fluid volume to a greater extent compared with blood volume (i.e., preservation of intravascular volume and reduced volume overload), whereas loop diuretics reduced intravascular volume more than interstitial fluid volume. Patients allocated to the empagliflozin group in the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes trial had a loop diuretic added to their regimen less often, suggesting that empagliflozin had a “loop diuretic–sparing” agent.…”

The heart in diabetes meeting

“…Two interesting aspects of sodium glucose transporter 2 inhibitor (SGLT2i) treatment were reviewed. Comparison of effects of loop diuretics in heart failure with those of SGLT2i suggest the latter offer a benefit not simply by natriuretic actions but rather by differentially regulating volume overload, leading to reduction in excess interstitial fluid volume without attendant decrease in plasma volume, potentially reducing heart failure‐related fluid overload without causing renal insufficiency . Another novel potential mechanism of benefit of SGLT2i is related to the SGLT2 overexpression in the renal tubules occurring in diabetes.…”