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

Hallow, K. M., Helmlinger, G., Greasley, P. J., McMurray, J. J.V. and Boulton, D. W. (2018) Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes, Obesity and Metabolism, 20(3), pp. 479-487. (doi:10.1111/dom.13126) (PMID:29024278)

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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 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 administered 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 due to 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McMurray, Professor John
Authors: Hallow, K. M., Helmlinger, G., Greasley, P. J., McMurray, J. J.V., and Boulton, D. W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Diabetes, Obesity and Metabolism
Publisher:Wiley
ISSN:1462-8902
ISSN (Online):1463-1326
Published Online:12 October 2017
Copyright Holders:Copyright © 2017 John Wiley and Sons Ltd
First Published:First published in Diabetes, Obesity and Metabolism 20(3):479-487
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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