Why do <scp>SGLT2</scp> inhibitors reduce heart failure hospitalization? <scp>A</scp> differential volume regulation hypothesis

Diabetes, Obesity and Metabolism - Tập 20 Số 3 - Trang 479-487 - 2018
Karen Melissa Hallow1,2, Gabriel Helmlinger3, Peter J. Greasley4, John J.V. McMurray5, David W. Boulton6
1Department of Epidemiology and Biostatistics, University of Georgia, Athens, Georgia
2School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, Georgia
3Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca, Waltham, Massachusetts
4Early Clinical Development, Innovative Medicines, AstraZeneca, Gothenburg, Sweden
5Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
6Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca, Gaithersburg, Maryland

Tóm tắt

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.

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Thông tin xuất bản

Diabetes, Obesity and Metabolism

Tập 20 Số 3

479-487

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