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Why do SGLT2 inhibitors reduce heart failure hospitalization? Adifferential volume regulation hypothesis
Open accessAbstract
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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“SGLT-2i has a role of improving the multi-functional status of cardiovascular activities, although the diuretics seem to elicit a more powerful effect on reducing fluid retention.64,65”
From Dapagliflozin Activates Neurons in the Central Nervous System and Regulates Cardiovascular Activity by Inhibiting SGLT-2 in Mice (2020) · cites this paper as [64]
In the citing paper
“In addition, a study that coupled plasma and urinary water and electrolyte data with mathematical modeling to compare effects of dapagliflozin and bumetanide on volumes of blood and interstitial fluid suggested that SGLT2 inhibitors have a preferential effect to mobilize fluid from the interstitial compartment rather than the intravascular space (38).”
From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [38]
In the citing paper
“Mathematical analyses suggest that the excess electrolyte-free water clearance associated with osmotic diuresis may result in greater clearance of interstitial fluid compared with other forms of diuretics (14).”
From Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data (2018) · cites this paper as [14]
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“This suggests that the capacity to store Na ϩ peripherally is associated with an ability to clear interstitial fluid, as we have described previously (14).”
From Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data (2018) · cites this paper as [14]
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Small, A. M., Patel, S. M., Thomas, C., Palazzolo, M. G., Bělohlávek, J., Desai, A. S., Dróżdż, J., Inzucchi, S. E., McMurray, J. J. V., Merkely, B., et al. (2026) · JACC Heart Failure · doi:10.1016/j.jchf.2026.103366
Self-citationType 2 Diabetes: Chronic Clinical Metabolic Effects of SGLT2 Inhibitors
Scheen, A. J. (2026) · Handbook of experimental pharmacology · doi:10.1007/164_2026_848
SGLT2 inhibitors: mechanisms, physiology and pharmacology, and clinical applications
Zheng, X.-T., Xie, H.-Y., Wang, X.-H., Zhao, Y., Yang, J.-Y., Liu, Y.-X., Yuan, X.-L., Tang, H.-F., Jiang, Z., & Hu, H.-J. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00604-3
Palazzuoli, A., Girerd, N., Piepoli, M. F., Ambrosy, A. P., Baudry, G., Lopez-Azor, J. C., Guzik, M., Miró, Ò., Dauw, J., Iwanek, G., et al. (2026) · European Heart Journal - Quality of Care and Clinical Outcomes · doi:10.1093/ehjqcco/qcag149
Reappraising Bumetanide in Heart Failure
Landman, S., Masha, H., Fishkin, T., Makaryus, A. N., Frishman, W. H., & Aronow, W. S. (2026) · Cardiology in Review · doi:10.1097/crd.0000000000001518
Metadata
- Authors
- Hallow, K. M., Helmlinger, G., Greasley, P. J., McMurray, J. J. V., & Boulton, D. W.
- Affiliations
- University of Georgia (US)
- AstraZeneca (United States) (US)
- AstraZeneca (Sweden) (SE)
- University of Glasgow (GB)
- Corresponding author
- Hallow, Karen M.
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2017-11-15
- Volume
- 20
- Issue
- 3
- Pages
- 479-487
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W2763866789
- Cited by
- 499
- References
- 24
- Citations by year
- 2026: 36 · 2025: 50 · 2024: 46 · 2023: 75 · 2022: 65 · 2021: 89 · 2020: 76 · 2019: 44 · 2018: 15
- FWCI
- 28.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Obesity and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Research Bank (Australian Catholic University) (submittedVersion)
- Funders
- AstraZeneca
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- SGLT2 inhibitors, dapagliflozin, heart failure hospitalization, interstitial fluid volume, osmotic diuresis, fluid congestion, loop diuretics, bumetanide, EMPA-REG OUTCOME
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Adult, Benzhydryl Compounds, Blood Volume, Bumetanide, Diuresis, Diuretics, Drug Combinations, Drug Interactions, Female, Glucosides, Heart Failure, Hospitalization, Humans, Male, Middle Aged, Osmolar Concentration, Sodium, Water-Electrolyte Imbalance, Young Adult
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