The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
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]
In the citing paper
“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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Citations
Cites
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504720 · Cited by 12,315
Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes
Neal, B., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Law, G., Desai, M., & Matthews, D. R. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1611925 · Cited by 7,830
CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis
Ferrannini, E., Mark, M., & Mayoux, E. (2016) · Diabetes Care · doi:10.2337/dc16-0330 · Cited by 975
Fitchett, D., Zinman, B., Wanner, C., Lachin, J. M., Hantel, S., Salsali, A., Johansen, O. E., Woerle, H. J., Broedl, U. C., & Inzucchi, S. E. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehv728 · Cited by 907
Francis, G. S., SIEGEL, R. M., Goldsmith, S. R., OLIVARI, M. T., Levine, T. B., & Cohn, J. N. (1985) · Annals of Internal Medicine · doi:10.7326/0003-4819-103-1-1 · Cited by 577
Aggravated renal dysfunction during intensive therapy for advanced chronic heart failure
Weinfeld, M. S., Chertow, G. M., & Stevenson, L. W. (1999) · American Heart Journal · doi:10.1016/s0002-8703(99)70113-4 · Cited by 279
Peacock, W. F., Costanzo, M. R., Marco, T. D., Lopatin, M., Wynne, J., Mills, R. M., & Emerman, C. L. (2008) · Cardiology · doi:10.1159/000164149 · Cited by 263
Body Fluid Volume Regulation in Health and Disease: A Unifying Hypothesis
Schrier, R. W. (1990) · Annals of Internal Medicine · doi:10.7326/0003-4819-113-2-155 · Cited by 263
Skin Sodium Concentration Correlates with Left Ventricular Hypertrophy in CKD
Schneider, M. P., Raff, U., Kopp, C., Scheppach, J. B., Toncar, S., Wanner, C., Schlieper, G., Saritas, T., Floege, J., Schmid, M., et al. (2017) · Journal of the American Society of Nephrology · doi:10.1681/asn.2016060662 · Cited by 195
Greenberg, A. (2000) · The American Journal of the Medical Sciences · doi:10.1016/s0002-9629(15)40676-7 · Cited by 154
Cited by
Sorted by citations
SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review
Verma, S., & McMurray, J. J. V. (2018) · Diabetologia · doi:10.1007/s00125-018-4670-7 · Cited by 999
Self-citationMechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors
Lopaschuk, G. D., & Verma, S. (2020) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2020.02.004 · Cited by 941
SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control
Cowie, M., & Fisher, M. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-020-0406-8 · Cited by 829
Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
Zelniker, T. A., & Braunwald, E. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.11.031 · Cited by 596
Petrie, M. C., Verma, S., Docherty, K. F., Inzucchi, S. E., Anand, I., Belohlávek, J., Böhm, M., Chiang, C.-E., Chopra, V. K., de Boer, R. A., et al. (2020) · JAMA · doi:10.1001/jama.2020.1906 · Cited by 531
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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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