Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential 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-2 inhibitors improve the multi-functional status of cardiovascular activities, although diuretics seem to elicit a more powerful effect on reducing fluid retention.
“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 <p>Dapagliflozin Activates Neurons in the Central Nervous System and Regulates Cardiovascular Activity by Inhibiting SGLT-2 in Mice</p> (2020) · cites this paper as [64]
A study coupling plasma and urinary water and electrolyte data with mathematical modeling suggested that SGLT2 inhibitors have a preferential effect to mobilize fluid from the interstitial compartment rather than the intravascular space.
“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]
Mathematical analyses suggest that excess electrolyte-free water clearance associated with osmotic diuresis may result in greater clearance of interstitial fluid compared with other forms of diuretics.
“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]
The capacity to store Na peripherally is associated with an ability to clear interstitial fluid.
“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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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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Greenberg, A. (2000) · The American Journal of the Medical Sciences · doi:10.1016/s0002-9629(15)40676-7 · Cited by 154 · see citing works
Greenberg, A. (2000) · The American Journal of the Medical Sciences · doi:10.1097/00000441-200001000-00002 · Cited by 137 · see citing works
Sodium balance is not just a renal affair
Titze, J. (2014) · Current Opinion in Nephrology and Hypertension · doi:10.1097/01.mnh.0000441151.55320.c3 · Cited by 130 · see citing works
Decreased Effective Blood Volume in Edematous Disorders
Schrier, R. W. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006111302 · Cited by 120 · see citing works
Hammon, M., Grossmann, S., Linz, P., Kopp, C., Dahlmann, A., Garlichs, C., Janka, R., Cavallaro, A., Luft, F. C., Uder, M., et al. (2015) · PLOS ONE · doi:10.1371/journal.pone.0141336 · Cited by 93 · see citing works
Heise, T., Jordan, J., Wanner, C., Heer, M. A., Macha, S., Mattheus, M., Lund, S. S., Woerle, H. J., & Broedl, U. C. (2016) · Clinical Therapeutics · doi:10.1016/j.clinthera.2016.09.001 · Cited by 89 · see citing works
Osmotic diuresis due to urea as the cause of hypernatraemia in critically ill patients
Lindner, G., Schwarz, C., & Funk, G. (2011) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfr428 · Cited by 83 · see citing works
Titze, J. (2009) · Seminars in Dialysis · doi:10.1111/j.1525-139x.2009.00569.x · Cited by 67 · see citing works
Relationship between absolute body-fluid deficits and fluid intake in the rat.
Rabe, E. F. (1975) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0077057 · Cited by 60 · see citing works
Titze, J. M., Luft, F. C., Bauer, K. H., Dietsch, P., Lang, R., Veelken, R. A., Wagner, H., Eckardt, K., & Hilgers, K. F. (2006) · Hypertension · doi:10.1161/01.hyp.0000221039.17735.1a · Cited by 58 · see citing works
Heise, T., Jordan, J., Wanner, C., Heer, M. A., Macha, S., Mattheus, M., Lund, S. S., Woerle, H. J., & Broedl, U. C. (2016) · Clinical Therapeutics · doi:10.1016/j.clinthera.2016.08.008 · Cited by 58 · see citing works
Hirose, S., Nakajima, S., Iwahashi, Y., Seo, A., Takahashi, T., & Tamori, Y. (2016) · Internal Medicine · doi:10.2169/internalmedicine.55.6367 · Cited by 33 · see citing works
Solute-Free versus Electrolyte-Free Water Clearance in the Analysis of Osmoregulation
Shimizu, K., Kurosawa, T., Sanjo, T., Hoshino, M., & Nonaka, T. (2002) · The Nephron journals/Nephron journals · doi:10.1159/000057604 · Cited by 31 · see citing works
Vecchis, R. D., Ariano, C., Esposito, C., Giasi, A., Cioppa, C., & Cantatrione, S. (2012) · PubMed · Cited by 10 · see citing works
OS 12-03 SGLT-2-INHIBITION WITH DAPAGLIFLOZIN REDUCES TISSUE SODIUM CONTENT
Schmieder, R. E., Ott, C., Linz, P. R., Jumar, A., Friedrich, S., Titze, J. M., Hammon, M., Uder, M., & Kistner, I. (2016) · Journal of Hypertension · doi:10.1097/01.hjh.0000500051.20830.98 · Cited by 10 · see citing works
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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 · see citing works
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 914 · see citing works
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 790 · see citing works
Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors
Zelniker, T. A., & D, E. B. M. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.11.031 · Cited by 586 · see citing works
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 · see citing works
Self-citationEffects of SGLT2 Inhibitors on Kidney and Cardiovascular Function
Vallon, V., & Verma, S. (2020) · Annual Review of Physiology · doi:10.1146/annurev-physiol-031620-095920 · Cited by 520 · see citing works
McMurray, J. J. V., DeMets, D. L., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Langkilde, A. M., Martinez, F. A., Bengtsson, O., Ponikowski, P., Sabatine, M. S., et al. (2019) · European Journal of Heart Failure · doi:10.1002/ejhf.1432 · Cited by 433 · see citing works
Self-citationCongestion in heart failure: a contemporary look at physiology, diagnosis and treatment
Boorsma, E. M., ter Maaten, J. M., Damman, K., Dinh, W., Gustafsson, F., Goldsmith, S. R., Burkhoff, D., Zannad, F. M., Udelson, J. E., & Voors, A. A. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-020-0379-7 · Cited by 379 · see citing works
Cardiovascular Effects of New Oral Glucose-Lowering Agents
Scheen, A. J. (2018) · Circulation Research · doi:10.1161/circresaha.117.311588 · Cited by 288 · see citing works
An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors
Salvatore, T., Galiero, R., Caturano, A., Rinaldi, L., Martino, A. D., Albanese, G., Salvo, J. D., Epifani, R., Marfella, R., Docimo, G., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073651 · Cited by 266 · see citing works
Anker, S. D., Butler, J., Filippatos, G. S., Jamal, W., Salsali, A., Schnee, J. M., Kimura, K. A., Zeller, C., George, J. T., Brueckmann, M., et al. (2019) · European Journal of Heart Failure · doi:10.1002/ejhf.1596 · Cited by 249 · see citing works
Mordi, N., Mordi, I. R., Singh, J. S., McCrimmon, R. J., Struthers, A. D., & Lang, C. C. (2020) · Circulation · doi:10.1161/circulationaha.120.048739 · Cited by 245 · see citing works
Herrington, W. G., Preiss, D., Haynes, R., von Eynatten, M., Staplin, N., Hauske, S. J., George, J. T., Green, J. B., Landray, M. J., Baigent, C., et al. (2018) · Clinical Kidney Journal · doi:10.1093/ckj/sfy090 · Cited by 237 · see citing works
SGLT2i: beyond the glucose-lowering effect
Ni, L.-H., Yuan, C., Chen, G., Zhang, C.-J., & Wu, X.-Y. (2020) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01071-y · Cited by 202 · see citing works
Sarafidis, P. A., Ferro, C. J., Morales, E., Ortíz, A., Małyszko, J., Hojs, R., Khazim, K., Ekart, R., Valdivielso, J. M., Fouque, D. P., et al. (2019) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfy407 · Cited by 212 · see citing works
Ikonomidis, I., Pavlidis, G., Thymis, J., Birba, D., Kalogeris, A., Kousathana, F., Kountouri, A., Balampanis, K., Parissis, J., Andreadou, I., et al. (2020) · Journal of the American Heart Association · doi:10.1161/jaha.119.015716 · Cited by 199 · see citing works
Rangaswami, J., Bhalla, V., de Boer, I. H., Staruschenko, A., Sharp, J. A., Singh, R. R., Lo, K. B., Tuttle, K., Vaduganathan, M., Ventura, H., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000920 · Cited by 192 · see citing works
JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure
Tsutsui, H., Ide, T., Ito, H., Kihara, Y., Kinugawa, K., Kinugawa, S., Makaya, M., Murohara, T., Node, K., Saito, Y., et al. (2021) · Circulation Journal · doi:10.1253/circj.cj-21-0431 · Cited by 189 · see citing works
SGLT‐2 Inhibitors in Heart Failure: Current Management, Unmet Needs, and Therapeutic Prospects
Lam, C. S. P., Chandramouli, C., Ahooja, V., & Verma, S. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.119.013389 · Cited by 188 · see citing works
Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure
Joshi, S. S., Singh, T., Newby, D. E., & Singh, J. S. (2021) · Heart · doi:10.1136/heartjnl-2020-318060 · Cited by 181 · see citing works
Kidney and heart failure outcomes associated with SGLT2 inhibitor use
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Jackson, A. M., Dewan, P., Anand, I. S., Bělohlávek, J., Bengtsson, O., de Boer, R. A., Böhm, M., Boulton, D. W., Chopra, V. K., DeMets, D. L., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.047077 · Cited by 175 · see citing works
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Packer, M., Anker, S. D., Butler, J., Filippatos, G. S., Ferreira, J. P., Pocock, S., Sattar, N. A., Brueckmann, M., Jamal, W., Cotton, D., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.01.033 · Cited by 172 · see citing works
Schernthaner, G., Shehadeh, N., As, A., Bazarova, A., Ebrahimi, F., Fasching, P., Janež, A., Kempler, P., Konrāde, I., Lalic, N. M., et al. (2020) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01154-w · Cited by 163 · see citing works
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Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure
Boorsma, E. M., Beusekamp, J. C., ter Maaten, J. M., Figarska, S. M., Danser, A. H. J., van Veldhuisen, D. J., van der Meer, P., Heerspink, H. J. L., Damman, K., & Voors, A. A. (2020) · European Journal of Heart Failure · doi:10.1002/ejhf.2066 · Cited by 156 · see citing works
Heerspink, H. J. L., Kiyosue, A., Wheeler, D. C., Lin, M., Wijkmark, E., Carlson, G. F., Mercier, A., Åstrand, M., Ueckert, S., Greasley, P. J., et al. (2023) · The Lancet · doi:10.1016/s0140-6736(23)02230-4 · Cited by 150 · see citing works
Self-citationSeferovic, P. M., Fragasso, G., Petrie, M. C., Müllens, W., Ferrari, R., Thum, T., Bauersachs, J. K., Anker, S. D., Ray, R., Çavuşoğlu, Y., et al. (2020) · European Journal of Heart Failure · doi:10.1002/ejhf.1954 · Cited by 132 · see citing works
Tuttle, K. R., Brosius, F. C., Cavender, M. A., Fioretto, P., Fowler, K. J., Heerspink, H. J. L., Manley, T., McGuire, D. K., Molitch, M. E., Mottl, A. K., et al. (2020) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2020.08.003 · Cited by 132 · see citing works
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Packer, M., Wilcox, C. S., & Testani, J. M. (2023) · Circulation · doi:10.1161/circulationaha.123.064346 · Cited by 126 · see citing works
Scholtes, R. A., Muskiet, M. H. A., van Baar, M. J. B., Hesp, A. C., Greasley, P. J., Karlsson, C., Hammarstedt, A., Arya, N., van Raalte, D. H., & Heerspink, H. J. L. (2021) · Diabetes Care · doi:10.2337/dc20-2604 · Cited by 125 · see citing works
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Self-citationTuttle, K. R., Brosius, F. C., Cavender, M. A., Fioretto, P., Fowler, K. J., Heerspink, H. J. L., Manley, T., McGuire, D. K., Molitch, M. E., Mottl, A. K., et al. (2021) · Diabetes · doi:10.2337/dbi20-0040 · Cited by 123 · see citing works
Jensen, J., Omar, M., Kistorp, C., Tuxen, C., Gustafsson, I., Køber, L., Gustafsson, F., Faber, J. O., Malik, M. E., Fosbøl, E. L., et al. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(20)30382-x · Cited by 119 · see citing works
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Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects
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Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics
Yeoh, S. E., Osmanska, J., Petrie, M. C., Brooksbank, K. J. M., Clark, A. L., Docherty, K. F., Foley, P. W. X., Guha, K., Halliday, C. A., Jhund, P. S., et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad341 · Cited by 110 · see citing works
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Nguyen, T., Wen, S., Gong, M., Yuan, X., Xu, D., Wang, C., Jin, J., & Zhou, L. (2020) · Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy · doi:10.2147/dmso.s258593 · Cited by 97 · see citing works
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Mason, T., Coelho‐Filho, O. R., Verma, S., Chowdhury, B., Zuo, F., Quan, A., Thorpe, K. E., Bonneau, C., Teoh, H., Gilbert, R. E., et al. (2021) · JACC. Cardiovascular imaging · doi:10.1016/j.jcmg.2020.10.017 · Cited by 96 · see citing works
Clegg, L. E., Penland, R. C., Bachina, S., Boulton, D. W., Thuresson, M., Heerspink, H. J. L., Gustavson, S., Sjöström, C. D., Ruggles, J. A., Hernandez, A. F., et al. (2019) · Cardiovascular Diabetology · doi:10.1186/s12933-019-0942-x · Cited by 94 · see citing works
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Eickhoff, M. K., Dekkers, C. C. J., Kramers, B. J., Laverman, G. D., Frimodt‐Møller, M., Jørgensen, N. R., Faber, J. O., Danser, A. H. J., Gansevoort, R. T., Rossing, P. R., et al. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8060779 · Cited by 93 · see citing works
SGLT2 Inhibitors as Potential Anticancer Agents
Basak, D., Gamez, D., & Deb, S. (2023) · Biomedicines · doi:10.3390/biomedicines11071867 · Cited by 87 · see citing works
Packer, M. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvaa064 · Cited by 86 · see citing works
Giorgino, F., Vora, J. P., Fenici, P., & Solini, A. (2020) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01163-9 · Cited by 85 · see citing works
Cardiorenal Syndrome: The Role of Neural Connections Between the Heart and the Kidneys
Patel, K. P., Katsurada, K., & Zheng, H. (2022) · Circulation Research · doi:10.1161/circresaha.122.319989 · Cited by 90 · see citing works
Potential Mechanisms of Sodium-Glucose Co-Transporter 2 Inhibitor-Related Cardiovascular Benefits
Verma, S. (2019) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2019.10.028 · Cited by 83 · see citing works
Garg, V., Verma, S., & Connelly, K. (2019) · Progress in Cardiovascular Diseases · doi:10.1016/j.pcad.2019.07.005 · Cited by 82 · see citing works
Zheng, R., Wang, Y., Tang, J., Duan, J.-Y., Yuan, M.-Y., & Zhang, J. (2022) · PubMed Central · doi:10.1097/fjc.0000000000001183 · Cited by 39 · see citing works
Kasiakogias, A., Rosei, E. A., Camafort, M., Ehret, G., Faconti, L., Ferreira, J. P., Brguljan-Hitij, J., Januszewicz, A., Kahan, T., Manolis, A. J., et al. (2021) · Journal of Hypertension · doi:10.1097/hjh.0000000000002910 · Cited by 79 · see citing works
Chen, X., Hocher, C., Shen, L., Krämer, B. K., & Hocher, B. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00177.2023 · Cited by 77 · see citing works
Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes
Davies, M. J., Drexel, H., Jornayvaz, F. R., Pataky, Z., Seferovic, P. M., & Wanner, C. (2022) · Cardiovascular Diabetology · doi:10.1186/s12933-022-01575-9 · Cited by 76 · see citing works
Helmlinger, G., Sokolov, V. V., Peskov, K. V., Hallow, K. M., Kosinsky, Y., Voronova, V., Chu, L., Yakovleva, T. A., Azarov, I., Kaschek, D., et al. (2019) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12426 · Cited by 74 · see citing works
Self-citationWater Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure
Marton, A., Saffari, S. E., Rauh, M., Sun, R.-N., Nagel, A. M., Linz, P. R., Lim, T. T., Takase‐Minegishi, K., Pajarillaga, A., Saw, S., et al. (2024) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2024.02.020 · Cited by 71 · see citing works
Self-citationNatali, A., Nesti, L., Tricò, D., & Ferrannini, E. (2021) · Cardiovascular Diabetology · doi:10.1186/s12933-021-01385-5 · Cited by 70 · see citing works
Tamargo, J. L. (2019) · European Cardiology Review · doi:10.15420/ecr.2018.34.2 · Cited by 70 · see citing works
Hwang, I., Cho, G., Yoon, Y. E., Park, J. J., Park, J., Lee, S., Kim, H., Kim, Y.-J., & Sohn, D. (2020) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01042-3 · Cited by 69 · see citing works
Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function
Salvatore, T., Caturano, A., Galiero, R., Martino, A. D., Albanese, G., Vetrano, E., Sardu, C., Marfella, R., Rinaldi, L., & Sasso, F. C. (2021) · Biomedicines · doi:10.3390/biomedicines9101356 · Cited by 71 · see citing works
Hallow, K. M., Greasley, P. J., Helmlinger, G., Chu, L., Heerspink, H. J., & Boulton, D. W. (2018) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00202.2018 · Cited by 68 · see citing works
Self-citationRau, M., Thiele, K., Hartmann, N. K., Schuh, A., Altiok, E., Möllmann, J., Keszei, A. P., Böhm, M., Marx, N., & Lehrke, M. (2021) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01175-5 · Cited by 68 · see citing works
Empagliflozin restores the integrity of the endothelial glycocalyx in vitro
Cooper, S., Teoh, H., Campeau, M.-A., Verma, S., & Leask, R. L. (2019) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-019-03555-2 · Cited by 68 · see citing works
Packer, M. (2020) · Journal of the American Heart Association · doi:10.1161/jaha.120.016270 · Cited by 66 · see citing works
Leccisotti, L., Cinti, F., Sorice, G. P., D’Amario, D., Lorusso, M., Guzzardi, M. A., Mezza, T., Gugliandolo, S., Cocchi, C., Capece, U., et al. (2022) · Cardiovascular Diabetology · doi:10.1186/s12933-022-01607-4 · Cited by 68 · see citing works
Bashier, A. M., Hussain, A. K. B., Abdelgadir, E., Alawadi, F., Sabbour, H. M., & CHILTON, R. J. (2019) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-019-0476-0 · Cited by 63 · see citing works
SGLT2 inhibitors: the future for treatment of type 2 diabetes mellitus and other chronic diseases
Wanner, C., & Marx, N. (2018) · Diabetologia · doi:10.1007/s00125-018-4678-z · Cited by 65 · see citing works
Fediuk, D. J., Nucci, G., Dawra, V. K., Cutler, D. L., Amin, N. B., Terra, S. G., Boyd, R. A., Krishna, R., & Sahasrabudhe, V. (2020) · Clinical Pharmacokinetics · doi:10.1007/s40262-020-00875-1 · Cited by 64 · see citing works
Wang, C., Chen, C., Lin, M.-H., Su, H., Ho, M.-Y., Yeh, J., Tsai, M., Hsieh, C., & Wen, M. (2020) · Biology · doi:10.3390/biology9110369 · Cited by 61 · see citing works
Scheen, A. J. (2018) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2018.06.008 · Cited by 60 · see citing works
SGLT-2 inhibitors as cardio-renal protective agents
Caruso, I., & Giorgino, F. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154937 · Cited by 59 · see citing works
Oxidative stress as a culprit in diabetic kidney disease
Su, S., Ma, Z., Wu, H., Xu, Z., & Yi, H. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121661 · Cited by 60 · see citing works
Mechanisms and Evidence for Heart Failure Benefits from SGLT2 Inhibitors
Wójcik, C., & Warden, B. A. (2019) · Current Cardiology Reports · doi:10.1007/s11886-019-1219-4 · Cited by 61 · see citing works
Delanaye, P., & Scheen, A. J. (2021) · Diabetes & Metabolism · doi:10.1016/j.diabet.2021.101285 · Cited by 62 · see citing works
Iacobellis, G., & Baroni, M. G. (2021) · Journal of Endocrinological Investigation · doi:10.1007/s40618-021-01687-1 · Cited by 58 · see citing works
Biegus, J., Fudim, M., Salah, H. M., Heerspink, H. J. L., Voors, A. A., & Ponikowski, P. P. (2023) · European Journal of Heart Failure · doi:10.1002/ejhf.2967 · Cited by 57 · see citing works
Mechanisms of SGLT2 Inhibitors in Heart Failure and Their Clinical Value
Xie, Y., Wei, Y., Li, D., Pu, J., Ding, H., & Zhang, X. (2023) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000001380 · Cited by 58 · see citing works
Katsurada, K., Nandi, S. S., Sharma, N. M., & Patel, K. P. (2021) · Circulation Heart Failure · doi:10.1161/circheartfailure.121.008365 · Cited by 57 · see citing works
DAPA-HF trial: dapagliflozin evolves from a glucose-lowering agent to a therapy for heart failure
Kaplinsky, E. (2020) · Drugs in Context · doi:10.7573/dic.2019-11-3 · Cited by 54 · see citing works
Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD
Mayne, K. J., Staplin, N., Keane, D. F., Wanner, C., Brenner, S., Cejka, V., Stegbauer, J., Judge, P. K., Preiss, D., Emberson, J., et al. (2023) · Journal of the American Society of Nephrology · doi:10.1681/asn.0000000000000271 · Cited by 58 · see citing works
Margonato, D., Galati, G., Mazzetti, S., Cannistraci, R., Perseghin, G., Margonato, A., & Mortara, A. (2020) · Heart Failure Reviews · doi:10.1007/s10741-020-10024-2 · Cited by 54 · see citing works
Carvalho, P. E. P., Veiga, T. M. A., Silva, A. C. S. E., Gewehr, D. M., Dagostin, C. S., Fernandes, A. D. F., Nasi, G. M., & Cardoso, R. N. (2023) · Clinical Research in Cardiology · doi:10.1007/s00392-022-02148-2 · Cited by 55 · see citing works
Butler, J., Handelsman, Y., Bakris, G. L., & Verma, S. (2020) · European Journal of Heart Failure · doi:10.1002/ejhf.1708 · Cited by 52 · see citing works
Jensen, J., Omar, M., Kistorp, C., Poulsen, M. K., Tuxen, C., Gustafsson, I., Køber, L., Gustafsson, F., Fosbøl, E. L., Bruun, N. E., et al. (2019) · Trials · doi:10.1186/s13063-019-3474-5 · Cited by 52 · see citing works
Ujjawal, A., Schreiber, B., & Verma, A. (2022) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188221090001 · Cited by 51 · see citing works
Anti-Oxidative Therapy in Diabetic Nephropathy
Hernandez, L. F., Eguchi, N., Whaley, D., Alexander, M., Tantisattamo, E., & Ichii, H. (2022) · Frontiers in Bioscience-Scholar · doi:10.31083/j.fbs1402014 · Cited by 52 · see citing works
Bertoccini, L., & Baroni, M. G. (2020) · Advances in Experimental Medicine and Biology · doi:10.1007/5584_2020_494 · Cited by 49 · see citing works
SGLT2 inhibition and adipose tissue metabolism: current outlook and perspectives
Morciano, C., Gugliandolo, S., Capece, U., Giuseppe, G. D., Mezza, T., Ciccarelli, G., Soldovieri, L., Brunetti, M., Avolio, A., Splendore, A., et al. (2024) · Cardiovascular Diabetology · doi:10.1186/s12933-024-02539-x · Cited by 49 · see citing works
Bonora, B. M., Cappellari, R., Albiero, M., Avogaro, A., & Fadini, G. P. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00824 · Cited by 49 · see citing works
- 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 · 2016: 1 · 2012: 1
- 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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