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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Renal Effects of Dapagliflozin in People with and without Diabetes with Moderate or Severe Renal Dysfunction: Prospective Modeling of an Ongoing Clinical Trial

K. Melissa Hallow, David W. Boulton, Robert C. Penland, Gabriel Helmlinger, Emily H. Nieves, Daniël H. van Raalte, Hiddo L. Heerspink and Peter J. Greasley
Journal of Pharmacology and Experimental Therapeutics October 2020, 375 (1) 76-91; DOI: https://doi.org/10.1124/jpet.120.000040
K. Melissa Hallow
Department of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia (K.M.W., E.N.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland (D.W.B.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts (R.C.P., G.H.); Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands (D.H.v.R.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (H.L.H.); The George Institute for Global Health, Sydney, Australia (H.L.H.); and Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.J.G.)
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David W. Boulton
Department of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia (K.M.W., E.N.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland (D.W.B.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts (R.C.P., G.H.); Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands (D.H.v.R.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (H.L.H.); The George Institute for Global Health, Sydney, Australia (H.L.H.); and Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.J.G.)
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Robert C. Penland
Department of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia (K.M.W., E.N.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland (D.W.B.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts (R.C.P., G.H.); Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands (D.H.v.R.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (H.L.H.); The George Institute for Global Health, Sydney, Australia (H.L.H.); and Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.J.G.)
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Gabriel Helmlinger
Department of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia (K.M.W., E.N.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland (D.W.B.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts (R.C.P., G.H.); Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands (D.H.v.R.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (H.L.H.); The George Institute for Global Health, Sydney, Australia (H.L.H.); and Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.J.G.)
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Emily H. Nieves
Department of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia (K.M.W., E.N.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland (D.W.B.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts (R.C.P., G.H.); Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands (D.H.v.R.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (H.L.H.); The George Institute for Global Health, Sydney, Australia (H.L.H.); and Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.J.G.)
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Daniël H. van Raalte
Department of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia (K.M.W., E.N.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland (D.W.B.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts (R.C.P., G.H.); Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands (D.H.v.R.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (H.L.H.); The George Institute for Global Health, Sydney, Australia (H.L.H.); and Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.J.G.)
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Hiddo L. Heerspink
Department of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia (K.M.W., E.N.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland (D.W.B.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts (R.C.P., G.H.); Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands (D.H.v.R.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (H.L.H.); The George Institute for Global Health, Sydney, Australia (H.L.H.); and Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.J.G.)
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Peter J. Greasley
Department of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia (K.M.W., E.N.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland (D.W.B.); Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, Massachusetts (R.C.P., G.H.); Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUMC, Amsterdam, The Netherlands (D.H.v.R.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands (H.L.H.); The George Institute for Global Health, Sydney, Australia (H.L.H.); and Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.J.G.)
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Abstract

Sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular events and onset and progression of renal disease by mechanisms that remain incompletely understood but may include clearance of interstitial congestion and reduced glomerular hydrostatic pressure. The ongoing DAPASALT mechanistic clinical study will evaluate natriuretic, diuretic, plasma/extracellular volume, and blood pressure responses to dapagliflozin in people with type 2 diabetes with normal or impaired renal function (D-PRF and D-IRF, respectively) and in normoglycemic individuals with renal impairment (N-IRF). In this study, a mathematical model of renal physiology, pathophysiology, and pharmacology was used to prospectively predict changes in sodium excretion, blood and interstitial fluid volume (IFV), blood pressure, glomerular filtration rate, and albuminuria in DAPASALT. After validating the model with previous diabetic nephropathy trials, virtual patients were matched to DAPASALT inclusion/exclusion criteria, and the DAPASALT protocol was simulated. Predicted changes in glycosuria, blood pressure, glomerular filtration rate, and albuminuria were consistent with other recent studies in similar populations. Predicted albuminuria reductions were 46% in D-PRF, 34.8% in D-IRF, and 14.2% in N-IRF. The model predicts a similarly large IFV reduction between D-PRF and D-IRF and less, but still substantial, IFV reduction in N-IRF, even though glycosuria is attenuated in groups with impaired renal function. When DAPASALT results become available, comparison with these simulations will provide a basis for evaluating how well we understand the cardiorenal mechanism(s) of SGLT2i. Meanwhile, these simulations link dapagliflozin’s renal mechanisms to changes in IFV and renal biomarkers, suggesting that these benefits may extend to those with impaired renal function and individuals without diabetes.

SIGNIFICANCE STATEMENT Mechanisms of SGLT2 inhibitors’ cardiorenal benefits remain incompletely understood. We used a mathematical model of renal physiology/pharmacology to prospectively predict responses to dapagliflozin in the ongoing DAPASALT study. Key predictions include similarly large interstitial fluid volume (IFV) reductions between subjects with normal and impaired renal function and less, but still substantial, IFV reduction in those without diabetes, even though glycosuria is attenuated in these groups. Comparing prospective simulations and study results will assess how well we understand the cardiorenal mechanism(s) of SGLT2 inhibitors.

Footnotes

    • Received March 27, 2020.
    • Accepted June 9, 2020.
  • This study was funded by AstraZeneca Pharmaceuticals.

  • https://doi.org/10.1124/jpet.120.000040.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 1
1 Oct 2020
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Modeling Renal Effects of Dapagliflozin

K. Melissa Hallow, David W. Boulton, Robert C. Penland, Gabriel Helmlinger, Emily H. Nieves, Daniël H. van Raalte, Hiddo L. Heerspink and Peter J. Greasley
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 76-91; DOI: https://doi.org/10.1124/jpet.120.000040

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Modeling Renal Effects of Dapagliflozin

K. Melissa Hallow, David W. Boulton, Robert C. Penland, Gabriel Helmlinger, Emily H. Nieves, Daniël H. van Raalte, Hiddo L. Heerspink and Peter J. Greasley
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 76-91; DOI: https://doi.org/10.1124/jpet.120.000040
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