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, Peter J. Greasley

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)76-91
Number of pages16
JournalJournal of Pharmacology and Experimental Therapeutics
Volume375
Issue number1
DOIs
Publication statusPublished - 1 Oct 2020

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