PT - JOURNAL ARTICLE AU - Karen Melissa Hallow AU - David Boulton AU - Robert C Penland AU - Gabriel Helmlinger AU - Emily Nieves AU - Daniel H van Raalte AU - Hiddo L Heerspink AU - Peter J Greasley TI - Renal effects of dapagliflozin in people with and without diabetes with moderate or severe renal dysfunction: prospective modeling of an ongoing clinical trial. AID - 10.1124/jpet.120.000040 DP - 2020 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - JPET-AR-2020-000040 4099 - http://jpet.aspetjournals.org/content/early/2020/08/06/jpet.120.000040.short 4100 - http://jpet.aspetjournals.org/content/early/2020/08/06/jpet.120.000040.full AB - 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 (T2D) with normal or impaired renal function (D-NRF 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, GFR, and albuminuria were consistent with other recent studies in similar populations. Predicted albuminuria reductions were 46% in D-NRF, 34.8% in D-IRF, and 14.2% in N-IRF. The model predicts similarly large IFV reduction between D-NRF and D-IRF, and less but still substantial IFV reduction in N-IRF, even though glycosuria 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 these benefits may extend to those with impaired renal function and nondiabetics. 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 non-diabetics, 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 SGLT2i.