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.)
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.).
J Pharmacol Exp Ther. 2020 Oct;375(1):76-91. doi: 10.1124/jpet.120.000040. Epub 2020 Aug 6.
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.
钠-葡萄糖协同转运蛋白 2 抑制剂（SGLT2i）通过尚未完全明确的机制减少心血管事件以及肾脏疾病的发生和进展，这些机制可能包括清除间质充血和降低肾小球静水压力。正在进行的 DAPASALT 机制临床研究将评估 dapagliflozin 在具有正常或受损肾功能的 2 型糖尿病患者（分别为 D-PRF 和 D-IRF）和肾功能受损的血糖正常个体（N-IRF）中的利钠、利尿、血浆/细胞外液和血压反应。在这项研究中，使用肾脏生理学、病理生理学和药理学的数学模型来前瞻性预测 DAPASALT 中钠排泄、血液和间质液体积（IFV）、血压、肾小球滤过率和蛋白尿的变化。在用以前的糖尿病肾病试验验证模型后，虚拟患者与 DAPASALT 的纳入/排除标准相匹配，并模拟 DAPASALT 方案。预测的糖尿、血压、肾小球滤过率和蛋白尿变化与类似人群的其他最近研究一致。在 D-PRF 中预测的白蛋白尿减少 46%，在 D-IRF 中减少 34.8%，在 N-IRF 中减少 14.2%。该模型预测 D-PRF 和 D-IRF 之间的 IFV 减少量相似，而在肾功能受损的人群中，IFV 减少量较小，但仍相当可观，尽管在肾功能受损的人群中，糖尿减少。当 DAPASALT 结果可用时，将其与这些模拟进行比较将为评估我们对 SGLT2i 的心脏肾脏机制的理解程度提供依据。同时，这些模拟将 dapagliflozin 的肾脏机制与 IFV 和肾脏生物标志物的变化联系起来，表明这些益处可能扩展到肾功能受损的人群和没有糖尿病的个体。意义：SGLT2i 的心脏肾脏益处的机制仍不完全清楚。我们使用肾脏生理学/药理学的数学模型来前瞻性预测正在进行的 DAPASALT 研究中对 dapagliflozin 的反应。关键预测包括在具有正常和受损肾功能的受试者之间类似的间质液体积（IFV）减少，以及在没有糖尿病的受试者中仍有相当大的 IFV 减少，尽管这些组中的糖尿减少。将前瞻性模拟和研究结果进行比较将评估我们对 SGLT2i 的心脏肾脏机制的理解程度。
