Yu Hongtao, Basu Sanchita, Tang Weifeng, Penland Robert C, Greasley Peter J, Oscarsson Jan, Boulton David W, Hallow K Melissa
School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia, USA.
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
J Clin Pharmacol. 2022 Apr;62(4):541-554. doi: 10.1002/jcph.1987. Epub 2022 Jan 5.
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to reduce the risk of worsening heart failure (HF) in subjects with HF and a reduced ejection fraction (HFrEF) in multiple clinical trials. The DAPACARD clinical trial was conducted to examine the effects of dapagliflozin on cardiac substrate uptake, myocardial efficiency, and myocardial contractile work in subjects with type 2 diabetes mellitus. As a complement to the clinical study, a mechanistic mathematical model of cardiorenal physiology was used to quantify the influence of established natriuretic/diuretic effects of SGLT2i on cardiac function (myocardial efficiency and global longitudinal strain). Virtual participants reflecting the participant-level characteristics in the DAPACARD trial were produced by varying model parameters over physiologically plausible ranges. A second virtual population was generated by inducing a state of HFrEF in the DAPACARD virtual participants with type 2 diabetes mellitus for comparison. Cardiac responses to placebo and SGLT2i were simulated over 42 days. Cardiac hemodynamic improvements were predicted in DAPACARD-HFrEF virtual participants but not in DAPACARD virtual participants. In particular, the natriuresis/diuresis induced by SGLT2i improved the global longitudinal strain and myocardial efficiency in DAPACARD-HFrEF virtual participants within the first 14 days (change from baseline: global longitudinal strain, -0.95%; and myocardial efficiency, 0.34%), whereas the global longitudinal strain and myocardial efficiency in DAPACARD virtual participants were slightly worse (change from baseline: global longitudinal strain, 0.35%; and myocardial efficiency: -0.01%). The results of the DAPACARD virtual participants modeling were in line with the clinical data but do not preclude additional effects from other mechanisms of SGLT2i.
钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）已在多项临床试验中被证明可降低射血分数降低的心力衰竭（HFrEF）患者心力衰竭恶化的风险。DAPACARD临床试验旨在研究达格列净对2型糖尿病患者心脏底物摄取、心肌效率和心肌收缩功的影响。作为临床研究的补充，使用了一个心脏肾脏生理学的机制数学模型来量化SGLT2i既定的利钠/利尿作用对心脏功能（心肌效率和整体纵向应变）的影响。通过在生理上合理的范围内改变模型参数，生成了反映DAPACARD试验中参与者水平特征的虚拟参与者。通过在患有2型糖尿病的DAPACARD虚拟参与者中诱导HFrEF状态，生成了第二个虚拟人群以进行比较。模拟了42天内对安慰剂和SGLT2i的心脏反应。预测DAPACARD-HFrEF虚拟参与者的心脏血流动力学有所改善，但DAPACARD虚拟参与者则不然。特别是，SGLT2i诱导的利钠/利尿作用在第14天内改善了DAPACARD-HFrEF虚拟参与者的整体纵向应变和心肌效率（相对于基线的变化：整体纵向应变，-0.95%；心肌效率，0.34%），而DAPACARD虚拟参与者的整体纵向应变和心肌效率则略有恶化（相对于基线的变化：整体纵向应变，0.35%；心肌效率：-0.01%）。DAPACARD虚拟参与者建模的结果与临床数据一致，但并不排除SGLT2i其他机制产生的额外作用。
