School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia, USA.
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
J Clin Pharmacol. 2021 May;61(5):636-648. doi: 10.1002/jcph.1769. Epub 2020 Oct 22.
The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study demonstrated that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), reduced heart failure hospitalization and cardiovascular death in patients with heart failure with reduced ejection fraction (HF-rEF), with and without type 2 diabetes mellitus. Multiple potential mechanisms have been proposed to explain this benefit, which may be multifactorial. This study aimed to quantify the contribution of the known natriuretic/diuretic effects of SGLT2is to changes in cardiac hemodynamics, remodeling, and fluid homeostasis in the setting of HF-rEF. An integrated cardiorenal mathematical model was used to simulate inhibition of SGLT2 and its consequences on cardiac hemodynamics in a virtual population of HF-rEF patients generated by varying model parameters over physiologically plausible ranges and matching to baseline characteristics of individual DAPA-HF trial patients. Cardiovascular responses to placebo and SGLT2i over time were then simulated. The baseline characteristics of the HF-rEF virtual population and DAPA-HF were in good agreement. SGLT2i-induced diuresis and natriuresis that reduced blood volume and interstitial fluid volume, relative to placebo within 14 days. This resulted in decreased left ventricular end-diastolic volume and pressure, indicating reduced cardiac preload. Thereafter, blood volume and interstitial fluid volume again began to accumulate, but pressures and volumes remained shifted lower relative to placebo. After 1 year, left ventricle mass was lower and ejection fraction was higher than placebo. These simulations considered only hemodynamic consequences of the natriuretic/diuretic effects of SGLT2i, as other mechanisms may contribute additional benefits besides those predictions.
达格列净和心力衰竭结局预防（DAPA-HF）研究表明，钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）达格列净可降低射血分数降低的心力衰竭（HF-rEF）患者心力衰竭住院和心血管死亡风险，无论是否合并 2 型糖尿病。已经提出了多种潜在的机制来解释这种益处，这些益处可能是多因素的。本研究旨在量化 SGLT2i 的已知利钠/利尿作用对 HF-rEF 中心脏血液动力学、重构和液体平衡变化的贡献。采用整合的心肾数学模型，通过在生理上合理的范围内改变模型参数并与 DAPA-HF 试验个体患者的基线特征相匹配，模拟 HF-rEF 患者虚拟人群中 SGLT2 抑制及其对心脏血液动力学的影响。然后模拟 SGLT2i 和安慰剂随时间对心血管的影响。HF-rEF 虚拟人群和 DAPA-HF 的基线特征具有良好的一致性。SGLT2i 诱导的利尿和利钠作用在 14 天内使血容量和细胞外液体积相对于安慰剂减少，从而导致左心室舒张末期容积和压力降低，表明前负荷降低。此后，血容量和细胞外液体积再次开始积聚，但压力和体积相对于安慰剂仍较低。1 年后，左心室质量低于安慰剂，射血分数高于安慰剂。这些模拟仅考虑了 SGLT2i 的利钠/利尿作用的血液动力学后果，因为除了这些预测之外，其他机制可能会带来额外的益处。
