Predicted Cardiac Hemodynamic Consequences of the Renal Actions of SGLT2i in the DAPA‐HF Study Population: A Mathematical Modeling Analysis

• Published in: Journal of clinical pharmacology 2021-05, Vol.61 (5), p.636-648
• Main Authors: Yu, Hongtao, Tang, Weifeng, Greasley, Peter J., Penland, Robert C., Boulton, David W., Hallow, K. Melissa
• Format: Article
• Language: English
• Subjects: Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Blood Glucose; Blood pressure; Blood Volume - drug effects; cardiac improvements; cardiorenal physiology; Cardiovascular system; Computer Simulation; Congestive heart failure; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diuresis; Diuresis - drug effects; Diuretics; Ejection fraction; Glomerular Filtration Barrier; Glucosides - pharmacology; Glucosides - therapeutic use; Heart failure; Heart Failure - drug therapy; Hematocrit; Hemodynamics; Hemodynamics - drug effects; HF‐rEF virtual patients; Homeostasis; Humans; Mathematical models; Models, Theoretical; Na+/glucose cotransporter; Natriuresis - drug effects; Placebos; Population studies; QSP modeling; SGLT2i; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Ventricle
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.1769

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.