Predicted Cardiac Functional Responses to Renal Actions of SGLT2i in the DAPACARD Trial Population: A Mathematical Modeling Analysis

• Published in: Journal of clinical pharmacology 2022-04, Vol.62 (4), p.541-554
• Main Authors: Yu, Hongtao, Basu, Sanchita, Tang, Weifeng, Penland, Robert C., Greasley, Peter J., Oscarsson, Jan, Boulton, David W., Hallow, K. Melissa
• Format: Article
• Language: English
• Subjects: cardiorenal modeling; Clinical trials; Congestive heart failure; dapagliflozin; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diuresis; Diuretics; Efficiency; global longitudinal strain; Heart Failure - drug therapy; HFrEF; Humans; Mathematical models; Models, Theoretical; Muscle contraction; myocardial efficiency; Na+/glucose cotransporter; SGLT2i; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Stroke Volume
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.1987

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.