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Dapagliflozin was recently approved for use in adults with chronic heart failure with reduced ejection fraction (HFrEF) with/without type 2 diabetes mellitus (T2DM). The objectives of this analysis were to characterize dapagliflozin pharmacokinetics in patients with HFrEF and to compare dapagliflozin systemic exposure between adults with HFrEF with/without T2DM and adults with T2DM. A nonlinear mixed‐effects modelling approach was applied; the population‐pharmacokinetic model was developed using 9735 dapagliflozin plasma concentrations from 2744 patients. The final two‐compartmental model adequately described the observed dapagliflozin concentrations, with a similar estimated apparent clearance compared with a previous estimate in patients with T2DM without HF and in healthy subjects (23.0 [95% CI: 22.6–23.9] L/h vs. 22.9 [95% CI: 22.1–23.7] L/h). The model‐predicted median area under the dapagliflozin concentration–time profile was ≤1.2‐fold higher in patients with HFrEF vs. those with T2DM without HFrEF, which is not considered clinically relevant. Dapagliflozin exposure was similar between patients with HFrEF with/without T2DM and T2DM patients without HFrEF. [ABSTRACT FROM AUTHOR]

Potassium (K+) is the main intracellular cation in the body. Elevated K+ levels (hyperkalemia) increase the risk of life‐threatening arrhythmias and sudden cardiac death. However, the details of K+ homeostasis and the effects of orally administered K+ binders, such as sodium zirconium cyclosilicate (SZC), on K+ redistribution and excretion in patients remain incompletely understood. We built a fit‐for‐purpose systems pharmacology model to describe K+ homeostasis in hyperkalemic subjects and capture serum K+ (sK+) dynamics in response to acute and chronic administration of SZC. The resulting model describes K+ distribution in the gastrointestinal (GI) tract, blood, and extracellular and intracellular spaces of tissue, renal clearance of K+, and K+–SZC binding and excretion in the GI tract. The model, which was fit to time‐course sK+ data for individual patients from two clinical trials, accounts for bolus delivery of K+ in meals and oral doses of SZC. The virtual population of patients derived from fitting the model to these trials was then modified to predict the SZC dose–response and inform clinical trial design in two new applications: emergency lowering of sK+ in severe hyperkalemia and prevention of hyperkalemia between dialysis sessions in patients with end‐stage chronic kidney disease. In both cases, the model provided novel and useful insight that was borne out by the now completed clinical trials, providing a concrete case study of fit‐for‐purpose, model‐informed drug development after initial approval of a drug. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole.Research Design and Methods: SGLT2i drop-in therapy occurred in 10.6% of EXSCEL participants, with 5.2% taking dapagliflozin. Propensity-matched cohorts of SGLT2i users and nonusers (n = 709 per group) were generated on the basis of their characteristics before open-label SGLT2i drop-in or at baseline for participants taking SGLT2i at enrollment and an equivalent study visit for non-SGLT2i users. Time to first adjudicated MACE and ACM was analyzed using Cox regression. eGFR slopes were compared between matched cohorts using a mixed-model repeated-measures analysis.Results: In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49-1.28]), as did dapagliflozin users (0.55 [0.26-1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27-0.95]; dapagliflozin: 0.66 [0.25-1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87-2.69] mL/min/1.73 m2 per year) and for dapagliflozin users (+2.28 [1.01-3.54] mL/min/1.73 m2 per year).Conclusions: This post hoc analysis of the placebo arm of EXSCEL supports a beneficial class effect for all SGLT2i, including dapagliflozin, for reduced ACM and less eGFR decline. [ABSTRACT FROM AUTHOR]