Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition

Chen, Sha; Overberg, Kenneth; Ghouse, Zakiya; Hollmann, Markus W.; Weber, Nina C.; Coronel, Ruben; Zuurbier, Coert J.

doi:10.1016/j.biopha.2024.116477

Cited by 6 publications

(1 citation statement)

References 63 publications

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“…Empagliflozin is a commonly used SGLT2 inhibitor that has been shown to be effective at reducing blood glucose levels and improving cardiovascular outcomes in people with T2DM [ 8 ]. Recently, some new findings showed that empagliflozin can reduce brain pathology in Alzheimer’s disease and T2DM, and it can also mitigate cardiac hypertrophy and improve autoimmune myocarditis [ 9 , 10 , 11 , 12 ]. Pharmacokinetic (PK) studies of empagliflozin in healthy subjects have been conducted in many countries [ 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects

Jiang,

Yu,

Nam

et al. 2024

Pharmaceuticals

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Empagliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that is commonly used for the treatment of type 2 diabetes mellitus (T2DM). CKD-370 was newly developed as a cocrystal formulation of empagliflozin with co-former L-proline, which has been confirmed to be bioequivalent in South Korea. This study aimed to quantify the differences in the absorption phase and pharmacokinetic (PK) parameters of two empagliflozin formulations in healthy subjects by using population PK analysis. The plasma concentration data of empagliflozin were obtained from two randomized, open-label, crossover, phase 1 clinical studies in healthy Korean subjects after a single-dose administration. A population PK model was constructed by using a nonlinear mixed-effects (NLME) approach (Monolix Suite 2021R1). Interindividual variability (IIV) and interoccasion variability (IOV) were investigated. The final model was evaluated by goodness-of-fit (GOF) diagnostic plots, visual predictive checks (VPCs), prediction errors, and bootstrapping. The PK of empagliflozin was adequately described with a two-compartment combined transit compartment model with first-order absorption and elimination. Log-transformed body weight significantly influenced systemic clearance (CL) and the volume of distribution in the peripheral compartment (V2) of empagliflozin. GOF plots, VPCs, prediction errors, and the bootstrapping of the final model suggested that the proposed model was adequate and robust, with good precision at different dose strengths. The cocrystal form did not affect the absorption phase of the drug, and the PK parameters were not affected by the different treatments.

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Section: Introductionmentioning

confidence: 99%

A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects

Jiang,

Yu,

Nam

et al. 2024

Pharmaceuticals

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Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

Chen,

Wang,

Bakker

et al. 2024

Basic Res Cardiol

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Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.

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Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction

Ma,

Wu,

Dong

et al. 2024

Sci Rep

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Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition

Cited by 6 publications

References 63 publications

A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects

A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects

Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

Effects of Empagliflozin and Dapagliflozin in alleviating cardiac fibrosis through SIRT6-mediated oxidative stress reduction

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