TY - JOUR
T1 - Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes
AU - van der Hoek, Sjoukje
AU - Koomen, Jeroen V.
AU - van Bommel, Erik J. M.
AU - Mosterd, Charlotte M.
AU - Scholtes, Rosalie A.
AU - Hesp, Anne C.
AU - Stevens, Jasper
AU - van Raalte, Daniel H.
AU - Heerspink, Hiddo J. L.
N1 - Funding Information: The empagliflozin and placebo medication for the RECOLAR study were provided by Boehringer Ingelheim. The authors thank Renee de Meijer, Ingrid Knufman, and Jeannette Boerop for their technical support. DVR is supported by a senior fellowship of the Dutch Diabetes Foundation and a PIONEER grant from the Dutch Kidney Foundation. Funding Information: The RED study was funded by AstraZeneca as an investigator-initiated study (grant number ESR-14-10753). The funder had no role in the study design, the analyses or drafting of the report of the original nor this publication. Publisher Copyright: © 2023 by the authors.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Sodium–glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure–response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure–response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC0–tau,ss) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, p < 0.001), systolic blood pressure (0.80 mmHg, p = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, p = 0.03), and filtration fraction (0.09%, p = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC0–tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, p = 0.002), systolic blood pressure (0.65 mmHg, p = 0.045), and mGFR (0.78 mL/min, p = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.
AB - Sodium–glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure–response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure–response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC0–tau,ss) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, p < 0.001), systolic blood pressure (0.80 mmHg, p = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, p = 0.03), and filtration fraction (0.09%, p = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC0–tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, p = 0.002), systolic blood pressure (0.65 mmHg, p = 0.045), and mGFR (0.78 mL/min, p = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.
KW - SGLT2 inhibitors
KW - dapagliflozin
KW - empagliflozin
KW - pharmacodynamics
KW - pharmacokinetics
KW - renal hemodynamics
KW - response variability
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85160364213&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/jpm13050747
DO - https://doi.org/10.3390/jpm13050747
M3 - Article
C2 - 37240917
SN - 2075-4426
VL - 13
JO - Journal of Personalized Medicine
JF - Journal of Personalized Medicine
IS - 5
M1 - 747
ER -