Exposure-Response Analysis of the Sodium-Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes

• Published in: Journal of personalized medicine Vol. 13; no. 5; p. 747
• Main Authors: van der Hoek, Sjoukje, Koomen, Jeroen V, van Bommel, Erik J M, Mosterd, Charlotte M, Scholtes, Rosalie A, Hesp, Anne C, Stevens, Jasper, van Raalte, Daniel H, Heerspink, Hiddo J L
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27-04-2023; MDPI
• Subjects: Anti-inflammatory agents; Blood pressure; Body weight; Chromatography; Diabetes; Diabetes mellitus (non-insulin dependent); Diuretics; Drug dosages; Glomerular filtration rate; Glucose; Hemodynamics; Kidneys; Pharmacokinetics; Pharmacy; Plasma; Precision medicine; Spectrum analysis; Urine; Variables; Variation; empagliflozin; type 2 diabetes; dapagliflozin; pharmacodynamics; renal hemodynamics; pharmacokinetics; response variability; SGLT2 inhibitors
• ISSN: 2075-4426; 2075-4426
• DOI: 10.3390/jpm13050747

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 (AUC
) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg,
< 0.001), systolic blood pressure (0.80 mmHg,
= 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min,
= 0.03), and filtration fraction (0.09%,
= 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC
was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg,
= 0.002), systolic blood pressure (0.65 mmHg,
= 0.045), and mGFR (0.78 mL/min,
= 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.