Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes
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–...
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MDPI AG
2023-04-01
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| Series: | Journal of Personalized Medicine |
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| author | Sjoukje van der Hoek Jeroen V. Koomen Erik J. M. van Bommel Charlotte M. Mosterd Rosalie A. Scholtes Anne C. Hesp Jasper Stevens Daniel H. van Raalte Hiddo J. L. Heerspink |
| author_facet | Sjoukje van der Hoek Jeroen V. Koomen Erik J. M. van Bommel Charlotte M. Mosterd Rosalie A. Scholtes Anne C. Hesp Jasper Stevens Daniel H. van Raalte Hiddo J. L. Heerspink |
| author_sort | Sjoukje van der Hoek |
| collection | DOAJ |
| description | 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<sub>0–tau,ss</sub>) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, <i>p</i> < 0.001), systolic blood pressure (0.80 mmHg, <i>p</i> = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, <i>p</i> = 0.03), and filtration fraction (0.09%, <i>p</i> = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC<sub>0–tau,ss</sub> was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, <i>p</i> = 0.002), systolic blood pressure (0.65 mmHg, <i>p</i> = 0.045), and mGFR (0.78 mL/min, <i>p</i> = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables. |
| first_indexed | 2024-03-11T03:36:04Z |
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| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-11T03:36:04Z |
| publishDate | 2023-04-01 |
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| series | Journal of Personalized Medicine |
| spelling | doaj.art-fbafa3fe33dc4129b7fd7af3e02460392023-11-18T02:03:33ZengMDPI AGJournal of Personalized Medicine2075-44262023-04-0113574710.3390/jpm13050747Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 DiabetesSjoukje van der Hoek0Jeroen V. Koomen1Erik J. M. van Bommel2Charlotte M. Mosterd3Rosalie A. Scholtes4Anne C. Hesp5Jasper Stevens6Daniel H. van Raalte7Hiddo J. L. Heerspink8Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Anesthesiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The NetherlandsDepartment of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The NetherlandsDepartment of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The NetherlandsDepartment of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsSodium–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<sub>0–tau,ss</sub>) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, <i>p</i> < 0.001), systolic blood pressure (0.80 mmHg, <i>p</i> = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, <i>p</i> = 0.03), and filtration fraction (0.09%, <i>p</i> = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC<sub>0–tau,ss</sub> was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, <i>p</i> = 0.002), systolic blood pressure (0.65 mmHg, <i>p</i> = 0.045), and mGFR (0.78 mL/min, <i>p</i> = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.https://www.mdpi.com/2075-4426/13/5/747SGLT2 inhibitorsdapagliflozinempagliflozinpharmacokineticspharmacodynamicsrenal hemodynamics |
| spellingShingle | Sjoukje van der Hoek Jeroen V. Koomen Erik J. M. van Bommel Charlotte M. Mosterd Rosalie A. Scholtes Anne C. Hesp Jasper Stevens Daniel H. van Raalte Hiddo J. L. Heerspink Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes Journal of Personalized Medicine SGLT2 inhibitors dapagliflozin empagliflozin pharmacokinetics pharmacodynamics renal hemodynamics |
| title | Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes |
| title_full | Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes |
| title_fullStr | Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes |
| title_full_unstemmed | Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes |
| title_short | Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes |
| title_sort | exposure response analysis of the sodium glucose cotransporter 2 inhibitors dapagliflozin and empagliflozin on kidney hemodynamics in patients with type 2 diabetes |
| topic | SGLT2 inhibitors dapagliflozin empagliflozin pharmacokinetics pharmacodynamics renal hemodynamics |
| url | https://www.mdpi.com/2075-4426/13/5/747 |
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