Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Pharmacokinetic Measurements
2.3. Pharmacodynamic Measurements
2.4. Estimation of Individual Plasma Exposure to Dapagliflozin and Empagliflozin
2.5. Evaluation of Association between Demographics and Plasma Exposure
2.6. Evaluation of the Association between Exposure and Response
3. Results
3.1. Dapagliflozin Exposure
3.2. Empagliflozin Exposure
3.3. Evaluation of Association between Demographics and Plasma Exposure
3.4. Evaluation of the Association between Exposure and Treatment Response
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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RED (n = 23) | RECOLAR (n = 20) | |
---|---|---|
Age (yr) | 63 ± 7 | 66 ± 6.3 |
Female sex, n (%) | 5 (22) | 2 (10) |
Body weight (kg) | 96.6 ± 18.3 | 97.9 ± 16.4 |
Body mass index (kg/m2) | 30.8 ± 4.0 | 31.1 ± 4.0 |
Systolic blood pressure (mmHg) | 137.9 ± 13.9 | 136.2 ± 9.7 † |
Hemoglobin (mmol/L) | 8.5 ± 0.7 | 8.5 ± 0.9 |
mGFR (mL/min) | 113.6 ± 20.0 | 108.4 ± 21.1 |
eGFR (CKD-EPI) (mL/min/1.73 m2) | 84.8 ± 13.7 | 87.4 ± 11.8 |
HbA1c (mmol/mol) | 57.6 ± 7.2 | 57.3 ± 9.9 |
Albumin (g/L) | 38.0 ± 2.5 | 37.5 ± 2.0 |
Alkaline phosphatase (U/L) | 76.6 ± 21.6 | NA |
Gamma-glutamyl transferase (U/L) | 33.0 [19.5, 53.0] | 31 [22.0, 50.5] |
Aspartate aminotransferase (U/L) | 21.0 [17.3, 26.0] | 21 [19.3, 28.3] † |
Alanine aminotransferase (U/L) | 30.6 ± 14.5 | NA |
Albuminuria (mg/24 h) | 11.0 [7.5, 16.9] | 12.1 [6.1, 22.0] |
UACR (mg/mmol) | 0.81 [0.51, 1.16] | 1.18 [0.66, 1.44] |
Diabetes duration (yr) | 9.7 ± 4.2 | 12.5 ± 5.7 |
Metformin, n (%) | 23 (100) | 20 (100) |
Sulfonylurea derivative, n (%) | 0 | 9 (45) |
RAS inhibitor, n (%) | 15 (65.2) | 0 (0.0) |
RED (n = 23) | RECOLAR (n = 20) | |||||||
---|---|---|---|---|---|---|---|---|
Dapagliflozin 10 mg | Empagliflozin 10 mg | |||||||
Univariate | Multivariable | Univariate | Multivariable | |||||
β (% Change) | p | β | p | β (% Change) | p | β | p | |
Age (yr) | −1.37 | 0.63 | 2.47 | 0.18 | ||||
Female sex | −57.72 | 0.06 | −49.89 | 0.13 | −13.43 | 0.71 | ||
Body weight (kg) | 0.55 | 0.62 | −1.68 | 0.01 | −1.39 | 0.008 | ||
eGFR (CKD-EPI) (mL/min/1.73 m2) | −1.05 | 0.47 | −2.60 | 0.003 | −1.41 | 0.06 | ||
mGFR (mL/min) | −0.31 | 0.77 | −0.73 | 0.18 | ||||
UACR (%) | −0.025 | 0.89 | 0.21 | 0.04 | ||||
HbA1c (mmol/mol) | −0.57 † | 0.73 | 0.94 | 0.44 | ||||
Serum albumin (g/L) | −6.41 | 0.40 | 11.64 | 0.052 | 10.36 | 0.002 | ||
Alkaline phosphatase (U/L) | −1.14 | 0.21 | NA | |||||
Gamma-glutamyl transferase (%) | −0.44 † | 0.049 | 0.015 †,‡ | 0.93 | ||||
Aspartate aminotransferase (%) | −0.56 † | 0.36 | 0.35 † | 0.30 | ||||
Alanine aminotransferase (U/L) | −2.43 | 0.06 | −1.94 | 0.13 | NA |
RED Study (n = 23) | RECOLAR Study (n = 20) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Dapagliflozin 10 mg | Empagliflozin 10 mg | |||||||||||
Baseline | End of Treatment | Change | p | β per Doubling AUC | p | Baseline | End of Treatment | Change | p | β per Doubling AUC | p | |
Body weight (kg) | 96.6 ± 18.3 | 93.6 ± 17.3 | −3.0 (−4.0, −2.0) | <0.001 | −0.29 (−0.39, −0.19) | <0.001 | 97.9 ± 17.1 | 96.6 ± 17.1 | −1.3 (−2.0, −0.6) | 0.002 | −0.13 (−0.20, −0.06) | 0.002 |
SBP (mmHg) | 137.9 ± 13.9 | 129.8 ± 10.6 | −8.1 (−12.9, −3.2) | 0.003 | −0.80 (−1.27, −0.34) | 0.002 | 136.2 ± 9.7 † | 130.3 ± 14.9 ‡ | −6.1 (−12.3, 0.04) | 0.06 | −0.65 (−1.26, −0.03) | 0.045 |
HbA1c (mmol/mol) | 57.6 ± 7.2 | 52.3 ± 5.9 | −5.3 (−7.5, −3.0) | <0.001 | −0.51 (−0.73, −0.29) | <0.001 | NA | NA | NA | NA | NA | NA |
FPG (mmol/L) | 9.20 ± 1.54 | 8.20 ± 1.55 | −1.00 (−1.5, −0.5) | <0.001 | −0.09 (−0.14, −0.04) | 0.002 | 9.4 ± 2.6 | 7.4 ± 1.2 ‡ | −1.6 (−2.2, −1.0) | <0.001 | −0.16 (−0.22, −0.01) | <0.001 |
UGE (mmol/24 h) | 7.6 [0.8–39.7] | 480 [391–703] | 409 (170, 974) § | <0.001 | 48.69 (35.88, 62.71) | <0.001 | 6.1 [0.8, 60.9] | 517 [331, 719] ‡ | 477 (212, 1017) § | <0.001 | 48.05 (36.82, 60.20) | <0.001 |
mGFR (mL/min) ¶ | 109.4 ± 27.8 | 100.1 ± 30.4 | −9.3 (−16.5, −2.0) | 0.01 | −0.83 (−1.53, −0.12) | 0.03 | 108.4 ± 21.1 | 100.5 ± 14.8 | −7.9 (−12.2, −3.6) | 0.002 | −0.78 (−1.22, −0.33) | 0.002 |
ERPF (mL/min) ¶ | 506.7 ± 124.7 | 474.3 ± 122.6 | −32.3 (−60.4, −4.3) | 0.03 | −2.69 (−5.46, 0.08) | 0.06 | 623.2 ± 169.6 | 634.7 ± 164.5 | 11.5 (−60.9, 83.9) | 0.75 | 0.69 (−6.65, 8.03) | 0.85 |
FF (%) | 21.8 ± 2.9 | 20.9 ± 3.3 | −1.0 (−1.9, −0.04) | 0.04 | −0.09 (−0.18, −0.005) | 0.04 | 18.2 ± 4.1 | 16.7 ± 4.0 | −1.5 (−3.5, 0.6) | 0.16 | −0.13 (−0.34, 0.08) | 0.22 |
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van der Hoek, S.; Koomen, J.V.; van Bommel, E.J.M.; Mosterd, C.M.; Scholtes, R.A.; Hesp, A.C.; Stevens, J.; van Raalte, D.H.; Heerspink, H.J.L. Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes. J. Pers. Med. 2023, 13, 747. https://doi.org/10.3390/jpm13050747
van der Hoek S, Koomen JV, van Bommel EJM, Mosterd CM, Scholtes RA, Hesp AC, Stevens J, van Raalte DH, Heerspink HJL. 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. 2023; 13(5):747. https://doi.org/10.3390/jpm13050747
Chicago/Turabian Stylevan der Hoek, Sjoukje, Jeroen V. Koomen, Erik J. M. van Bommel, Charlotte M. Mosterd, Rosalie A. Scholtes, Anne C. Hesp, Jasper Stevens, Daniel H. van Raalte, and Hiddo J. L. Heerspink. 2023. "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 13, no. 5: 747. https://doi.org/10.3390/jpm13050747