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Randomized Controlled Trial
. 2020 Jun;22(6):916-921.
doi: 10.1111/dom.13976. Epub 2020 Feb 17.

Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers

Marjolein Y A M Kroonen  1 , Jeroen V Koomen  1 , Sergei I Petrykiv  2 , Gozewijn D Laverman  3 , Hiddo J L Heerspink  1 , Jasper Stevens
Affiliations
Randomized Controlled Trial

Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers

Marjolein Y A M Kroonen et al. Diabetes Obes Metab. 2020 Jun.

Abstract

Aims: To quantitate the consistency of an individual's plasma exposure to dapagliflozin upon re-exposure, and to investigate whether the individual's systemic exposure to dapagliflozin explains inter-individual variation in response to dapagliflozin with regard to multiple renal risk markers.

Methods: Data were used from a crossover randomized clinical trial that assessed the albuminuria-lowering effect of dapagliflozin in 33 people with type 2 diabetes and elevated albuminuria. Fifteen participants were exposed twice to dapagliflozin. Trough plasma concentrations of dapagliflozin were measured for each participant at steady state. Dapagliflozin plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and pharmacokinetic characteristics were simulated based on a population pharmacokinetic model. Linear mixed-effects models were used to quantify the exposure-response relationships.

Results: The median plasma concentration after first and second exposure to dapagliflozin was 5.3 ng/mL vs 4.6 ng/mL, respectively (P = 0.78). Lin's concordance correlation coefficient between occasions was 0.73 (P < 0.0021). Every 100 ng.h/mL increment in area under the dapagliflozin plasma concentration curve was associated with a decrease in log-transformed urinary albumin:creatinine ratio (β = -5.9, P < 0.01), body weight (β = -0.3, P < 0.01) and estimated glomerular filtration rate (β = -0.7, P = 0.01) and an increase in urinary glucose excretion (β = 17.0, P < 0.001).

Conclusion: An individual's exposure to dapagliflozin is consistent upon re-exposure and correlates with pharmacodynamic response in renal risk markers.

Keywords: SGLT2; dapagliflozin; diabetic nephropathy; pharmacodynamics; pharmacokinetics.

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Conflict of interest statement

M.Y.A.M.K., J.S., S.P. and J.V.K. have no conflict of interest to declare. H.J.L.H. is consultant to Abbvie, AstraZeneca, Boehringer Ingelheim, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi Tanabe. He has received research support from AstraZeneca, Abbvie, Boehringer Ingelheim and Janssen. G.D.L. has received lecture fees from Sanofi, Astra Zeneca and Jansen, and has served as a consultant for Abbvie, Sanofi, Novo Nordisk, Astra Zeneca, Boehringer Ingelheim and MSD.

Figures

Figure 1
Figure 1
Consistency in exposure to dapagliflozin between occasions (left) and between occasions per individual (right)
See this image and copyright information in PMC

References

    1. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther. 2009;85(5):513‐519. - PubMed
    1. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347‐357. - PubMed
    1. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: An analysis from the DECLARE‐TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7(8):606‐617. - PubMed
    1. Petrykiv SI, Laverman GD, de Zeeuw D, Heerspink HJL. The albuminuria‐lowering response to dapagliflozin is variable and reproducible among individual patients. Diabetes Obes Metab. 2017;19(10):1363‐1370. - PubMed
    1. Heerspink HJL, Sjostrom CD, Inzucchi SE, et al. Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers. Diabetes Obes Metab. 2019;21(3):720‐725. - PMC - PubMed

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