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Exposure-response relationships of dapagliflozin on cardiorenal risk markers and adverse events: A pooled analysis of 13 phase II/III trials

Koomen, J. V., Stevens, J. & Heerspink, H. J. L., 10-May-2020, In : British Journal of Clinical Pharmacology. 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

AIMS: Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor which has been developed as oral glucose lowering drug. The original dose finding studies focused on optimal glycaemic effects. However, dapagliflozin also affects various cardio-renal risk markers and provides cardio-renal protection. In order to evaluate whether the currently registered doses of 5 and 10 mg are optimal for cardio-renal efficacy and safety, we characterized the relationship between dapagliflozin exposure and non-glycaemic cardio-renal risk markers as well as adverse events.

METHODS: Data were obtained from a pooled database of thirteen 24-week randomized controlled clinical trials of the clinical development program of dapagliflozin. The exposure-response relationship was quantified using population pharmacodynamic- and repeated time-to-event models.

RESULTS: A dose of 10 mg dapagliflozin resulted in an average individual exposure of 638 ng.h/mL (95% Prediction Interval (PI): 354 to 1061 ng.h/mL), which translated in 71.2% (95% PI: 57.9 to 80.5%), 61.1 % (95% PI: 58.0 to 64.8%), 91.3 % (95% PI: 85.4 to 94.6%) and 25.7% (95% PI: 23.5 to 28.3%) of its estimated maximum effect for fasting plasma glucose, haematocrit, serum creatinine and urinary albumin-creatinine ratio, respectively.

CONCLUSIONS: We demonstrate that doses higher than 10 mg could provide additional beneficial effects in hematocrit, systolic blood pressure, urinary albumin creatinine ratio and uric acid, without obvious increases in the rate of adverse events. These results raise the question whether future outcome studies assessing the benefits of higher than currently registered dapagliflozin doses are merited.

Original languageEnglish
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Early online date20-Apr-2020
Publication statusPublished - 10-May-2020

    Keywords

  • albuminuria, cardiovascular risk markers, dapagliflozin, exposure-response, pharmacodynamics, SGLT-2 inhibition, type 2 diabetes, GLYCEMIC CONTROL, SELECTIVE INHIBITOR, SGLT2 INHIBITOR, TYPE-2, PHARMACODYNAMICS, PHARMACOKINETICS, RENOPROTECTION, EMPAGLIFLOZIN

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