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

Jeroen V Koomen, Jasper Stevens, Hiddo J L Heerspink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

Aims: Dapagliflozin is a sodium–glucose co-transporter 2 inhibitor that has been developed as oral glucose lowering drug. The original dosefinding studies focused on optimal glycaemic effects. However, dapagliflozin also affects various cardiorenal risk markers and provides cardiorenal protection. To evaluate whether the currently registered doses of 5 and 10 mg are optimal for cardiorenal efficacy and safety, we characterized the relationship between dapagliflozin exposure and nonglycaemic cardiorenal risk markers as well as adverse events. Methods: Data were obtained from a pooled database of 13 24-week randomized controlled clinical trials of the clinical development programme 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]: 354–1061 ng h/mL), which translated to 71.2% (95% PI: 57.9–80.5%), 61.1% (95% PI: 58.0–64.8%), 91.3% (95% PI: 85.4–94.6%) and 25.7% (95% PI: 23.5–28.3%) of its estimated maximum effect for fasting plasma glucose, haematocrit, serum creatinine and urinary albumin–creatinine ratio, respectively. Conclusion: We demonstrate that doses higher than 10 mg could provide additional beneficial effects in haematocrit, 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
Pages (from-to)2192-2203
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Volume86
Issue number11
Early online date20-Apr-2020
DOIs
Publication statusPublished - Nov-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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