Triple fixed-dose combination empagliflozin, linagliptin, and metformin for patients with type 2 diabetes

Ildiko Lingvay, Nadine Beetz, Regina Sennewald, Annette Schuler-Metz, Julia Bertulis, Christina Loley, Benjamin Lang, Caroline Lippert, Jisoo Lee, Linda Shapiro Manning, Derek Terada

Research output: Contribution to journalArticle

Abstract

Objectives: Fixed-dose combination (FDC) therapy can improve outcomes in type 2 diabetes (T2D). We evaluated the bioequivalence of 2 doses of an FDC of extended-release metformin (metformin XR), empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and linagliptin, a dipeptidyl peptidase-4 inhibitor, versus corresponding free tablet combinations. Methods: Two randomized, open-label, two-way crossover studies in healthy adults compared: 2 FDC tablets of empagliflozin 5 mg/linagliptin 2.5 mg/metformin XR 1000 mg (Study 1; N = 30), 1 FDC tablet of empagliflozin 25 mg/linagliptin 5 mg/metformin XR 1000 mg (Study 2; N = 30) versus corresponding dose of free combinations. Subjects received study medication under fed conditions; washout was ≥35 days between treatments. Primary endpoints: area under the plasma concentration–time curve (AUC) from time 0 to last quantifiable data point for empagliflozin and metformin; AUC from time 0 to 72 hours for linagliptin, and peak plasma concentration (Cmax) for empagliflozin, linagliptin, and metformin. Bioequivalence was defined as adjusted geometric mean ratios (FDC: free combination) and two-sided 90% confidence intervals (CIs) of AUC and Cmax for each component within 80.00–125.00%. Results: Study 1: 27/29 and 28/30 treated participants were included in the pharmacokinetic analysis for the FDC and free combination periods, respectively. Study 2: 29/29 treated participants were included in the pharmacokinetic analysis for both periods. The adjusted geometric mean ratios of FDCs to their respective free tablet combinations and two-sided 90% CIs were all within the predefined range. The shapes of the mean plasma concentration–time profile of empagliflozin, linagliptin, and metformin XR were similar for subjects in the FDC and free combination groups in both studies. No serious adverse events were reported. Conclusion: The evaluated doses of empagliflozin/linagliptin/metformin XR FDC tablets were bioequivalent to the corresponding free combinations. Based on these two bioequivalence studies and existing phase 3 data, the FDA has recently approved this triple FDC to improve glycemic control in adults with T2D.

Original languageEnglish (US)
Pages (from-to)337-345
Number of pages9
JournalPostgraduate medicine
Volume132
Issue number4
DOIs
StatePublished - May 18 2020

Keywords

  • Linagliptin
  • bioequivalence
  • empagliflozin
  • fixed-dose combination
  • metformin
  • pharmacokinetics
  • type 2 diabetes

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Lingvay, I., Beetz, N., Sennewald, R., Schuler-Metz, A., Bertulis, J., Loley, C., Lang, B., Lippert, C., Lee, J., Manning, L. S., & Terada, D. (2020). Triple fixed-dose combination empagliflozin, linagliptin, and metformin for patients with type 2 diabetes. Postgraduate medicine, 132(4), 337-345. https://doi.org/10.1080/00325481.2020.1750228