TY - JOUR
T1 - Triple fixed-dose combination empagliflozin, linagliptin, and metformin for patients with type 2 diabetes
AU - Lingvay, Ildiko
AU - Beetz, Nadine
AU - Sennewald, Regina
AU - Schuler-Metz, Annette
AU - Bertulis, Julia
AU - Loley, Christina
AU - Lang, Benjamin
AU - Lippert, Caroline
AU - Lee, Jisoo
AU - Manning, Linda Shapiro
AU - Terada, Derek
N1 - Funding Information:
This article was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and approved the ?nal version that reflects the authors? interpretations and conclusions. The authors received no direct compensation related to the development of the manuscript. Writing support was provided by Jennifer Garrett, MBBS, of Elevate Scientific Solutions, which was contracted and compensated by BIPI for this service. The authors would like to thank Jennifer Garrett of Elevate Scientific Solutions for providing writing support which was contracted and compensated by BIPI.
Publisher Copyright:
© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/5/18
Y1 - 2020/5/18
N2 - 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.
AB - 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.
KW - Linagliptin
KW - bioequivalence
KW - empagliflozin
KW - fixed-dose combination
KW - metformin
KW - pharmacokinetics
KW - type 2 diabetes
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U2 - 10.1080/00325481.2020.1750228
DO - 10.1080/00325481.2020.1750228
M3 - Article
C2 - 32366156
AN - SCOPUS:85084302599
SN - 0032-5481
VL - 132
SP - 337
EP - 345
JO - Postgraduate Medicine
JF - Postgraduate Medicine
IS - 4
ER -