Linagliptin as add-on to empagliflozin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a two-part, randomized, placebo-controlled trial

Kohei Kaku, Masakazu Haneda, Yuko Tanaka, Ganghyuck Lee, Kosuke Shiki, Yuki Miyamoto, Fernando Solimando, Jisoo Lee, Christopher Lee, Jyothis George, Kohei Kaku, Masakazu Haneda, Yuko Tanaka, Ganghyuck Lee, Kosuke Shiki, Yuki Miyamoto, Fernando Solimando, Jisoo Lee, Christopher Lee, Jyothis George

Abstract

Aims: This two-part, double-blind, double-dummy, randomized, placebo-controlled trial (83 sites) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg and linagliptin (Lina) 5 mg fixed-dose combinations (FDCs) in Japanese patients with type 2 diabetes mellitus (T2DM) who were poorly controlled with Empa.

Materials and methods: Patients (previously drug-naive or using one oral antidiabetic drug for ≥ 12 weeks) entered an open-label stabilization period (16 weeks, Empa 10 mg [Part A] or Empa 25 mg [Part B]). Subsequently, they received Empa 10 mg plus placebo (Plc) for Empa/Lina10/5 (Empa/Plc 10/5; Part A) or Empa 25 mg plus Plc for Empa/Lina 25/5 (Empa/Plc 25/5; Part B) for 2 weeks. Patients with HbA1c 7.5-10.0% were randomized (1:1) to a 24-week regimen of once-daily Empa/Lina 10/5 (n = 107) or Empa/Plc 10/5 (n = 108) in Part A, or to Empa/Lina 25/5 (n = 116) or Empa/Plc 25/5 (n = 116) in Part B, with a 28-week extension period in Part B.

Results: Change from baseline in HbA1c at Week 24 was greater (P < 0.0001) with Empa/Lina than with Empa/Plc (primary outcome, Empa/Lina 10/5: -0.94 vs -0.12%; adjusted mean difference, -0.82%; Empa/Lina 25/5: -0.91 vs -0.33%; adjusted mean difference, -0.59%). Over 24- and 52-week periods, higher proportions of patients achieved HbA1c < 7.0% and greater decreases in fasting plasma glucose were observed with Empa/Lina compared with Empa/Plc. Empa/Lina was well tolerated, with no unexpected adverse events or diabetic ketoacidosis. One case of confirmed hypoglycaemia with Empa/Plc 25/5 was reported.

Conclusions: These results support Empa/Lina FDC as a potential option for Japanese patients with T2DM who require combination therapy. ClinicalTrials.gov NCT02489968.

Keywords: empagliflozin; glycaemic control; linagliptin; phase III study; randomized trial; type 2 diabetes.

Conflict of interest statement

Boehringer Ingelheim International GmbH and Nippon Boehringer Ingelheim Co. Ltd. were involved in the study design, data collection, data analysis and preparation of the manuscript. Y. T., G. L., K. S. and Y.M. are employees of Nippon Boehringer Ingelheim Co. Ltd. F. S., J. L. and J. G. are employees of Boehringer Ingelheim GmbH & Co. KG. C. L. is a former employee of Boehringer Ingelheim GmbH & Co. KG. K. K. has received research funding and/or honoraria for lectures from Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Kowa Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma, Ono Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Sanwa Kagaku Kenkyusho Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd. and Takeda Pharmaceutical Co. Ltd. M. H. has received research funding and/or honoraria for lectures from Astellas Pharma Inc., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Johnson & Johnson, Kissei Pharmaceutical Co. Ltd., Kowa Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma, Novo Nordisk Pharma, Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Sanofi, Shionogi & Co. Ltd., Taisho Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd. and Takeda Pharmaceutical Company Ltd.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Change in HbA1c. A, Change from baseline in HbA1c at Week 24 in patients receiving Empa/Plc 10/5 or Empa/Lina 10/5. B, Change in HbA1c over time during double‐blind period in patients receiving Empa/Plc 10/5 or Empa/Lina 10/5. C, Change from baseline in HbA1c at Week 24 in patients receiving Empa/Plc 25/5 or Empa/Lina 25/5. D, Change in HbA1c over time during double‐blind period in patients receiving Empa/Plc 25/5 or Empa/Lina 25/5. Baseline was defined as the last observation before the first intake of double‐blind randomized trial medication. Data are given as adjusted mean (±SE) from MMRM analyses in the full analysis set using observed cases. Abbreviations: CI, confidence intervals; Empa/Lina 10/5, empagliflozin 10 mg/linagliptin 5 mg fixed‐dose combination; Empa/Plc 10/5, empagliflozin 10 mg/placebo for linagliptin 5 mg fixed‐dose combination; Empa/Lina 25/5, empagliflozin 25 mg/linagliptin 5 mg fixed‐dose combination; Empa/Plc 25/5, empagliflozin 25 mg/placebo for linagliptin 5 mg fixed‐dose combination; HbA1c, glycated haemoglobin; MMRM, mixed model repeated measures; SE, standard error. aNumber of patients analysed during the 24‐week double‐blind treatment period
Figure 2
Figure 2
Patients who reached HbA1c P values were determined by logistic regression in the full analysis set with non‐completers considered failures. Abbreviations: CI, confidence intervals; Empa/Lina 10/5, empagliflozin 10 mg/linagliptin 5 mg fixed‐dose combination; Empa/Plc 10/5, empagliflozin 10 mg/placebo for linagliptin 5 mg fixed‐dose combination; Empa/Lina 25/5, empagliflozin 25 mg/linagliptin 5 mg fixed‐dose combination; Empa/Plc 25/5, empagliflozin 25 mg/placebo for linagliptin 5 mg fixed‐dose combination; HbA1c, glycated haemoglobin
Figure 3
Figure 3
Change in FPG. A, Change from baseline in FPG at Week 24 in patients receiving Empa/Plc 10/5 or Empa/Lina 10/5. B, Change in FPG over time during double‐blind period in patients receiving Empa/Plc 10/5 or Empa/Lina 10/5. C, Change from baseline in FPG at Week 24 in patients receiving Empa/Plc 25/5 or Empa/Lina 25/5. D, Change in FPG over time during double‐blind period in patients receiving Empa/Plc 25/5 or Empa/Lina 25/5. Baseline was defined as the last observation before the first intake of double‐blind randomized trial medication. Data are given as adjusted mean (±SE) from MMRM analyses in the full analysis set using observed cases. Abbreviations: CI, confidence intervals; Empa/Lina 10/5, empagliflozin 10 mg/linagliptin 5 mg fixed‐dose combination; Empa/Plc 10/5, empagliflozin 10 mg/placebo for linagliptin 5 mg fixed‐dose combination; Empa/Lina 25/5, empagliflozin 25 mg/linagliptin 5 mg fixed‐dose combination; Empa/Plc 25/5, empagliflozin 25 mg/placebo for linagliptin 5 mg fixed‐dose combination; MMRM, mixed model repeated measures; SE, standard error. aNumber of patients analysed during the 24‐week double‐blind treatment period

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