Received: 2 September 2016
Revised: 14 November 2016
Accepted: 24 November 2016
DOI 10.1111/dom.12837
BRIEF REPORT
Randomized, double-blind, phase III study to evaluate the efficacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in Japanese patients with type 2 diabetes Kohei Kaku1 | Shuuji Sumino2 | Masafumi Katou2 | Yuya Nishiyama2 | Yoshinobu Kinugawa2 1
Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan
This randomized, double-blind, phase III study evaluated the efficacy and safety of once-daily
2
Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan
treatment with alogliptin (25 mg once daily), alone or with metformin hydrochloride (500 mg
Correspondence Dr. Kohei Kaku, Department of Internal Medicine, Kawasaki Medical School, 577, Matsushima, Kurashiki-shi, Okayama 701-0192, Japan. Email:
[email protected]
(week 24). The least squares (LS) mean (standard error) change in HbA1c from baseline to the
Funding information This study was sponsored by Takeda Pharmaceutical Company Ltd. Medical writing support was provided by BlueMomentum, a division of Ashfield Healthcare Communications (a UDG Healthcare plc company), and was funded by Takeda Pharmaceutical Company Ltd. [The copyright line for this article has been changed on 31 August 2017, after original online publication].
once daily or 250 mg twice daily), in Japanese patients with type 2 diabetes. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to the end of treatment end of treatment (week 24) was 0.16 (0.072)% in alogliptin alone, −0.49 (0.049)% in alogliptin/ metformin once daily, and −0.60 (0.049)% in alogliptin/metformin twice daily. The LS mean difference in HbA1c change from baseline between alogliptin/metformin once daily and alogliptin alone (alogliptin/metformin once daily minus alogliptin alone) was −0.65% (95% confidence interval [CI] −0.821, −0.480) and between alogliptin/metformin once daily and twice daily (once daily minus twice daily) was 0.11% (95% CI −0.026, 0.247). The overall frequency of adverse events was similar among the groups. This study showed that the efficacy of alogliptin/metformin once daily was superior to alogliptin alone and non-inferior to alogliptin/metformin twice daily, and that alogliptin/metformin once daily was safe and well tolerated in Japanese patients with type 2 diabetes. KEYWORDS
antidiabetic drug, DPP-IV inhibitor, metformin, phase III study, randomized trial, type 2 diabetes
1 | I N T RO D UC T I O N
Combination therapy of alogliptin and metformin is a reasonable treatment approach because these compounds have different
Alogliptin benzoate is a highly selective dipeptidyl peptidase-4 (DPP-
mechanisms of action that improve glucose metabolism (ie, aloglip-
4) inhibitor. As a result of the inhibition of DPP-4 activity, the level of
tin stimulates glucose-dependent insulin secretion and metformin
glucagon-like peptide-1 (GLP-1) increases, stimulating glucose-
improves insulin sensitivity in peripheral tissues). Indeed, the effec-
dependent insulin secretion from pancreatic β cells, thereby improv-
tiveness of this combination therapy has been reported in Japa-
ing glucose homeostasis.1
nese patients with type 2 diabetes whose blood glucose was not
Metformin is a biguanide antihyperglycaemic agent that sup-
adequately controlled with metformin alone2; however, the effec-
presses the release of glucose from the liver and improves insulin
tiveness of alogliptin and metformin combination therapy has not
sensitivity in peripheral tissues. Additionally, it suppresses intestinal
been confirmed in Japanese patients with type 2 diabetes whose
absorption of glucose. These pharmacological actions produce a
blood glucose is inadequately controlled with alogliptin treatment
blood glucose-lowering effect.
alone.
Diabetes Obes Metab 2017; 19(3):463–467
wileyonlinelibrary.com/journal/dom
© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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KAKU ET AL.
In general, the recommendation in Japan is to dose with metfor-
(s.e.) values and 2-sided 95% confidence intervals (CIs) of the LS
min two or three times a day. Increasing the frequency of dosing is
means were calculated for each treatment group. Last observation
considered to have a negative impact on treatment adherence in
carried forward imputation was used for missing values. A secondary
patients with chronic disease including type 2 diabetes,3 therefore,
analysis of the primary endpoint was performed without correction
once-daily dosing of metformin with alogliptin would be expected to
for baseline HbA1c level. The superiority of alogliptin/metformin
improve adherence. It has not yet been established, however,
once daily over alogliptin alone and non-inferiority of alogliptin/met-
whether or not different co-administration methods of metformin
formin once daily to alogliptin/metformin twice daily were also
(once daily or twice daily) with alogliptin (once daily) affect treatment
assessed. Secondary endpoints included HbA1c, fasting plasma glu-
efficacy and safety in the Japanese population.
cose (FPG) and assessment of safety.
The aim of the present study was to evaluate the efficacy and safety of a 24-week treatment with metformin 500 mg once daily added to alogliptin 25 mg once daily compared with metformin
3 | RE SU LT S
500 mg twice daily added to alogliptin 25 mg once daily and alogliptin 25 mg once daily alone in Japanese patients with type 2 diabetes
Of 524 patients undergoing screening, 374 were randomly assigned
who have inadequate glycaemic control, despite treatment with
to treatment with alogliptin alone (n = 71), alogliptin/metformin once
once-daily alogliptin 25 mg in addition to diet and exercise therapy.
daily (n = 152) or alogliptin/metformin twice daily (n = 151), and were included in the efficacy and safety populations (Figure S1). Patient demographic and clinical characteristics for the randomized
2 | METHODS
population were similar between study groups (Table S1, Appendix S1). Mean values of HbA1c at the beginning (week –12) and end
This was a phase III, randomized, double-blind, parallel-group, multi-
(week 0) of the screening period for the 374 patients who entered
centre study, conducted at 34 sites in Japan. The study was con-
the treatment period are shown in Table S2.
ducted in compliance with the protocol and ethical principles of the Declaration of Helsinki and the International Conference on Harmonisation Tripartite Guidelines for Good Clinical Practice. The study
3.1 | Efficacy
included a 12-week screening period (visits every 4 weeks, including
The primary analysis showed that the LS mean change (s.e.) in HbA1c
evaluations of eligibility, glycated haemoglobin [HbA1c] and safety)
from baseline to the end of treatment period (week 24) was 0.16
and a 24-week treatment period.
(0.072)% with alogliptin alone, −0.49 (0.049)% with alogliptin/metfor-
Patients aged ≥20 to
