Received: 12 October 2016
Revised: 20 December 2016
Accepted: 29 December 2016
DOI 10.1111/dom.12875
BRIEF REPORT
Efficacy and safety of fixed-dose combination therapy, alogliptin plus metformin, in Asian patients with type 2 diabetes: A phase 3 trial Linong Ji MD1
| Ling Li MD2 | Jian Kuang MD3 | Tao Yang MD4 |
Dong-Jun Kim MD, PhD5 | Azidah A. Kadir MD6 | Chien-Ning Huang MD7 | Douglas Lee MD8 1 Department of Endocrinology, Peking University People’s Hospital, Beijing, China
This study evaluated the efficacy and safety of 26 weeks of twice-daily (BID) alogliptin + met-
2
formin fixed-dose combination (FDC) therapy in Asian patients with type 2 diabetes. Patients
Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China 3 Department of Endocrinology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China 4
Department of Endocrinology, Jiangsu Province Hospital, Nanjing, China 5
Department of Internal Medicine, Ilsan Paik Hospital, Inje University, Goyang, Korea 6
Department of Family Medicine, Universiti Sains Malaysia, Kubang Kerian, Malaysia 7
Department of Endocrinology and Metabolism, Chung Shang Medical University Hospital, Taichung City, Taiwan, China
aged 18 to 75 years with hemoglobin A1c (HbA1c) of 7.5% to 10.0% after ≥2 months of diet and exercise and a 4-week placebo run-in were enrolled. Eligible patients were randomized (1:1:1:1) to placebo, alogliptin 12.5 mg BID, metformin 500 mg BID or alogliptin 12.5 mg plus metformin 500 mg FDC BID. The primary endpoint was change in HbA1c from baseline to end of treatment (Week 26). In total, 647 patients were randomized. The least-squares mean change in HbA1c from baseline to Week 26 was −0.19% with placebo, −0.86% with alogliptin, −1.04% with metformin and −1.53% with alogliptin + metformin FDC. Alogliptin + metformin FDC was significantly more effective (P < .0001) in lowering HbA1c than either alogliptin or metformin alone. The safety profile of alogliptin + metformin FDC was similar to that of the individual components alogliptin and metformin. The study demonstrated that treatment with alogliptin + metformin FDC BID resulted in better glycaemic control than either monotherapy and was well tolerated in Asian patients with type 2 diabetes.
8
Takeda Development Centre Europe, Ltd, London, United Kingdom Correspondence Linong Ji, Department of Endocrinology, People’s Hospital of Peking University, Xicheng District, Beijing 100044, China. Email:
[email protected] KEYWORDS
alogliptin, DPP-IV inhibitor, glycaemic control, metformin, type 2 diabetes
Funding information This study was sponsored by Takeda Pharmaceutical Company Limited.
1 | I N T RO D UC T I O N
These adverse events (AEs) often negatively affect treatment adherence and/or long-term use. Therefore, there is a need for effective,
The prevalence of diabetes mellitus and suboptimal achievement of
long-term glycaemic control regimens that can be administered safely.
glycaemic control is increasing in Asian populations.1–3 Evidence
Alogliptin is a potent, highly selective, orally available dipeptidyl
shows that there may be differences in the pathophysiology of type
peptidase-4 (DPP-4) inhibitor. Since 2013, alogliptin has been availa-
2 diabetes across ethnic subgroups, with Asian vs non-Asian patients
ble in the USA and the European Union as monotherapy and as a
exhibiting a propensity for lower body mass index, a higher proportion
fixed-dose combination (FDC) with metformin. The FDC formulation
4,5
Although
was developed to improve convenience and, ultimately, patient
pharmacologic agents are available to patients with type 2 diabetes
adherence. Mechanistically, inhibition of DPP-4 activity leads to an
who fail to achieve sufficient glycaemic control through diet and exer-
increase in hormone glucagon-like peptide 1 levels, which in turn sti-
cise, many of these agents may cause hypoglycaemia or weight gain.6,7
mulates glucose-dependent insulin secretion from pancreatic β-cells.8
of visceral fat and predominant insulin secretory defects.
754
© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
wileyonlinelibrary.com/journal/dom
Diabetes Obes Metab. 2017;19:754–758.
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755
JI ET AL.
This mechanism of achieving glucose homeostasis is distinct from
Changes from baseline in HbA1c and FPG (least-squares
that of metformin, which is a biguanide that suppresses hepatic glu-
[LS] means) were summarized at each time point using descriptive
cose release and also induces weight loss via reduced calorie intake.9
statistics. The incidences of hyperglycaemic rescue (for FPG ≥ 275
Given the complementary mechanisms of action of alogliptin and
mg/dL [≥15.27 mmol/L] before Week 12 or HbA1c ≥ 8.5% and
metformin, and the potential for incrementally improving glycaemic
≤0.5% reduction in HbA1c between Week 12 and the final visit),
control without exacerbating safety events, there has been interest in
marked hyperglycaemia (FPG > 200 mg/dL [11.1 mmol/L]) and clini-
the use of this FDC in patients with type 2 diabetes. Phase 3 clinical
cal response were also summarized (frequency and percentage) by
trials in Asian patients have shown that concomitant administration
treatment group. Continuous secondary endpoints were analysed
of alogliptin and metformin is effective and has a safety profile similar
using an appropriate statistical model with the Model 1 variables. The
10,11
The current phase 3 study
analysis was carried out using a Cox proportional hazard model, with
was designed to evaluate the efficacy and safety of alogliptin
treatment as an effect, country as a stratification factor and baseline
12.5 mg plus metformin 500 mg FDC BID vs alogliptin or metformin
HbA1c as a covariate. For each efficacy variable, the corresponding
alone in Asian patients with type 2 diabetes who are inadequately
baseline value for that variable was modeled as a covariate in place
controlled with diet and exercise.
of baseline HbA1c. All secondary variables were analysed at the 2-
to that of the individual components.
sided significance level of 5%. Treatment-emergent AEs (including all events, irrespective of
2 | MATERIALS AND METHODS
treatment relationship and treatment-related AEs), clinical laboratory changes and hypoglycaemic episodes were summarized.
This was a phase 3, randomized, double-blind, placebo-controlled, multicentre study that was conducted at 59 sites in China, Malaysia, Republic of Korea (South Korea) and Taiwan. It was conducted in
3 | RE SU LT S
compliance with the study protocol, the ethical principles originating in the Declaration of Helsinki and the International Conference on
Of 1258 screened patients, 647 were randomized to placebo
Harmonisation of Tripartite Guidelines for Good Clinical Practice. All
(n = 163), alogliptin (n = 163), metformin (n = 162) or alogliptin +
patients
metformin FDC (n = 159) and were included in the efficacy and
provided
written
informed
consent
prior
to
study
procedures.
safety populations (Figure S1, File S1). Demographic and clinical char-
Patients aged 18 to 75 years were eligible if they had an histori-
acteristics for the randomized population were similar between study
cal diagnosis of type 2 diabetes for which glycaemic control was inad-
groups (Table S1, File S1). Of the 647 treated patients, 511 (n = 104,
equate (ie, HbA1c of 7.5%-10.0% after at least 2 months of diet and
placebo; n = 126, alogliptin; n = 135, metformin; n = 146, alogliptin +
exercise prior to the screening period). Key exclusion criteria included
metformin FDC) completed the study. The most common reason for
a significant history of hepatic and cardiovascular disease.
study discontinuation was lack of efficacy (n = 86 [64.2%] all groups).
The study consisted of 4 periods: screening (≤2 weeks), placebo run-in (4 weeks), treatment (26 weeks) and follow-up (2 weeks). Eligible patients had HbA1c of 7.5% to 10.0% and fasting plasma glucose
3.1 | Efficacy
(FPG) ≤ 275 mg/dL (15.27 mmol/L) at the Week −1 visit of the pla-
The LS mean change in HbA1c from baseline to end of treatment
cebo run-in (1 week prior to the treatment phase). After stratifying
(Week 26) was −0.19% with placebo, −0.86% with alogliptin, −1.04%
patients by screening HbA1c (