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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

This randomized, double‐blind, phase III study evaluated the efficacy and safety of once‐daily treatment with alogliptin (25 mg once daily), alone or with metformin hydrochloride (500 mg 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 (week 24). The least squares (LS) mean (standard error) change in HbA1c from baseline to the 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.

[The copyright line for this article has been changed on 31 August 2017, after original online publication].
This randomized, double-blind, phase III study evaluated the efficacy and safety of once-daily treatment with alogliptin (25 mg once daily), alone or with metformin hydrochloride (500 mg 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 (week 24). The least squares (LS) mean (standard error) change in HbA1c from baseline to the 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.

| INTRODUCTION
Alogliptin benzoate is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor. As a result of the inhibition of DPP-4 activity, the level of glucagon-like peptide-1 (GLP-1) increases, stimulating glucosedependent insulin secretion from pancreatic β cells, thereby improving glucose homeostasis. 1 Metformin is a biguanide antihyperglycaemic agent that suppresses the release of glucose from the liver and improves insulin sensitivity in peripheral tissues. Additionally, it suppresses intestinal absorption of glucose. These pharmacological actions produce a blood glucose-lowering effect.
Combination therapy of alogliptin and metformin is a reasonable treatment approach because these compounds have different mechanisms of action that improve glucose metabolism (ie, alogliptin stimulates glucose-dependent insulin secretion and metformin improves insulin sensitivity in peripheral tissues). Indeed, the effectiveness of this combination therapy has been reported in Japanese patients with type 2 diabetes whose blood glucose was not adequately controlled with metformin alone 2 ; however, the effectiveness of alogliptin and metformin combination therapy has not been confirmed in Japanese patients with type 2 diabetes whose blood glucose is inadequately controlled with alogliptin treatment alone.
In general, the recommendation in Japan is to dose with metformin two or three times a day. Increasing the frequency of dosing is considered to have a negative impact on treatment adherence in patients with chronic disease including type 2 diabetes, 3 therefore, once-daily dosing of metformin with alogliptin would be expected to improve adherence. It has not yet been established, however, whether or not different co-administration methods of metformin (once daily or twice daily) with alogliptin (once daily) affect treatment efficacy and safety in the Japanese population.
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 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 who have inadequate glycaemic control, despite treatment with once-daily alogliptin 25 mg in addition to diet and exercise therapy.

| METHODS
This was a phase III, randomized, double-blind, parallel-group, multicentre study, conducted at 34 sites in Japan. The study was con- Patients aged ≥20 to <75 years were eligible for enrolment in the 12-week screening period if they were diagnosed with type 2 diabetes and had no hepatic, cardiovascular or pulmonary impairment.
On completion of the screening period, patients were randomized to the treatment period if they met the following criteria: HbA1c level ≥6.9% and <10.5% at week −4 (8 weeks after the start of the screening period); no more than 10% difference in HbA1c level between week −8 and −4; and on a stable diet and exercise therapy with alogliptin treatment (25 mg/d administered after breakfast) throughout the screening period.
Patients who used antidiabetic agents other than alogliptin during the screening period or had evident renal impairment were excluded before the treatment period.
Patient demographic and clinical characteristics for the randomized population were similar between study groups (Table S1, Appendix S1). Mean values of HbA1c at the beginning (week -12) and end (week 0) of the screening period for the 374 patients who entered the treatment period are shown in Table S2.

| Efficacy
The primary analysis showed that the LS mean change (s.e.) in HbA1c from baseline to the end of treatment period (week 24) was 0.16  Regarding other endpoints, the mean changes from baseline in fasting insulin, fasting glucagon, homeostatic model assessment of insulin resistance and body weight through to the end of the treatment period (week 24) were similar among the treatment groups ( Table 1).
The remaining endpoint, mean change in homeostatic model assessment of β-cell function, was greater with alogliptin/metformin once daily than alogliptin alone and similar between alogliptin/metformin once daily and alogliptin/metformin twice daily (Table 1).

| Safety
The overall frequency of adverse events (AEs) was similar among all treatment groups, with incidences of 57.7% (41/71) with alogliptin alone, 50.7% (77/152) with alogliptin/metformin once daily, and 52.3% (79/151) with alogliptin/metformin twice daily (Table S3, Appendix S1). Across all treatment groups, nasopharyngitis was the most common AE and the only AE with an incidence ≥5% in all 3 groups (11.3%, 14.5% and 12.6% with alogliptin alone, alogliptin/ metformin once daily and alogliptin/metformin twice daily, respectively). No patients developed serious hypoglycaemia or acute pancreatitis, both of which are AEs of special interest for this combination therapy.

| DISCUSSION
This phase III, randomized trial showed that alogliptin/metformin once daily is superior to alogliptin alone and non-inferior to alogliptin/metformin twice daily with regard to reducing HbA1c over a period of 24 weeks in Japanese patients with type 2 diabetes.
In the once-daily alogliptin/metformin group there was a greater reduction in HbA1c and FPG levels, and a greater proportion of patients achieving HbA1c <7.0% compared with alogliptin alone. Alogliptin/metfomin once daily also led to a similar reduction in HbA1c and proportion of patients achieving HbA1c <7.0% at 24 weeks as with alogliptin/metformin twice daily Although a reduction in FPG at week 24 with alogliptin/metformin twice daily was higher than that achieved with alogliptin/ No serious hypoglycaemia or acute pancreatitis were reported in any treatment group and all treatments were generally well tolerated, with a similar overall frequency of AEs among the treatment groups.
Because alogliptin/metformin once daily led to a similar HbA1c reduction to alogliptin/metformin twice daily and was well tolerated in the present study, this once-daily treatment regimen should be beneficial for patients with type 2 diabetes who usually take several medications including antidiabetic drugs multiple times a day.
Decreasing medication frequency within a day has a remarkable impact on improving medication adherence in patients with type 2 diabetes. 5 Indeed, patients with chronic disease, including type 2 diabetes, have a greater adherence to once-daily treatment than to more frequent dosing schedules. 3 Furthermore, improving medication adherence is also associated with better glycaemic control 6,7 ; combination therapy with alogliptin 25 mg once daily and metformin 500 mg once daily, therefore, would be expected not only to improve medication adherence but also to provide better glycaemic control in patients currently treated with multiple doses of alogliptin and metformin within a day.
The main limitation of the present study is that patients aged <20 or ≥75 years, or with evident liver or renal impairment were excluded and, therefore, the effectiveness of the combination therapy was not confirmed in these patients. In addition, this study was conducted in Japanese patients with type 2 diabetes within a treatment environment in Japan, therefore expansion of these findings to other populations needs careful consideration.
In conclusion, treatment with alogliptin/metformin once daily was superior in efficacy to alogliptin alone and non-inferior to alogliptin/metformin twice daily. This once-daily combination was safe and well tolerated in Japanese patients with type 2 diabetes who had inadequate glycaemic control with alogliptin 25 mg monotherapy.

Author contributions
K.K., S.S. and M.K. contributed to the design of the study. K.K., Y.N. and Y.K. contributed to study conduct/data collection. S.S. and M.K.
contributed to data analysis. All authors contributed to writing the manuscript.