Effect of combination therapy with repaglinide and metformin hydrochloride on glycemic control in Japanese patients with type 2 diabetes mellitus Ryuzo Kawamori1, Kohei Kaku2, Toshiaki Hanafusa3, Tatsuya Oikawa4*, Shigeru Kageyama5, Nigishi Hotta6 1
Sportology Center, Juntendo University Graduate School of Medicine, Supported by High Technology Research Center, 5Division of Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine, Tokyo, 2Department of Medicine, Kawasaki Medical School, Okayama, 3Department of Internal Medicine (I), Osaka Medical College, 4Dainippon Sumitomo Pharma Co., Ltd, Osaka, and 6Japan Labor, Health and Welfare Organization Chubu Rosai Hospital, Nagoya, Japan
Keywords Combination therapy, Metformin, Repaglinide *Correspondence Tatsuya Oikawa Tel.: +81-6-6337-5044 Fax: +81-6-6310-7128. E-mail address: [email protected]
J Diabetes Invest 2014; 5: 72–79 doi: 10.1111/jdi.12121
ABSTRACT Aims/Introduction: We investigated the efficacy and safety of repaglinide as an addon therapy for Japanese patients with type 2 diabetes mellitus receiving metformin monotherapy (at a dose of 1,500 mg/day, mainly) in addition to diet and exercise. Materials and methods: In the 16-week multicenter, placebo-controlled, randomized, double-blind, parallel-group trial (the phase III study), patients with type 2 diabetes mellitus with metformin monotherapy were randomly assigned to the repaglinide or placebo group. Thereafter, a 36-week, multicenter, uncontrolled, dose-titration method study was extended to a total duration of 52 weeks (the long-term study). The primary end-point of each study was a change in glycated hemoglobin (HbA1c) from baseline. Results: After 16 weeks, mean reductions in HbA1c were significantly greater for the repaglinide group than for the placebo group (–0.98 – 0.72% vs 0.13 – 0.63%, P < 0.001). In the long-term study, the mean change in HbA1c was -0.76 – 0.83%. The rate of adverse events was 60.6 and 50.0% in the repaglinide and placebo groups, respectively, in the phase III study, and 78.3% in the long-term study. Hypoglycemia was reported in 11.7, 0 and 13.3% of patients in the repaglinide group, placebo group and long-term study, respectively. Conclusions: Combination therapy with repaglinide and metformin resulted in an approximately 1% reduction in HbA1c at week 16 and in a significant long-term improvement in HbA1c at the end of the study. No safety problems were noted during the concomitant use of repaglinide and metformin. These studies were registered with JapicCTI (nos. JapicCTI-101202 and JapicCTI-101203).
INTRODUCTION Repaglinide is a short-acting insulin secretagogue that is excreted into bile, and it promotes insulin secretion by a mechanism similar to sulfonylurea (SU) agents1. However, unlike SU agents, repaglinide is characterized by a short duration of action with transient insulin secretion because of its rapid absorption after oral administration just before a meal and early disappearance from the circulation. Thus, repaglinide reduces postpranReceived 21 March 2013; revised 9 May 2013; accepted 22 May 2013
J Diabetes Invest Vol. 5 No. 1 January 2014
dial hyperglycemia by targeting early-phase insulin release and restoring the normal pattern of insulin secretion. Furthermore, previous studies have conﬁrmed that repaglinide monotherapy for 16 weeks reduced glycated hemoglobin (HbA1c) by 1.17%2, and that its effect was maintained over a long period in Japanese patients with type 2 diabetes. On the basis of these results, The Ministry of Health, Labor and Welfare in Japan approved repaglinide, and it was launched in 2011. Metformin mainly inhibits hepatic gluconeogenesis and shows a hypoglycemic effect without affecting insulin secretion
ª 2013 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modiﬁcations or adaptations are made.
CLINICAL TRIAL Repaglinide and metformin combination
from pancreatic b-cells. It also promotes glucose uptake in peripheral tissues and controls glucose absorption in the small intestine3. Although metformin has long been widely used as the ﬁrst-line drug for oral treatment of type 2 diabetes overseas4,5, in Japan, the global standard dose of metformin (usually 750–1,500 mg/day, maximum dose of 2,250 mg/day) was only approved in 20106. Since then, its use has increased sharply as a result of its efﬁcacy and safety. The combined use of repaglinide, a short-acting insulin secretagogue, and metformin, an insulin sensitizer, is complementary and expected to improve glycemic control over a long period of time without exhausting pancreatic b-cells. In fact, combined therapy with repaglinide and metformin was approved in the USA in 1997 and in Europe in 1998, and has been widely used since. However, the efﬁcacy and safety of combination therapy with repaglinide and metformin in Japanese patients have not yet been established. Therefore, we carried out a phase III study on the combined use of metformin (at a dose of 1,500 mg/day, mainly) and repaglinide, as well as a continued long-term study, and investigated the efﬁcacy and safety of repaglinide as an add-on therapy for Japanese patients with type 2 diabetes receiving metformin monotherapy.
METHOD Enrolled Patients
In the phase III study, patients with type 2 diabetes were screened and enrolled if they were aged over 20 years, had received metformin monotherapy at a ﬁxed dose (750, 1,500 or 2,250 mg/day) in addition to diet and exercise therapies in the previous 12 weeks, and had HbA1c of 6.9–9.4%. Patients who had been treated with insulin or a SU agent during the previous 24 weeks, or with other oral hypoglycemic agents (excluding metformin), glucagon-like peptide-1 receptor agonists or corticosteroids (oral preparation, suppository, or injection) during the previous 12 weeks were excluded. The following patients were also excluded: those with heart diseases (heart failure [New York Heart Association class III or IV]; unstable angina; myocardial infarction during the previous 12 months); diabetes complications (diabetic proliferative retinopathy or preproliferative retinopathy and serious diabetic neuropathy requiring treatment); aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) levels of >2.5-fold the upper normal limit; serum creatinine level of ≥1.3 mg/dL (males) or ≥1.2 mg/dL (females); contraindication to metformin; and malignant tumors, as well as pregnant women, possibly pregnant women and lactating women. In the long-term study, patients who completed the phase III study and voluntarily agreed to participate in the present study were enrolled. These studies were examined and approved by the institutional review board (IRB) of each participating institution and subsequently carried out in accordance with Good Clinical Practice. At each participating institution, the investigator
ª 2013 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd
informed each candidate patient of the study design using the leaﬂet and consent form authorized by the IRB before the patient was enrolled in the study, and the patient’s informed consent to the study was obtained in writing. Study Design and Methods
The phase III study was a 16-week, multicenter, placebo-controlled, randomized, double-blind, parallel-group, comparative study. Eligible patients were randomized (2:1) to either the repaglinide or the placebo group. In each group, oral medication was given three times daily, immediately (within 10 min) before each meal, for a period of 16 weeks. On completion of the phase III study, patients were entered into a 36-week, multicenter, uncontrolled, dose-titration method study. In the phase III study, patients in the repaglinide group received repaglinide at a dose of 0.75 mg/day for the ﬁrst 2 weeks and 1.5 mg/day for the following 14 weeks. Patients in the placebo group received a placebo for 16 weeks. After the phase III study, all patients who moved onto the long-term study received repaglinide at a dose of 0.75 mg/day in week 17 and 18 (initial 2 weeks of the long-term study). If no safety issues were noted, the dose was increased to 1.5 mg/day from week 19 up to week 32. The dose could be increased to 3 mg/day after week 32. A ﬁxed dose of metformin was also administered during 52 weeks. The primary end-point in both studies was a change in HbA1c at the end of the study. Secondary end-points were the proportion of patients who achieved the HbA1c targets of