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Effect of repaglinide, administered two or three times daily for 3 months, on glycaemic control in Japanese patients with type 2 diabetes mellitus Hiroshi Kamiyama, Kazutaka Aoki, Shigeru Nakajima, Kazuaki Shinoda, Kazunari Kamiko, Masataka Taguri and Yasuo Terauchi Journal of International Medical Research published online 11 July 2014 DOI: 10.1177/0300060514534644 The online version of this article can be found at: http://imr.sagepub.com/content/early/2014/07/11/0300060514534644
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Effect of repaglinide, administered two or three times daily for 3 months, on glycaemic control in Japanese patients with type 2 diabetes mellitus
Journal of International Medical Research 0(0) 1–11 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060514534644 imr.sagepub.com
Hiroshi Kamiyama1, Kazutaka Aoki1,2, Shigeru Nakajima3, Kazuaki Shinoda3, Kazunari Kamiko1, Masataka Taguri2 and Yasuo Terauchi1
Abstract Objectives: To compare the efficacy, safety and compliance of repaglinide, administered either two or three times daily, regarding glycaemic control in patients with type 2 diabetes mellitus. Methods: Japanese adults with type 2 diabetes mellitus, who had been treated without sulphonylureas or glinides for >3 months, were randomly assigned to two groups to receive either 0.25 mg repaglinide, oral, twice daily (group A) or 0.25 mg repaglinide, oral, three times daily (group B). Glycosylated haemoglobin (HbA1c), glycoalbumin (GA) and 1,5-anhydroglucitol (1,5-AG) levels were measured at 0, 1, 2 and 3 months after treatment commenced. Results: Out of 43 patients who enrolled (group A, n ¼ 22; group B, n ¼ 21), 33 patients completed the trial (group A, n ¼ 16; group B, n ¼ 17). No significant between-group differences in HbA1c, GA, or 1,5-AG levels were seen at 1–3 months. No severe hypoglycaemic episodes or other adverse events were observed. Conclusions: Minimal-dose repaglinide administered twice daily was similar in efficacy and safety to three-times-daily administration, in Japanese patients with type 2 diabetes mellitus. Administration of repaglinide twice daily could be an alternative regimen for patients who cannot take repaglinide three times daily. Keywords Repaglinide, type 2 diabetes, drug adherence Date received: 21 November 2013; accepted: 14 April 2014 1
Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan 2 Department of Biostatistics and Epidemiology, Yokohama City University Hospital, Yokohama, Japan 3 Nakajima Naika Clinic, Yokosuka, Japan
Corresponding author: Yasuo Terauchi, Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan. Email: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work isOF attributed as on specified on the SAGE and Open Access page Downloaded from imr.sagepub.com at UNIVERSITY BRIGHTON July 16, 2014 (http://www.uk.sagepub.com/aboutus/openaccess.htm).
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Introduction Epidemiological research has demonstrated that postprandial hyperglycaemia is necessary to reduce the risk of cardiovascular complications, in patients with diabetes mellitus.1,2 One such study in Japan demonstrated that the incidence of cardiovascular complications was significantly higher for patients with diabetes and persons with impaired glucose tolerance, compared with subjects with normal glucose tolerance, but no significant difference was observed between patients with impaired fasting glucose and those with normal fasting glucose.2 One of the characteristics of Japanese patients with type 2 diabetes mellitus is a decline in insulin secretion from an early disease stage.3 Glinides are oral hypoglycaemic agents that improve impaired insulin secretion following meals, in patients with type 2 diabetes mellitus.4–6 Repaglinide is available clinically in Japan and has the potential to play an important role in the treatment of Japanese patients with type 2 diabetes. Patients are instructed to take repaglinide before meals (two, three or even four times daily, preprandially) in the USA.7 Repaglinide must be taken just before a meal three times daily when administered according to the standard therapy regimen in Japan. Like a-glucosidase inhibitors (a-GIs), however, the need to take this drug just before meals and the three-timesdaily dosing schedule are associated with poor adherence.8 Poor compliance with medication instructions is common among patients with diabetes and is associated with adverse clinical outcomes.9 Poor compliance with glinide therapy may be due, in part, to the need to take the medication immediately before meals, and the three-times-daily standard dosing schedule. The present research group previously evaluated ways of improving drug adherence in patients receiving a-GIs and found that administering a-GIs following meals
improved compliance.10–12 Furthermore, administration of miglitol at breakfast was found to increase plasma active glucagon-like peptide-1 levels, and improve plasma glucose levels following lunch, even if miglitol was not taken at lunchtime.13,14 The present researchers also reported that twice-daily administration of acarbose improved glycaemic control in patients with type 2 diabetes mellitus.15 These studies demonstrated the efficacy, in terms of glycaemic control, of administering a-GIs twice daily. Administration of repaglinide/metformin in a fixed-dose combination twice daily has been reported as being similar to threetimes-daily administration, in terms of glycaemic control.16 Thus, the theory behind the present study was that administration of repaglinide two times daily might enable similar glycaemic control to that of threetimes-daily administration in Japanese patients with type 2 diabetes mellitus, and might also improve treatment compliance. In the present study, the efficacy and safety of two- or three-times-daily administration of a minimum fixed dose of 0.25 mg repaglinide was compared in Japanese patients with type 2 diabetes mellitus.
Patients and methods Study population Japanese adults with type 2 diabetes mellitus, treated with dietary therapy alone or fixed-dose oral hypoglycaemic agents (with the exception of sulphonylureas and glinides) for over 3 months at Yokohama City University Hospital, Yokohama, Japan and Nakajima Naika Clinic, Yokosuka, Japan between August 2011 and September 2012, were enrolled. Primary endpoints were changes in glycosylated haemoglobin (HbA1c), glycoalbumin (GA) and 1,5-anhydroglucitol (1,5-AG) levels; secondary endpoints were changes in body mass index (BMI), drug adherence, and adverse events
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(particularly the frequency and degree of hypoglycaemia). HbA1c (%) values were expressed in accordance with the National Glycohemoglobin Standardization Program (NGSP). Patients with liver dysfunction (including liver cirrhosis or malignancy) and patients with severe diabetic complications (active proliferative diabetic retinopathy, or severe diabetic nephropathy) were excluded from the study. If a doctor (H.K., K.A., S.N., K.S., K.K. and Y.T.) considered a patient to be at risk of hypoglycaemia, or if the patient refused to provide informed consent, the patient’s participation in the study was terminated and the patient was treated with other appropriate drugs as soon as possible. Patients who experienced hypoglycaemic symptoms were instructed to take glucose, to stop taking repaglinide, and to call or visit the hospital as soon as possible. Doses of oral hypoglycaemic drugs, including repaglinide, were not changed throughout the study. Since the primary outcome of this study was change in glycaemic control in the two groups, patients who could not take the study drug two or three times daily for 3 months were excluded from analysis. This study was approved by the Institutional Ethics Review Committee of Yokohama City University, and written informed consent was obtained from all participants. The trial was registered with the UMIN (University Hospital Medical Information Network) Clinical Trials Registry (UMIN000006855).
Study design Patients were randomized to two groups using the envelope method: group A was assigned to take 0.25 mg repaglinide, oral, twice daily; group B was assigned to take 0.25 mg repaglinide, oral, three times daily. Patients in both groups were instructed to take repaglinide just before meals. Baseline characteristics, including
age, sex, duration of diabetes, BMI, and HbA1c, GA, and 1,5-AG levels were recorded immediately prior to initiating repaglinide therapy. Blood samples were collected at 0, 1, 2, and 3 months following initiation of repaglinide treatment. Blood samples were obtained from the antecubital vein into Fuoride tubes containing sodium citrate and ethylenediaminetetra-acetic acid or heparin for the analysis of plasma glucose and HbA1c, and into plain siliconized tubes for the analysis of 1,5-AG and GA. Following collection, samples for analysis of 1,5-AG and GA levels were allowed to stand for 5 min at room temperature, then centrifuged at 4 C, 2330 g for 7 min. All samples were analysed at Hokenkagaku Institute Inc. (Yokohama, Japan) or the clinical laboratory of Yokohama City University Hospital. Adherence to the dosing regimen was assessed using a questionnaire survey. Each patient was asked to complete a written questionnaire in the presence of medical doctors at 1, 2, and 3 months following initiation of repaglinide therapy. Adherence was scored for each patient, at each timepoint, as follows: 1, 0–49%; 2, 50%–69%; 3, 70%–89%; 4, 90–100%.
Statistical analyses Data were presented as mean SD and were analysed using Statistical Analysis System (SASÕ ) software, version 9.2 (SAS Institute Inc., Cary, NC, USA). Between-group differences in age, BMI and duration of diabetes at baseline were estimated using unpaired Student’s t-test. Between-group differences in sex were estimated using 2-test. Between- and within-group changes in HbA1c, GA, 1,5-AG and BMI levels in patients who completed the trial were analysed using a linear mixed model. A random intercept was used for each patient including time, group and these interactions as
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covariates, followed by the Bonferroni correction. 1,5-AG levels 0.25 mg. In the present study, repaglinide therapy was as effective as results reported for glimepiride or glibenclamide therapy,25–27 therefore, we also hope to evaluate the effectiveness of a two- or three-times-daily repaglinide regimen after switching from sulphonylurea treatment. In the present study, patients were instructed to take 0.25 mg repaglinide two- or three-times daily, and no significant between-group difference in drug adherence was observed. A questionnaire to survey the total amount of medication taken in this study was not conducted. An assumption was made that administration of repaglinide twice daily could improve drug adherence in daily clinical practice because the number of administrations was decreased. Based on the results of the present study, starting a twice-daily treatment, rather than a three-times-daily treatment, may be beneficial for patients with poor compliance. The present study had several limitations. The number of patients included was relatively small and the term of the study was short, therefore, large-scale and longterm studies may elucidate a more representative effect on glycaemic control of repaglinide two or three times daily on the population of Japanese patients with diabetes. In conclusion, twice-daily administration of a minimal dose of repaglinide (0.25 mg) had similar efficacy and safety profiles to three-times-daily administration, in Japanese patients with type 2 diabetes mellitus. Thus, administration of repaglinide twice daily may be useful as a substitute regimen in patients who are unlikely to adhere to a three-times-daily regimen. Declaration of conflicting interest The authors declare that there are no conflicts of interest.
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Funding This work was supported in part by Grants-inAid for Scientific Research (B) 19390251, (B) 21390282, and (B) 24390235 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and a Medical Award from the Japan Medical Association.
Acknowledgements The authors thank the following nurses and medical clerks: M. Toyoda, I. Mutou, M. Funaoka,Y. Tokunaga, K. Murata, Y. Kotachi, K. Kanda, Y. Hamamoto, and M. Suzuki.
References 1. Nakagami T and DECODA Study Group. Hyperglycaemia and mortality from all causes and from cardiovascular disease in five populations of Asian origin. Diabetologia 2004; 47: 385–394. 2. Tominaga M, Eguchi H, Manaka H, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 1999; 22: 920–924. 3. Fukushima M, Suzuki H and Seino Y. Insulin secretion capacity in the development from normal glucose tolerance to type 2 diabetes. Diabetes Res Clin Pract 2004; 66(suppl 1): S37–S43. 4. Rizzo MR, Barbieri M, Grella R, et al. Repaglinide is more efficient than glimepiride on insulin secretion and post-prandial glucose excursions in patients with type 2 diabetes. A short term study. Diabetes Metab 2004; 30: 81–89. 5. Gao X and Mitiglinide Versus Nateglinide Comparison Study Group. Multicentre, double-blind, randomized study of mitiglinide compared with nateglinide in type 2 diabetes mellitus patients in China. J Int Med Res 2009; 37: 812–821. 6. Konya H, Miuchi M, Konishi K, et al. Pleiotropic effects of mitiglinide in type 2 diabetes mellitus. J Int Med Res 2009; 37: 1904–1912.
7. Novo Nordisk Inc. Prandin (package insert). Version 12. New Jersey: Novo Nordisk Inc, 2011. www.novo-pi.com/prandin.pdf (2011, accessed 8 June 2014). 8. Hertz RP, Unger AN and Lustik MB. Adherence with pharmacotherapy for type 2 diabetes: a retrospective cohort study of adults with employer-sponsored health insurance. Clin Ther 2005; 27: 1064–1073. 9. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med 2006; 166: 1836–1841. 10. Aoki K, Nakamura A, Ito S, et al. Administration of miglitol until 30 min after the start of a meal is effective in type 2 diabetic patients. Diabetes Res Clin Pract 2007; 78: 30–33. 11. Aoki K, Nakajima S, Nezu U, et al. Comparison of pre- vs. postmeal administration of miglitol for 3 months in type 2 diabetic patients. Diabetes Obes Metab 2008; 10: 970–972. 12. Aoki K, Ito Y, Saito K, et al. Comparison of pre- vs. post-meal administration of voglibose in men with or without impaired glucose tolerance. Diabetes Res Clin Pract 2009; 83: e31–e32. 13. Aoki K, Kamiyama H, Yoshimura K, et al. Miglitol administered before breakfast increased plasma active glucagon-like peptide-1 (GLP-1) levels after lunch in patients with type 2 diabetes treated with sitagliptin. Acta Diabetol 2012; 49: 225–230. 14. Masuda K, Aoki K and Terauchi Y. Effects of miglitol taken just before or after breakfast on plasma glucose, serum insulin, glucagon and incretin levels after lunch in men with normal glucose tolerance, impaired fasting glucose or impaired glucose tolerance. J Diabetes Invest 2011; 2: 435–440. 15. Aoki K and Terauchi Y. Effect of acarbose therapy once or twice a day on glycemic control in Japanese patients with type 2 diabetes. Jpn J Clin Pharmacol Ther 2012; 43: 17–20. 16. Raskin P, Lewin A, Reinhardt R, et al. Twice-daily and three-times-daily dosing of a repaglinide/metformin fixed-dose
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combination tablet provide similar glycaemic control. Diabetes Obes Metab 2009; 11: 947–952. Hollander PA, Schwartz SL, Gatlin MR, et al. Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes. Diabetes Care 2001; 24: 983–988. Moses R. Fixed combination of repaglinide and metformin in the management of type 2 diabetes. Diabetes Metab Syndr Obes 2009; 2: 101–109. Paes AH, Bakker A and Soe-Agnie CJ. Impact of dosage frequency on patient compliance. Diabetes Care 1997; 20: 1512–1517. Welch S, Gebhart SS, Bergman RN, et al. Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab 1990; 71: 1508–1518. Taniguchi A, Nakai Y, Fukushima M, et al. Pathogenic factors responsible for glucose intolerance in patients with NIDDM. Diabetes 1992; 41: 1540–1546. Takihata M, Nakamura A, Tajima K, et al. Comparative study of sitagliptin with pioglitazone in Japanese type 2 diabetic
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patients: the COMPASS randomized controlled trial. Diabetes Obes Metab 2013; 15: 455–462. Kawamori R, Kaku K, Hanafusa T, et al. Efficacy and safety of repaglinide vs. nateglinide for treatment of Japanese patients with type 2 diabetes mellitus. J Diabetes Invest 2012; 3: 302–308. Moses RG, Gomis R, Frandsen KB, et al. Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes. Diabetes Care 2001; 24: 11–15. Scott LJ. Repaglinide: a review of its use in type 2 diabetes mellitus. Drugs 2012; 72: 249–272. Landgraf R, Bilo HJ and Mu¨ller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol 1999; 55: 165–171. Derosa G, Mugellini A, Ciccarelli L, et al. Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year, randomized, doubleblind assessment of metabolic parameters and cardiovascular risk factors. Clin Ther 2003; 25: 472–484.
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Effect of repaglinide, administered two or three times daily for 3 months, on glycaemic control in Japanese patients with type 2 diabetes mellitus Hiroshi Kamiyama, Kazutaka Aoki, Shigeru Nakajima, Kazuaki Shinoda, Kazunari Kamiko, Masataka Taguri and Yasuo Terauchi Journal of International Medical Research published online 11 July 2014 DOI: 10.1177/0300060514534644 The online version of this article can be found at: http://imr.sagepub.com/content/early/2014/07/11/0300060514534644
Published by: http://www.sagepublications.com
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Research Note
Effect of repaglinide, administered two or three times daily for 3 months, on glycaemic control in Japanese patients with type 2 diabetes mellitus
Journal of International Medical Research 0(0) 1–11 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060514534644 imr.sagepub.com
Hiroshi Kamiyama1, Kazutaka Aoki1,2, Shigeru Nakajima3, Kazuaki Shinoda3, Kazunari Kamiko1, Masataka Taguri2 and Yasuo Terauchi1
Abstract Objectives: To compare the efficacy, safety and compliance of repaglinide, administered either two or three times daily, regarding glycaemic control in patients with type 2 diabetes mellitus. Methods: Japanese adults with type 2 diabetes mellitus, who had been treated without sulphonylureas or glinides for >3 months, were randomly assigned to two groups to receive either 0.25 mg repaglinide, oral, twice daily (group A) or 0.25 mg repaglinide, oral, three times daily (group B). Glycosylated haemoglobin (HbA1c), glycoalbumin (GA) and 1,5-anhydroglucitol (1,5-AG) levels were measured at 0, 1, 2 and 3 months after treatment commenced. Results: Out of 43 patients who enrolled (group A, n ¼ 22; group B, n ¼ 21), 33 patients completed the trial (group A, n ¼ 16; group B, n ¼ 17). No significant between-group differences in HbA1c, GA, or 1,5-AG levels were seen at 1–3 months. No severe hypoglycaemic episodes or other adverse events were observed. Conclusions: Minimal-dose repaglinide administered twice daily was similar in efficacy and safety to three-times-daily administration, in Japanese patients with type 2 diabetes mellitus. Administration of repaglinide twice daily could be an alternative regimen for patients who cannot take repaglinide three times daily. Keywords Repaglinide, type 2 diabetes, drug adherence Date received: 21 November 2013; accepted: 14 April 2014 1
Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan 2 Department of Biostatistics and Epidemiology, Yokohama City University Hospital, Yokohama, Japan 3 Nakajima Naika Clinic, Yokosuka, Japan
Corresponding author: Yasuo Terauchi, Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan. Email: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work isOF attributed as on specified on the SAGE and Open Access page Downloaded from imr.sagepub.com at UNIVERSITY BRIGHTON July 16, 2014 (http://www.uk.sagepub.com/aboutus/openaccess.htm).
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Introduction Epidemiological research has demonstrated that postprandial hyperglycaemia is necessary to reduce the risk of cardiovascular complications, in patients with diabetes mellitus.1,2 One such study in Japan demonstrated that the incidence of cardiovascular complications was significantly higher for patients with diabetes and persons with impaired glucose tolerance, compared with subjects with normal glucose tolerance, but no significant difference was observed between patients with impaired fasting glucose and those with normal fasting glucose.2 One of the characteristics of Japanese patients with type 2 diabetes mellitus is a decline in insulin secretion from an early disease stage.3 Glinides are oral hypoglycaemic agents that improve impaired insulin secretion following meals, in patients with type 2 diabetes mellitus.4–6 Repaglinide is available clinically in Japan and has the potential to play an important role in the treatment of Japanese patients with type 2 diabetes. Patients are instructed to take repaglinide before meals (two, three or even four times daily, preprandially) in the USA.7 Repaglinide must be taken just before a meal three times daily when administered according to the standard therapy regimen in Japan. Like a-glucosidase inhibitors (a-GIs), however, the need to take this drug just before meals and the three-timesdaily dosing schedule are associated with poor adherence.8 Poor compliance with medication instructions is common among patients with diabetes and is associated with adverse clinical outcomes.9 Poor compliance with glinide therapy may be due, in part, to the need to take the medication immediately before meals, and the three-times-daily standard dosing schedule. The present research group previously evaluated ways of improving drug adherence in patients receiving a-GIs and found that administering a-GIs following meals
improved compliance.10–12 Furthermore, administration of miglitol at breakfast was found to increase plasma active glucagon-like peptide-1 levels, and improve plasma glucose levels following lunch, even if miglitol was not taken at lunchtime.13,14 The present researchers also reported that twice-daily administration of acarbose improved glycaemic control in patients with type 2 diabetes mellitus.15 These studies demonstrated the efficacy, in terms of glycaemic control, of administering a-GIs twice daily. Administration of repaglinide/metformin in a fixed-dose combination twice daily has been reported as being similar to threetimes-daily administration, in terms of glycaemic control.16 Thus, the theory behind the present study was that administration of repaglinide two times daily might enable similar glycaemic control to that of threetimes-daily administration in Japanese patients with type 2 diabetes mellitus, and might also improve treatment compliance. In the present study, the efficacy and safety of two- or three-times-daily administration of a minimum fixed dose of 0.25 mg repaglinide was compared in Japanese patients with type 2 diabetes mellitus.
Patients and methods Study population Japanese adults with type 2 diabetes mellitus, treated with dietary therapy alone or fixed-dose oral hypoglycaemic agents (with the exception of sulphonylureas and glinides) for over 3 months at Yokohama City University Hospital, Yokohama, Japan and Nakajima Naika Clinic, Yokosuka, Japan between August 2011 and September 2012, were enrolled. Primary endpoints were changes in glycosylated haemoglobin (HbA1c), glycoalbumin (GA) and 1,5-anhydroglucitol (1,5-AG) levels; secondary endpoints were changes in body mass index (BMI), drug adherence, and adverse events
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(particularly the frequency and degree of hypoglycaemia). HbA1c (%) values were expressed in accordance with the National Glycohemoglobin Standardization Program (NGSP). Patients with liver dysfunction (including liver cirrhosis or malignancy) and patients with severe diabetic complications (active proliferative diabetic retinopathy, or severe diabetic nephropathy) were excluded from the study. If a doctor (H.K., K.A., S.N., K.S., K.K. and Y.T.) considered a patient to be at risk of hypoglycaemia, or if the patient refused to provide informed consent, the patient’s participation in the study was terminated and the patient was treated with other appropriate drugs as soon as possible. Patients who experienced hypoglycaemic symptoms were instructed to take glucose, to stop taking repaglinide, and to call or visit the hospital as soon as possible. Doses of oral hypoglycaemic drugs, including repaglinide, were not changed throughout the study. Since the primary outcome of this study was change in glycaemic control in the two groups, patients who could not take the study drug two or three times daily for 3 months were excluded from analysis. This study was approved by the Institutional Ethics Review Committee of Yokohama City University, and written informed consent was obtained from all participants. The trial was registered with the UMIN (University Hospital Medical Information Network) Clinical Trials Registry (UMIN000006855).
Study design Patients were randomized to two groups using the envelope method: group A was assigned to take 0.25 mg repaglinide, oral, twice daily; group B was assigned to take 0.25 mg repaglinide, oral, three times daily. Patients in both groups were instructed to take repaglinide just before meals. Baseline characteristics, including
age, sex, duration of diabetes, BMI, and HbA1c, GA, and 1,5-AG levels were recorded immediately prior to initiating repaglinide therapy. Blood samples were collected at 0, 1, 2, and 3 months following initiation of repaglinide treatment. Blood samples were obtained from the antecubital vein into Fuoride tubes containing sodium citrate and ethylenediaminetetra-acetic acid or heparin for the analysis of plasma glucose and HbA1c, and into plain siliconized tubes for the analysis of 1,5-AG and GA. Following collection, samples for analysis of 1,5-AG and GA levels were allowed to stand for 5 min at room temperature, then centrifuged at 4 C, 2330 g for 7 min. All samples were analysed at Hokenkagaku Institute Inc. (Yokohama, Japan) or the clinical laboratory of Yokohama City University Hospital. Adherence to the dosing regimen was assessed using a questionnaire survey. Each patient was asked to complete a written questionnaire in the presence of medical doctors at 1, 2, and 3 months following initiation of repaglinide therapy. Adherence was scored for each patient, at each timepoint, as follows: 1, 0–49%; 2, 50%–69%; 3, 70%–89%; 4, 90–100%.
Statistical analyses Data were presented as mean SD and were analysed using Statistical Analysis System (SASÕ ) software, version 9.2 (SAS Institute Inc., Cary, NC, USA). Between-group differences in age, BMI and duration of diabetes at baseline were estimated using unpaired Student’s t-test. Between-group differences in sex were estimated using 2-test. Between- and within-group changes in HbA1c, GA, 1,5-AG and BMI levels in patients who completed the trial were analysed using a linear mixed model. A random intercept was used for each patient including time, group and these interactions as
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covariates, followed by the Bonferroni correction. 1,5-AG levels 0.25 mg. In the present study, repaglinide therapy was as effective as results reported for glimepiride or glibenclamide therapy,25–27 therefore, we also hope to evaluate the effectiveness of a two- or three-times-daily repaglinide regimen after switching from sulphonylurea treatment. In the present study, patients were instructed to take 0.25 mg repaglinide two- or three-times daily, and no significant between-group difference in drug adherence was observed. A questionnaire to survey the total amount of medication taken in this study was not conducted. An assumption was made that administration of repaglinide twice daily could improve drug adherence in daily clinical practice because the number of administrations was decreased. Based on the results of the present study, starting a twice-daily treatment, rather than a three-times-daily treatment, may be beneficial for patients with poor compliance. The present study had several limitations. The number of patients included was relatively small and the term of the study was short, therefore, large-scale and longterm studies may elucidate a more representative effect on glycaemic control of repaglinide two or three times daily on the population of Japanese patients with diabetes. In conclusion, twice-daily administration of a minimal dose of repaglinide (0.25 mg) had similar efficacy and safety profiles to three-times-daily administration, in Japanese patients with type 2 diabetes mellitus. Thus, administration of repaglinide twice daily may be useful as a substitute regimen in patients who are unlikely to adhere to a three-times-daily regimen. Declaration of conflicting interest The authors declare that there are no conflicts of interest.
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Funding This work was supported in part by Grants-inAid for Scientific Research (B) 19390251, (B) 21390282, and (B) 24390235 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and a Medical Award from the Japan Medical Association.
Acknowledgements The authors thank the following nurses and medical clerks: M. Toyoda, I. Mutou, M. Funaoka,Y. Tokunaga, K. Murata, Y. Kotachi, K. Kanda, Y. Hamamoto, and M. Suzuki.
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