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A Prospective, Randomized, Multicenter Trial Comparing The Endocrine Journal 2015, 62 (12), 1049-1057 Original A prospective, randomized, multicenter trial comparing the efficacy and safety of the concurrent use of long-acting insulin with mitiglinide or voglibose in patients with type 2 diabetes Jang-Won Son1), In-Kyu Lee2), Jeong-taek Woo3), Sei Hyun Baik4), Hak Chul Jang5), Kwan Woo Lee6), Bong Soo Cha7), Yeon-Ah Sung8), Tae Sun Park9), Soon-Jib Yoo1)** and Kun-Ho Yoon10)* 1) Department of Internal Medicine, College of Medicine, Bucheon St. Mary’s Hospital, The Catholic University of Korea, Bucheon, Korea 2) Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea 3) Department of Endocrinology and Metabolism, Research Institute of Endocrinology, School of Medicine, Kyung Hee University, Seoul, Korea 4) Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea 5) Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea 6) Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea 7) Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea 8) Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea 9) Department of Internal Medicine, Chonbuk National University Hospital, Jeonju, Korea 10)Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea Abstract. This trial was conducted to compare the efficacy and safety of combination therapy with basal insulin glargine plus mitiglinide to that of basal insulin glargine plus voglibosein patients with type 2 diabetes. This was a 20-week, randomized, multicenter non-inferiority trial. Patients with HbA1c levels over 7.0% were randomly assigned to receive either mitiglinide (10 mg tid) or voglibose (0.2 mg tid) concurrent with insulin glargine for 16 weeks after a 4-week of basal insulin glargine monotherapy. The intention-to-treat population included 156 patients; 79 were placed in the mitiglinide group, and 77 were placed in the voglibose group. At 20 weeks, there was no significant difference between the mitiglinide group and the voglibose group in terms of the mean HbA1c level or the mean decrease of the HbAlc level from baseline (−0.9% [−7.5 mmol/mol] and −0.7%, [−5.3 mmol/mol] respectively). The mean fasting plasma glucose level and data of self-monitoring blood glucosewere significantly decreased from baseline to week 20 in both groups, but there was no significant difference between the two groups. The changes in the basal insulin requirements of each group were not significant. The prevalence of adverse events and the risk of hypoglycemia were similar for both groups. Combination therapy with mitiglinide plus basal insulin glargine was non-inferior to voglibose plus basal insulin glargine in terms of the effect on overall glycemic control. Key words: Diabetes mellitus, Type 2, Mitiglinide, Voglibose CAREFUL glycemic control is critical for protection betes [1, 2]. The goal of therapy is to normalize glu- against the disease-related complications of type 2 dia- cose levels by reducing the levels of the components Submitted Jun. 19, 2015; Accepted Aug. 26, 2015 as EJ15-0325 of the glucose triad, which include glycated hemoglo- Released online in J-STAGE as advance publication Sep. 25, 2015 bin (HbA1c), fasting plasma glucose (FPG) and post- *Correspondence to: Kun-Ho Yoon, M.D., Ph.D., Division of prandial glucose (PPG). Increasing evidences support Endocrinology and Metabolism, Department of Internal Medicine, the importance of PPG control, in addition to FPG and College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-040, HbAlc, for the management of type 2 diabetes [3, 4]. Korea. E-mail: [email protected] PPG was a predominant contributor to excess hyper- **Co-correspondence: Soon-Jib Yoo, M.D., Ph.D., Division of glycemia, and was recognized as an important target Endocrinology and Metabolism, Department of Internal Medicine, for treatment, especially in Asian populations with type Bucheon St. Mary’s Hospital , The Catholic University of Korea, 327 Sosa-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-717, Korea. 2 diabetes [5]. Many lines of evidence also indicate E-mail: [email protected] that PPG and glucose variability are major risk factors ©The Japan Endocrine Society 1050 Son et al. for cardiovascular disease and that lowered PPG lev- cal trial has compared the effect of mitiglinide with the els are associated with a reduced risk of atherosclerosis alpha-glucosidase inhibitor voglibose in combination and cardiovascular events [6-8]. Thus, many clinicians with basal insulin for the treatment of type 2 diabetes. consider several therapeutic strategies for reducing The present study was designed to compare the safety PPG excursions. and efficacy of mitiglinide versus voglibose in combi- Data from several studies suggest that initiation of nation therapy with once-daily insulin glargine for the basal insulin therapy earlier than recommended by the improvement of overall glycemic control. current standard of care would be a simple and effective method of improving FPG [9, 10]. However, for many Methods patients with type 2 diabetes, this does not improve the PPG level. Although a bolus of insulin administered at Subjects each meal is the best technique for PPG control, it is dif- Subjects with type 2 diabetes were enrolled if they ficult to maintain patient compliance with this protocol. were between 30 and 70 years old, had an HbA1c level Therefore, the addition of oral hypoglycemia agents above 7.0% (even after the administration of at least (OHAs) to basal insulin therapy as an effort to lower 2 oral antihyperglycemic drugs for 6 months prior to PPG levels is preferred over basal-bolus insulin therapy screening or after the administration of insulin glargine [11, 12]. Several classes of OHAs may be used for PPG monotherapy for at least 3 months prior to screening) control. Glinides enhance early-phase insulin release, and a body mass index (BMI) between 21 and 40 kg/ and their rapid onset and short duration of action make m2. We excluded subjects who were using types of insu- them effective at reducing PPG excursions [13]. Alpha- lin other than insulin glargine, who had an FPG over 15 glucosidase inhibitors reduce PPG by inhibiting car- mmol/L, who had C-peptide levels below 0.3 nmol/L or bohydrate digestion in the small intestine and delay- who had a history of gastrointestinal resection. In addi- ing its absorption [13]. Considering that the loss of tion, subjects with severe hepatic dysfunction, decom- first-phase insulin secretion and carbohydrate absorp- pensated cirrhosis, aspartate transaminase (AST) or tion play important roles in determining the extent of alanine transaminase (ALT) levels 2.5 times the upper PPG fluctuations, the combined use of either glinides or normal limit, unstable angina or episodes of acute myo- alpha-glucosidase inhibitors with basal insulin therapy cardial infarction within 3 months, renal failure, uncon- may provide additional PPG control, but neither reg- trolled hypertension with diastolic pressure above 110 imen is currently included in the consensus treatment mmHg (even after treatment), life-threatening diseases algorithms. Various studies have demonstrated the effi- such as cancer, severe infections, a history of drug aller- cacy of glinides or alpha-glucosidase inhibitors in com- gies, those who required the administration of oral or bination with basal insulin for the glycemic control of intravenous corticosteroids and those who were preg- patients with type 2 diabetes [14-16]. nant or lactating were not eligible for the study. This However, few studies have compared the effect of trial complied with the ethical principles defined by the each combination therapy on the glycemic control of Declaration of Helsinki and the Korean Good Clinical patients with type 2 diabetes. In one recent crossover Practice (KGCP) guidelines. The protocol was approved study, nateglinide and acarbose were reported to be by the local institutional review boards, and all subjects equally effective at controlling the mean glucose level provided written and informed consent before the initia- when combined with insulin glargine therapy, but their tion of any trial-related activities. This study is regis- effects on HbA1c were inconclusive due to the short tered ClinicalTrials.gov, number NCT00663884. duration of the study [17]. Given the different mecha- nisms of action between glinides and alpha-glucosidase Study design and methods inhibitors, the specific response to both regimen remains This was a multi-center, active drug-controlled, ran- to be determined. Recently, mitiglinide, a novel class of domized, open labeled, two-parallel-group-compari- glinide, was shown to be safe and effective both as a son, 20 weeks study. The clinical trial was carried out monotherapy and in combination with insulin glargine at 9 clinical trial centers from February 2008 to June [18, 19]. In two previous studies, mitiglinide and nat- 2009. Patients were divided into groups and received eglinide had similar effects on the glycemic control of either insulin glargine plus 10 mg of mitiglinide three patients with type 2 diabetes [20, 21]. To date, no clini- times daily or insulin glargine plus 0.2 mg of voglib- Mitiglinide or voglibose with glargine 1051 ose three times daily. The subjects who had agreed to control (0 - 18 points), fair control (19 - 31 points) or participate in the trial were given insulin glargine as a poor control (32 points or more). monotherapy for 4 weeks after a run-in period and were The investigators measured vital signs and body then randomly selected to receive either mitiglinide or weight and assessed the occurrence of adverse events at voglibose concurrent with the insulin glargine for 16 each visit. Routine complete blood counts, blood chem- weeks. If the subjects’ insulin glargine compliance istries and urinalysis tests were also carried out to moni- was less than 75% at week 4, they were dropped from tor drug safety.
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