A prospective, randomized, multicenter trial comparing the ... - J-Stage

Endocrine Journal 2015

Original

Advance Publication

doi: 10.1507/endocrj. EJ15-0325

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 BundangHospital, 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 against the disease-related complications of type 2 diaSubmitted Jun. 19, 2015; Accepted Aug. 26, 2015 as EJ15-0325 Released online in J-STAGE as advance publication Sep.25, 2015

*Correspondence to: Kun-Ho Yoon, M.D., Ph.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-040, Korea. E-mail: [email protected] **Co-correspondence: Soon-Jib Yoo, M.D., Ph.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, Bucheon St. Mary’s Hospital , The Catholic University of Korea, 327 Sosa-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-717, Korea. E-mail: [email protected] ©The Japan Endocrine Society

betes [1, 2]. The goal of therapy is to normalize glucose levels by reducing the levels of the components of the glucose triad, which include glycated hemoglobin (HbA1c), fasting plasma glucose (FPG) and postprandial glucose (PPG). Increasing evidences support the importance of PPG control, in addition to FPG and HbAlc, for the management of type 2 diabetes [3, 4]. PPG was a predominant contributor to excess hyperglycemia, and was recognized as an important target for treatment, especially in Asian populations with type 2 diabetes [5]. Many lines of evidence also indicate that PPG and glucose variability are major risk factors

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Son et al.

for cardiovascular disease and that lowered PPG levels are associated with a reduced risk of atherosclerosis and cardiovascular events [6-8]. Thus, many clinicians consider several therapeutic strategies for reducing PPG excursions. Data from several studies suggest that initiation of basal insulin therapy earlier than recommended by the current standard of care would be a simple and effective method of improving FPG [9, 10]. However, for many patients with type 2 diabetes, this does not improve the PPG level. Although a bolus of insulin administered at each meal is the best technique for PPG control, it is difficult to maintain patient compliance with this protocol. Therefore, the addition of oral hypoglycemia agents (OHAs) to basal insulin therapy as an effort to lower PPG levels is preferred over basal-bolus insulin therapy [11, 12]. Several classes of OHAs may be used for PPG control. Glinides enhance early-phase insulin release, and their rapid onset and short duration of action make them effective at reducing PPG excursions [13]. Alphaglucosidase inhibitors reduce PPG by inhibiting carbohydrate digestion in the small intestine and delaying its absorption [13]. Considering that the loss of first-phase insulin secretion and carbohydrate absorption play important roles in determining the extent of PPG fluctuations, the combined use of either glinides or alpha-glucosidase inhibitors with basal insulin therapy may provide additional PPG control, but neither regimen is currently included in the consensus treatment algorithms. Various studies have demonstrated the efficacy of glinides or alpha-glucosidase inhibitors in combination with basal insulin for the glycemic control of patients with type 2 diabetes [14-16]. However, few studies have compared the effect of each combination therapy on the glycemic control of patients with type 2 diabetes. In one recent crossover study, nateglinide and acarbose were reported to be equally effective at controlling the mean glucose level when combined with insulin glargine therapy, but their effects on HbA1c were inconclusive due to the short duration of the study [17]. Given the different mechanisms of action between glinides and alpha-glucosidase inhibitors, the specific response to both regimen remains to be determined. Recently, mitiglinide, a novel class of glinide, was shown to be safe and effective both as a monotherapy and in combination with insulin glargine [18, 19]. In two previous studies, mitiglinide and nateglinide had similar effects on the glycemic control of patients with type 2 diabetes [20, 21]. To date, no clini-

cal trial has compared the effect of mitiglinide with the alpha-glucosidase inhibitor voglibose in combination with basal insulin for the treatment of type 2 diabetes. The present study was designed to compare the safety and efficacy of mitiglinide versus voglibose in combination therapy with once-daily insulin glargine for the improvement of overall glycemic control.

Methods Subjects Subjects with type 2 diabetes were enrolled if they were between 30 and 70 years old, had an HbA1c level above 7.0% (even after the administration of at least 2 oral antihyperglycemic drugs for 6 months prior to screening or after the administration of insulin glargine monotherapy for at least 3 months prior to screening) and a body mass index (BMI) between 21 and 40 kg/ m2. We excluded subjects who were using types of insulin other than insulin glargine, who had an FPG over 15 mmol/L, who had C-peptide levels below 0.3 nmol/L or who had a history of gastrointestinal resection. In addition, subjects with severe hepatic dysfunction, decompensated cirrhosis, aspartate transaminase (AST) or alanine transaminase (ALT) levels 2.5 times the upper normal limit, unstable angina or episodes of acute myocardial infarction within 3 months, renal failure, uncontrolled hypertension with diastolic pressure above 110 mmHg (even after treatment), life-threatening diseases such as cancer, severe infections, a history of drug allergies, those who required the administration of oral or intravenous corticosteroids and those who were pregnant or lactating were not eligible for the study. This trial complied with the ethical principles defined by the Declaration of Helsinki and the Korean Good Clinical Practice (KGCP) guidelines. The protocol was approved by the local institutional review boards, and all subjects provided written and informed consent before the initiation of any trial-related activities. This study is registered ClinicalTrials.gov, number NCT00663884. Study design and methods This was a multi-center, active drug-controlled, randomized, open labeled, two-parallel-group-comparison, 20 weeks study. The clinical trial was carried out at 9 clinical trial centers from February 2008 to June 2009. Patients were divided into groups and received either insulin glargine plus 10 mg of mitiglinide three

Endocrine Journal Advance Publication

Mitiglinide or voglibose with glargine

times daily or insulin glargine plus 0.2 mg of voglibose three times daily. The subjects who had agreed to participate in the trial were given insulin glargine as a monotherapy for 4 weeks after a run-in period and were then randomly selected to receive either mitiglinide or voglibose concurrent with the insulin glargine for 16 weeks. If the subjects’ insulin glargine compliance was less than 75% at week 4, they were dropped from the trial. Randomization was conducted with the block stratified randomization method. The trial subjects visited the clinic at 4 weeks, 12 weeks and 20 weeks after registration and received insulin glargine for basal insulin management throughout the entire course of the trial. The initial insulin glargine dose was 10 units before bed and was injected subcutaneouslyonce daily at the scheduled time. Adjustments to the insulin dose during the trial were made according to the mean FPG value, which the patient monitored for consecutive 3 days in the morning. When the mean morning FPG level exceeded 7.8mmol/L, the dose was increased by 4 units; when the mean value was between 6.1 and 7.8 mmol/L, the dose was increased by 2 units; when the mean value was between 4.4 to 6.1 mmol/L, the dose was maintained and when the mean value was below 4.4 mmol/L, the dose was decreased by 2 units. The patients received education about diet/exercise therapy and about how to manage hypoglycemia, if necessary. After an overnight fast, the levels of FPG, HbA1c, fasting C-peptide and high sensitivity C-reactive protein (hsCRP) were measured. The serum samples collected from the trial centers were analyzed at the central laboratory. The subjects were required to measure and record the SMBG data 3 days before the hospital visit until the day prior to the visit. Patients measured SMBG 7 times, which included the measurements before and after each meal and before going to bed, and recorded their daily insulin doses on the log sheet. The M-value, i.e., the glycemic variability index based on the SMBG data, was calculated according to the following formula [22]: M-value =

log(blood glucose) 120 n

|

3

{

{|

∑ 10×

+W 20 ,

where W is the difference between the maximum and minimum blood glucose values during the period and n is the number of blood glucose measurements taken. The M-value was used to evaluate the adequacy of blood glucose control via the monitoring of plasma glucose levels. Patients were categorized as having good

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control (0 - 18 points), fair control (19 - 31 points) or poor control (32 points or more). The investigators measured vital signs and body weight and assessed the occurrence of adverse events at each visit. Routine complete blood counts, blood chemistries and urinalysis tests were also carried out to monitor drug safety. Safety was evaluated for each of the patients who made at least one visit after beginning the study medication. The primary endpoint evaluated was the change in the HbA1c level, as measured before and at the end of the study. The secondary endpoints evaluated were the mean changes in the FPG and SMBG values, the mean change in the insulin dose, the proportion of subjects who attained a HbA1c level less than 7.0% and the mean change in the plasma CRP level. Statistical analysis The minimum clinically relevant treatment difference in HbA1c level between the groups was assumed to be 0.3%, and the standard deviation was estimated at 0.7. For a study with 80% power and a 5% type I error rate, a sample size of 68 per treatment group was required to detect the non-inferiority of mitiglinide compared to voglibose. Assuming an overall dropout rate of 10% and a 1:1 randomization ratio, we enrolled 80 subjects in each treatment group. The cases were divided into two groups for an efficacy analysis: an intention-to-treat (ITT) analysis group and a per-protocol (PP) analysis group. The majority of cases for efficacy analysis were in the ITT analysis group. The population that was used for the efficacy analysis (ITT population) consisted of patients with at least one measured efficacy parameter among the randomized subjects. For the subjects who dropped out of the trial, the final measurements were substituted with those from week 16. For the subjects who did not drop out but for whom no values had been measured for the pertinent measurement period, the values were processed without the missing value. We tested the differences between the mitiglinide group and the voglibose group using a two-sample t-test for each continuous variable, and we tested the changes observed before and after the administration of mitiglinide or voglibose within the groups using paired t-tests. The between-group differences in achieving the HbA1c target level were tested using the Chi-squared or Fisher’s exact tests. The statistical analysis was carried out using SAS 9.1 for Windows (SAS Institute Inc., Cary, NC). P values less than 0.05 were considered to be statistically significant.


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Son et al.

Screening n=167 patients

Enrollment n=160 patients

Mitiglinide group n=79 patients

Voglibose group n=81 patients

Cases for safety analysis n=79 patients

Cases for safety analysis n=81 patients

Cases for efficacy analysis (ITT) n=79 patients

Cases for efficacy analysis (ITT) n=77 patients

Drop-outs: 7 Violation of inclusion & exclusion criteria/withdrawal of consent: 7

Excluded cases from ITT analysis: 4 Violation of inclusion criteria: 1 Withdrawal of consent due to AE: 2 Discontinuation of trial: 1

Excluded cases from PP analysis: 20

Excluded cases from PP analysis: 31

Violation of visit schedule: 10 Drug compliance below 75% & data missing: 4 Concurrent administration of prohibited drug: 2 Withdrawal of consent & discontinuation of trial: 4

Violation of visit schedule: 16 Drug compliance below 75% & data missing: 5 Concurrent administration of prohibited drug: 4 Withdrawal of consent & discontinuation of trial: 6

Cases for efficacy analysis (PP) n=59 patients

Cases for efficacy analysis (PP) n=46 patients

Fig. 1 Disposition of subjects in the trial

Results We screened 167 subjects and included 156 subjects in the ITT population, 79 in the mitiglinide group and 77 in the voglibose group. Within the ITT analysis group, 105 patients (mitiglinide group: 59; voglibose group: 46) were selected for the PP-analysis group (Fig. 1). There were no statistically significant differences in the clinical characteristics of the subjects in each group besides age (p = 0.0011) and a history of smoking (p = 0.0430) in Table 1. Efficacy At the conclusion of the study, the HbA1c levels had decreased by 0.9 ± 1.0% (7.5 ± 8.6 mmol/mol) in the mitiglinide group and by 0.7 ± 1.2% (5.3±10.8mmol/ mol) in the voglibose group (Fig. 2A). The decreases were significant in both groups, and the 95% one-sided confidence interval for the mean change between the two groups was -∞ to 0.09%. This value did not exceed the 0.3% non-inferiority margin and hence demonstrated the non-inferiority of mitiglinide compared to voglibose. The change in the daily profiles of SMBG levels from baseline to the end of study are shown in

Fig. 2. Both groups showed significant decreases in FPG levels during the study period. The FPG levels decreased by 1.25 ± 3.55 mmol/L in the mitiglinide group and by 0.94 ± 3.05 mmol/L in the voglibose group. The SMBG measurements of all the other time points at week 20 also significantly decreased compared with baseline within each mitiglinide (Fig. 2B) and voglibose groups (Fig. 2C). The mitiglinide group exhibited a greater decrease, but the difference between groups was not significant. As shown in Table 2, the M-values that were calculated from the SMBG measurements indicated that the mitiglinide group scored 41.4 ± 29.4 points prior to combination therapy and 23.8 ± 19.0 points after 20 weeks, while the voglibose group scored 49.6 ± 34.4 points at the beginning of the study and 28.7 ± 25.8 points after 20 weeks. These decreases were significant in both groups, but the difference in the decreased M-values between the groups was not significant. After the completion of the study protocol, there were 2 (2.5%) subjects in the mitiglinide group and 1 (1.3%) subject in the voglibose group with HbA1c levels below 6.5% (48 mmol/mol), whereas there were 13 (16.5%) subjects in the mitiglinide group and 5 (6.5%) subjects


5


Variables Age (yrs)

51.9 ± 8.3

Men, n (%)

Voglibose group (n = 77)

Mitiglinide group (n = 79)

56.1 ± 7.6

45 (57.0)

Duration of diabetes (yrs)

10.6 ± 5.5

47 (61.0)

A 11.0

12.2 ± 6.1

Smokers, n (%)

12 (15.2)

22 (28.6)

Bodyweight (kg)

67.5 ± 10.2

67.0 ± 10.1

BMI (kg/m2)

25.1 ± 2.5

25.0 ± 2.8

8.9 ±1.0

9.1 ± 1.0

Mitiglinide Voglibose

10.0 HbAlc (%)

Table 1 Baseline characteristics of the subjects in the intentionto-treat population

9.0 8.0 7.0 6.0

B

Baseline

400

77 ± 9.6 7.2 ± 2.6

0.85 ± 0.34

0.87 ± 0.53

Obese Obese (BMI>25) Non-obese (BMI≤25)

n C-peptide level n C-peptide level

34

28

0.98 ± 0.41

1.14 ± 0.77

45

49

0.76 ± 0.25

0.72 ± 0.21

69

70

0.86 ± 0.35

0.86 ± 0.55

10

7

0.82 ± 0.24

1.03 ± 0.30

Glucose (mg/dL)

Fasting C-peptide (nmol/L)

75 ± 9.5 7.2 ± 3.2

300

200

C

400

300

BB

≥ 5yrs < 5yrs

C-peptide level n C-peptide level

Total cholesterol (mmol/L)

4.5 ± 1.0

4.2 ± 0.9

Triglycerides (mmol/L)

1.7 ± 1.2

1.6 ± 1.0

HDL-cholesterol (mmol/L)

1.2 ± 0.2

1.2 ± 0.2

AB

BL

*

*

* AL

BD

AD

BS

Baseline (Voglibose) Week 20 (Voglibose)

Duration of DM n

*

* 0

*

*

100

Glucose (mg/dL)

IFCC (mmol/mol) Fasting plasma glucose (mmol/L)

20 Weeks

Baseline (Mitiglinide) Week 20 (Mitiglinide)

HbA1c NGSP (%)

12 Weeks

200 *

*

100

*

* *

*

* 0

BB

AB

BL

AL

BD

AD

BS

Data are expressed as the means ± SD or percentage.

Fig. 2 Changes in plasma glycated hemoglobin (HbA1c) level after combination therapy. (A) Changes in daily profiles of glucose levels at 7-points from baseline to week 20 in patients treated with mitiglinide (B) or voglibose (C). BB, before breakfast; AB, 2 hours after breakfast; BL, before lunch; AL, 2 hours after lunch; BD, before dinner; AD, 2 hours after dinner; BS, before sleep. * p < 0.05; Change from baseline

in the voglibose group with HbA1c levels below 7% (53 mmol/mol). Although the rate of individuals achieving the target HbA1c level was higher for the mitiglinide group, the between-group difference in these rates was not significant (p = 0.0515). Both groups received significantly increased insulin doses during the study period, as the mitiglinide group reported a 3.3 ± 10.3 unit increase and the voglibose group reported a 6.0 ± 10.4 unit increase. Once again, although the mitiglinide

group demonstrated a smaller increase in insulin dose, the difference between the two groups was not significant. The hsCRP level is commonly used as an inflammatory response index, and some reports indicate that it can also be related to insulin resistance. Therefore, the changes in hsCRP level before and after the administration of the investigated drugs was evaluated; the mitiglinide group experienced a 0.06 mg/dL decrease, and the voglibose group was found to have a 0.04 mg/dL

LDL-cholesterol (mmol/L)

2.4 ± 0.8

2.2 ± 0.7

C-reactive protein (mg/dL)

0.19 ± 0.32

0.17 ± 0.55

History of sulfonylurea medication, n (%)

78 (98.7)

74 (96.1)

History of insulin agent administration, n (%)

16 (20.3)

14 (18.2)


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Son et al.

Table 2 Changes in glycemic control over the 16 weeks of treatment Mitiglinide group (n = 79)

Voglibose group (n = 77)

Table 3 Adverse events by mitiglinide and voglibose Mitiglinide Voglibose group group p value (n = 79) (n = 81)

p value

HbA1c (%)

Serious adverse events (SAE)

Baseline

9.0 ± 1.1

9.2 ± 1.1

Liver and biliary disorders

End of study

8.0 ± 1.1

8.4 ± 1.3

Cholecystitis

Change from baseline

*

*,†

-0.9 ± 1.0

-0.7 ± 1.2

0.2445

1 (1.3)

5 (6.2)

0 (0.00)

1 (0.01)

Secondary terms

Fasting plasma glucose (mmol/L)

Intervertebral disc protrusion

1 (0.01)

0 (0.00)

Baseline

7.2 ± 3.2

7.2 ± 2.6

Burn

0 (0.00)

1 (0.01)

End of study

5.9 ± 1.7

6.2 ± 2.3

-1.2 ± 3.5*

-0.9 ± 3.0*

Respiratory system disorders Bronchopneumonia

0 (0.00)

1 (0.01)

Throat infection

0 (0.00)

1 (0.01)


0.5559

M-value Baseline

41.4 ± 29.4

49.6 ± 34.4

End of study

23.8 ± 19.0

28.7 ± 25.8

Change from baseline -18.5 ± 28.1*

-20.8 ± 33.4*

Neoplasm Gastric cancer, stage 0 0.6514

Daily insulin dose (U) Baseline

27.0 ± 12.4

26.7 ± 9.7

End of study

30.4 ± 13.8

32.7 ± 14.4

3.3 ± 10.3

6.0 ± 10.4

Baseline

0.2 ± 0.3

0.2 ± 0.6

End of study

0.1 ± 0.1

0.1 ± 0.2

Change from baseline -0.06 ± 0.3

-0.04 ± 0.5


0 (0.00)

1 (0.01)

Gastrointestinal adverse events

4 (5.1)

8 (9.9)

0.3693*

Any hypoglycemia

1 (1.3)

4 (4.9)

0.3673*

Adverse drug reaction Liver and biliary disorders

0.1069

C-reactive protein (mg/dL)

0.6898

67.6 ± 10.3

67.1 ± 10.2

End of study

68.5 ± 10.1

67.1 ± 10.4


0.93 ± 2.6*

0.01 ± 2.0

Achievement of treatment goal HbA1c < 7.0%, n (%)

13 (16.5)

5 (6.5)

0 (0.0)

1 (1.2)

0 (0.0)

1 (1.2)

Increased ALT

0 (0.0)

1 (1.2)

1 (1.3)

2 (2.5)

Hyperlipidemia

1 (1.3)

0 (0.0)

Hypoglycemia

0 (0.0)

1 (1.2)

Hypoglycemia, unperceived

0 (0.0)

2 (2.5)

1 (1.3)

0 (0.0)

Retinopathy, diabetes

1 (1.3)

0 (0.0)

Gastrointestinal disorders

1 (1.3)

0 (0.0)

1 (1.3)

0 (0.0)

Visual disorders 0.0137

Retching

0.0515

Systemic-general

Data are expressed as the means ± SD. *p < 0.05 was calculated by using paired t-test. †The 95% one-sided confidence interval of the mean-difference of the two groups was (-∞ to 0.09%), which did not exceed the 0.3% non-inferiority margin.

4 (5.1)

1 (1.2)

Tremor

0 (0.0)

1 (1.2)

Inertia

2 (2.5)

0 (0.0)

Weakness, systemic

2 (2.5)

0 (0.0)

Powerlessness Neuropsychologic disorders

decrease. Neither the difference between the pre- and post-treatment levels within each group nor the difference between the groups was significant. The drug efficacy was also evaluated in the PP-analysis group. Most of the variables evaluated were found to be similar to those of the ITT-analysis group, and no data for any of the categories were significantly different between the two groups. Safety A safety evaluation was carried out for 160 patients (mitiglinide group: 79; voglibose group: 81) in Table 3. There was at least one adverse event experienced

11 (13.9) 10 (12.3) 0.7675†

Increased AST Metabolic and nutritional disorders

Body Weight Baseline

0.2101*

Abnormal hunger Central and peripheral nerve

1 (1.3)

0 (0.0)

1 (1.3)

2 (2.5)

1 (1.3)

2 (2.5)

5 (6.3)

4 (4.9)

Myokymia

1 (1.3)

0 (0.0)

Headache

0 (0.0)

1 (1.2)

Tremor

1 (1.3)

0 (0.0)

Tremor, minor

1 (1.3)

0 (0.0)

Tremor, limbs

1 (1.3)

0 (0.0)

Vertigo

2 (2.5)

3 (3.7)

Skin disorder

2 (2.5)

1 (1.2)

Perspiration

2 (2.5)

0 (0.0)

Rosacea

0 (0.0)

1 (1.2)

*

Fisher’s exact test. †Pearson’s chi-square test.



by 35 patients (44.30%) in the mitiglinide group and 41 patients (50.62%) in the voglibose group, but the between-group difference was not significant (p = 0.4240). There were 5 subjects (3.13%) who experienced hypoglycemic adverse events; 1 (1.26%) of these were in the mitiglinide group and 4 (4.94%) were in the voglibose group, and there was no significant difference between groups (p = 0.3673). Adverse drug reactions were showed in 21 subjects; 11 (13.9%) of these were in the mitiglinide group and 10 (12.3%) of these were in the voglibose group, and there was not showing any difference of treatment groups (p = 0.7675). Six serious adverse events were reported in 6 subjects of which one subject was in the mitiglinide group and 5 subjects were in the voglibose group, but the events did not exhibit a causal relationship with the investigated drug treatments (p = 0.2101). There was no statistically significant between-group difference in the assignable variations for any laboratory test. For the differences between the groups in terms of vital sign measurement, body weight and BMI, the mitiglinide group showed a significant increase in body weight (gain of 0.9kg).

Discussion The objective of this trial was to comparatively evaluate the efficacy and safety of adding mitiglinide or voglibose to the basal insulin glargine treatment regimen of patients with type 2 diabetes. The primary and secondary efficacy endpoints assessed were the changes in the HbA1c, FPG, and SMBG values, the change in the insulin dose throughout treatment and the proportion of subjects who attained an HbA1c level < 7.0% (53 mmol/mol). Mitiglinide stimulates insulin secretion by blocking the KATP channel in pancreatic beta cells, which thereby induces an influx of excess calcium. This drug exhibits an extremely rapid onset and short duration for lowering the plasma glucose level, and it is therefore effective at reducing postprandial hyperglycemia and carries a lower risk of hypoglycemia than sulfonylurea [23]. Mitiglinide has been widely used alone or in combination with other OHA and basal insulin therapies for the glycemic control of type 2 diabetes. Voglibose is a well-established second-generation alpha-glucosidase inhibitor. In Asia, because of predominant high PPG, use of glinides and alpha-glucosidase is quite popular than western countries [24]. However, no studies have compared the effects of mitiglinide or voglibose in combination with

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insulin glargine for glycemic control. The primary endpoint of this study was the reduction of the HbA1c level after 16 weeks of treatment. For this measure, the administration of mitiglinide with insulin glargine was non-inferior to combination therapy with voglibose. At the end of the study, there was no significant between-group difference in the achievement rate of the HbA1c goal. However, more subjects in the mitiglinide group exhibited HbA1c decreases greater than 0.5% [mitiglinide group: 55 (69.9%); voglibose group: 44 (57.1%)]. The FPG and SMBG secondary endpoint values were also similar between the mitiglinide group and the voglibose group, although the mitiglinide group required a smaller increase in the insulin dose during basal insulin therapy. Both regimens were associated with similar frequencies of adverse events, including hypoglycemic events. These findings correspond well to those of similar comparative studies that have reported the efficacy of glinide and acarbose combined with insulin glargine therapy for glycemic control [17, 25]. A recent study, which evaluated the use of insulin glargine in combination with either repaglinide or acarbose, found that both combination therapies decreased HbA1c levels by approximately 3.0% (9 mmol/mol) and were equally effective at reducing FPG and PPG excursions [25]. However, the HbA1c, FPG and PPG levels remained above the recommended level at the end of the study period. These results were likely a result of the small number of study participants (each group consisted of 20 patients), the high HbA1c levels (11%) at the start of the trial and the absence of an insulin pre-treatment period. In addition, these studies reported that weight gain and severe hypoglycemic events were more prevalent in the repaglinide group. In our study, the mitiglinide group also experienced weight gain of 0.9kg, but there was no between-group difference in the number of hypoglycemic events. Another study compared the efficacy and safety of nateglinide or acarbose when combined with basal insulin for the control of PPG after the FPG had been optimized with insulin glargine prior to randomization [18]. This study also reported no significant differences in the mean glucose level, PPG excursions or the mean average glucose excursions between the two regimens, and these results were similar to those of our study. These authors did suggest that beta cell function may be an important factor for predicting the response to treatment. Similarly, in our study, the concurrent use


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of mitiglinide with insulin glargine was shown to be more effective for subjects with C-peptide levels above 1.0 nmol/L. For subjects with C-peptide levels above 1.0 nmol/L, the HbA1c levels were decreased by 1.2% (10.8 mmol/mol) in the mitiglinide group. In the voglibose group, there was no significant difference in the HbA1c level based on C-peptide level. Moreover, considering the different mechanisms of action of mitiglinide and voglibose, we carried out subgroup analyses to verify the effectiveness of each drug. By examining changes in HbA1c levels in regards to body weight before and after drug treatment, we found that patients with body weights greater than 80 kg in the mitiglinide group had a 1.2% (10.8 mmol/mol) decrease in their HbA1c levels and those patients in the voglibose group had a 0.5% (3.1 mmol/mol) decrease. The decrease seen for the mitiglinide group was significant, but the decrease of the voglibose group was not. A similar tendency was found when the results analyzed by BMI were examined. In the BMI subgroups of over 29, the mitiglinide group showed a statistically significant HbA1c decrease (−1.5% [−14 mmol/mol], p = 0.0196) unlike the voglibose group (−0.0% [0 mmol/ mol], p = 0.9063). Recently, one study showed that a greater effect of nateglinide was observed in patients with a more severe insulin resistance [26]. Obese type 2 diabetes patients were characterized by an increased insulin resistance rather than the loss of early phase of insulin secretion. In our study, we assumed that mitiglinide improve PPG level via amelioration of insulin resistance as well as augmentation of early insulin response in obese type 2 diabetes patients. When changes in HbA1c levels were analyzed according to the duration of diabetes, only patients with a duration of less than five years in the mitiglinide group exhibited significant decreases in their HbA1c levels upon drug therapy. It was anticipated that the concurrent use of mitiglinide with insulin glargine would be more effective for subjects with greater body weight, a shorter diabetic duration, relatively normal pancreatic beta cell function and high C-peptide levels. These findings were consistent with an earlier study, which had

reported that patients who responded to the combination of mitiglinide with insulin glargine were younger, more obese and had higher endogenous insulin secretion capacity than non-responders [27]. We found no significant differences between the two groups in terms of the frequency of adverse events, the frequency of hypoglycemic events, or abnormal laboratory test and physical examination results. The majority of the events observed were of mild to moderate intensity. The limitations of this study included the use of an open-label design and the fact that the analysis was restricted to Asian patients. Patient awareness as to thetreatment received may have influenced glycemic control-related lifestyle modifications and the reporting of adverse events during the study period. In addition, number of subjects who dropped out the study and excluded from the PP analysis in voglibose (n=35/81) is around 1.7 times more than that in mitiglinide (n=20/79). It is mainly due to the subject deviation rather than investigator selection bias. However, this protocol deviation does not affect the overall results in a PP analysis compared to the analysis of changes within andbetween the treatment groups for efficacy variables using an ITT analysis. In conclusion, this study confirmed the non-inferiority of the concomitant use of insulin glargine with mitiglinide compared to voglibose. Various evaluations verified that both regimens helped to control and improve glycemic control in patients with type 2 diabetes. Furthermore, the use of mitiglinide with insulin glargine is suggested as a more effective therapy for overall glycemic control.

Conflict of Interest The authors have no conflicts of interest to declare.

Acknowledgement This work was supported by JW Pharmaceutical Corporation, Korea. This study is registered ClinicalTrials.gov, number NCT00663884.

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