Journal of Diabetes • • (2018), • • – • •
ORIGINAL ARTICLE
Glucose excursions and hypoglycemia in patients with type 2 diabetes treated with mitiglinide/voglibose versus glimepiride: A randomized cross-over trial* Highlights • This is the first randomized cross-over trial using continuous glucose monitoring to compare glucose excursions and hypoglycemia frequency in patients with type 2 diabetes treated with mitiglinide/voglibose versus glimepiride as add-on to the dipeptidyl peptidase-4 (DPP-4) inhibitor. • The mean glucose levels in the mitiglinide/voglibose and glimepiride phases were identical, but fewer glucose excursions and no episodes of hypoglycemia were observed with mitiglinide/voglibose. • Mitiglinide/voglibose as an add-on to a DPP-4 inhibitor may be a suitable therapeutic option for preventing cardiovascular events.
Kanta FUJIMOTO ,1,2* Yui SHIBAYAMA,1 Eriko YAMAGUCHI,1 Sachiko HONJO,1 Akihiro HAMASAKI1 and Yoshiyuki HAMAMOTO1,3 1
Center for Diabetes and Endocrinology, Tazuke Kofukai Foundation Medical Research Institute Kitano Hospital, Osaka, Japan, 2Department of Diabetes and Endocrinology, Kobe City Medical Center General Hospital, Kobe, Japan, and 3Center for Diabetes and Endocrinology, Kansai Electric Power Hospital, Osaka, Japan
Correspondence Kanta Fujimoto, Department of Diabetes and Endocrinology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe 6500047, Japan. Tel: +81 78 302 4321 Fax: +81 78 302 7537 Email:
[email protected] *This study is registered with University Hospital Medical Information Network Clinical Trials Registry (ID: UMIN000024817). Received 27 September 2017; revised 22 January 2018; accepted 26 February 2018. doi: 10.1111/1753-0407.12658
Abstract Background: Glucose excursions and hypoglycemia are associated with cardiovascular complications. However, no studies have evaluated glucose excursions and the frequency of hypoglycemia in patients treated with mitiglinide/voglibose versus glimepiride as add-on to dipeptidyl peptidase-4 inhibitor therapy. Methods: This cross-over trial included 20 patients with type 2 diabetes. After initiating vildagliptin 100 mg, patients were randomly assigned to receive mitiglinide 10 mg/voglibose 0.2 mg three times daily for 3 days followed by glimepiride 1 mg once daily for the subsequent 3 days as add-on therapy, or vice versa. Glucose excursions and hypoglycemia frequency were measured using 24-h continuous glucose monitoring. Metabolic profile changes were evaluated using a meal tolerance test. Results: The mean glucose levels in the mitiglinide/voglibose and glimepiride phases were identical (8.01 vs 8.24 mmol/L, respectively). However, during the mitiglinide/voglibose phase compared with the glimepiride phase, the standard deviation of glucose (1.30 vs 2.10 mmol/L; P < 0.001), mean amplitude of glycemic excursions (3.47 vs 5.28 mmol/L; P < 0.001), M-value (24.6 vs 70.0; P < 0.001), continuous overlapping net glycemic action for a 1-h time interval (22.6 vs 31.0; P < 0.001), and area under the curve >10 mmol/L (0.18 vs 0.52 mmol/L per h; P < 0.001) were significantly lower. Hypoglycemia (glucose 2.5 days for insulin aspart and > 3 days for insulin glargine before the evaluation periods were scheduled. Mitiglinide 10 mg/voglibose 0.2 mg was administered as a fixed-dose combination drug (Kissei Pharma, Matsumoto, Japan) three times daily before meals. Glimepiride 1 mg (Sanofi, Gentilly, France) was administered after breakfast. Standard meal tolerance tests (MTT) containing approximately 500 kcal (60% carbohydrate, 20% protein, and 20% fat) were conducted after an overnight fast on the last day of both treatment phases, and changes in metabolic profiles were evaluated. The study strategy is shown in Fig. 1. The study protocol was approved by the Ethics Committee of Kitano Hospital, where the study was conducted, and the study was performed in accordance with the principles of the Declaration of Helsinki. All study participants provided written informed consent at the time of enrollment. This study is registered with University Hospital Medical Information Network Clinical Trials Registry (ID: UMIN000024817). Efficacy parameters The primary efficacy endpoint was the difference in glycemic excursions between the two phases, assessed by analyzing 24-h CGM data on the last day of each treatment phase. To minimize possible carryover effects, there was a 2-day period before each CGM period instead of having a washout period. This interval also provided almost enough time (>4 days) for stabilization
Randomization
K. FUJIMOTO et al. >2 days
3 days
3 days
>2 days
3 days
3 days
CGM
CGM
MTT
MTT
Figure 1 Study design: open-label two-way randomized cross-over trial. Evaluation periods are the last day of both periods. MV, mitiglinide and voglibose; CGM, continuous glucose monitoring; MTT, meal tolerance test.
of vildagliptin treatment. The following efficacy measures were assessed: glycemic variability, including the standard deviation (SD) of sensor glucose levels measured via CGM, the mean amplitude of glycemic excursions (MAGE), the M-value, the continuous overlapping net glycemic action for a 1-h time interval (CONGA 1), and the area under the curve (AUC) >10 mmol/L. The MAGE was obtained by measuring the arithmetic mean of the changes >1 SD between sequential peaks and nadirs; this method has been widely used to assess glycemic fluctuation and variability.7 The M-value was calculated for each glucose value using a formula and was then divided by the total number of values to produce a mean.8 The CONGA 1 value represents the SD of differences between the current period and the period 1 h earlier.9 The mean glucose level was obtained by averaging the 288 sensor values measured during the 24-h CGM period. The secondary endpoint was the difference in the frequency of hypoglycemic episodes (glucose level < 3.8 mmol/L) during the 24-h CGM period. During the MTT, metabolic profile changes in plasma glucose, insulin, and glucagon levels from premeal to 120 min after the meal were measured by standard radioimmunoassays.
Diet and exercise The diet during the study period was determined to provide a total caloric intake of 25–30 kcal/kg per day, with approximately 60% of calories derived from carbohydrates, 20% from proteins, and 20% from fats. Meals were served at 0800 hours (breakfast), 1200 hours (lunch), and 1800 hours (dinner). During the study period, patients were asked to exercise as previously and not to change the exercise intensity and period according to their capability.
© 2018 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.
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Low glucose variability with αGI/glinide Table 1
K. FUJIMOTO et al.
Baseline characteristics of the study subjects (n = 20)
Age (years) Male BMI (kg/m2) Duration of diabetes (years) HbA1c (%) HbA1c (mmol/mol) FPG (mmol/L) HOMA-R HOMA-β eGFR (mL/min/1.73 m2) Complications Retinopathy Nephropathy Neuropathy Macroangiopathy Medications used before the trial Sulfonylurea Metformin Pioglitazone DPP-4 inhibitor αGI
65.6 11.5 10 (50) 25.6 3.8 10.7 8.7 9.4 3.4 79 16 7.53 1.44 2.5 1.0 39.9 17.7 75.3 21.5 8 (40) 6 (30) 13 (65) 5 (25) 11 (55) 6 (30) 1 (5) 11 (55) 4 (20)
Data are given as the mean SD or as n (%). BMI, body mass index; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; HOMA-R, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment of β-cell function; eGFR, estimated glomerular filtration rate: αGI, α-glucosidase inhibitor.
Statistical analysis Because comparative data on the primary endpoints of both therapies have not been published, sample size calculations were based on the feasibility of conducting a study and clinical considerations, referencing results of a similar study that used CGM.10 An assumed the detectable difference between therapies of 0.52 mmol/L and an SD of 0.53 mmol/L for the “SD of glucose” as the primary endpoint were established. Using a twosided significance level of 0.05 and power of 80% in a cross-over study with an estimated dropout rate of 5%, we estimated that a sample size of 20 participants was required. Considering the possible carryover effect of both therapies due to non-washout (“sequence effect”), we performed subanalyses stratified by the order of drug use. In addition, efficacy endpoints were analyzed using an intention-to-treat approach with a linear mixedeffect model with treatment, sequence, and period as fixed effects and patients as a random effect. Normally distributed data are presented as the mean SD and effect sizes between therapies are presented as the standardized effect size of least square mean with biascorrected (Hedges’ g). Statistical analyses were performed using JMP 13 (SAS Institute, Cary, NC, USA) and statistical significance was defined as P < 0.05. 4
Results Twenty patients were enrolled in the study, and there was no attrition. The baseline characteristics of the study subjects are given in Table 1. More than 50% of patients had been treated with DPP-4 inhibitors before participating in this trial. Glucose fluctuations, assessed by 24-h CGM, are shown in Fig. 2. The mean glucose levels of the mitiglinide/voglibose and glimepiride phases were very similar (8.01 1.33 and 8.24 1.61 mmol/L, respectively; P = 0.184; Table 2). However, postprandial glucose levels were lower in the mitiglinide/voglibose than glimepiride phase, with a lower SD of glucose (1.30 0.45 vs 2.10 0.61 mmol/L, respectively; P < 0.001), MAGE (3.47 1.28 vs 5.28 2.15 mmol/ L, respectively; P < 0.001), M-value (24.6 27.2 vs 70.0 61.9, respectively; P < 0.001), CONGA 1 value (22.6 7.2 vs 31.0 9.1, respectively; P < 0.001), and AUC >10 mmol/L (0.18 0.27 vs 0.52 0.55 mmol/L per h, respectively; P < 0.001; Table 2). The linear mixed-effect model analyses of glucose fluctuations demonstrated no sequence or period effects (all P > 0.05). In the subanalysis of drug order, the mean glucose level in both phases was identical in the population receiving mitiglinide/voglibose first (8.18 1.36 vs 8.10 1.80 mmol/L; P = 0.838), whereas the population receiving glimepiride first had a lower mean glucose level with mitiglinide/voglibose than with glimepiride (7.70 1.45 vs 8.31 1.60 mmol/L, respectively; P = 0.003). The SD of glucose was lower in the mitiglinide/voglibose than in the glimepiride phase, regardless of drug order (mitiglinide/voglibose first: 1.36 0.53 vs 2.17 0.70 mmol/L, respectively [P = 0.008]; glimepiride first: 1.23 0.40 vs glucose (mmol/L)
percentile (75 50 25)
mitiglinide and voglibose (MV)
270
glimepiride (G)
234 198 162 126
90
MV
MV
MV G 1ᨩJ
54
time (hours)
breakfast
lunch
dinner
Figure 2 Glucose levels over 24 h during treatment with mitiglinide/voglibose (MV) or glimepiride (G) in 20 patients. Data show the 50th percentile (thick lines) with the corresponding 25th and 75th percentiles (thin lines).
© 2018 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.
Low glucose variability with αGI/glinide
K. FUJIMOTO et al. Table 2
Efficacy measures derived from continuous glucose monitoring
Mean glucose (mmol/L) Standard deviation (mmol/L) MAGE (mmol/L) M-value CONGA 1 value AUC >10 mmol/L (mmol/L per h) Hypoglycemia (no. times/day)
MV (n = 20)
Glimepiride (n = 20)
Effect size of LS mean difference (95% CI)
P-value
8.01 1.33 1.30 0.45 3.47 1.28 24.6 27.2 22.6 7.2 0.18 0.27 0
8.24 1.61 2.10 0.61 5.28 2.15 70.0 61.9 31.0 9.1 0.52 0.55 0.35
−0.15 (−0.77, 0.47) −1.46 (−2.16, −0.77) −1.00 (−1.66, −0.35) −0.93 (−1.58, −0.28) −1.00 (−1.66, −0.35) −0.77 (−1.41, −0.13)
0.184
