Repeated postprandial hyperglycemia may play an important role in the development of atherosclerosis by suppressing vascular endothelial function. Although miglitol suppresses the elevation of blood glucose levels shortly after a meal more than other α-glucosidase inhibitors, the effect of 3-month repeated administration of miglitol on endothelial dysfunction is unknown. Fifty patients with type 2 diabetes and coronary artery disease were enrolled in the present study. The patients were randomly divided into 2 groups, the first treated with miglitol and the second with voglibose for 3 months. Blood chemistry (lipid and blood glucose profiles, glycosylated hemoglobin, 1,5-anhydroglucitol, serum insulin levels, and C-reactive protein) and flow-mediated dilatation were measured at the beginning and end of the trial period. Patient characteristics and blood chemistry of the 2 groups were similar at the beginning of the trial. At the end of the trial, glycosylated hemoglobin decreased in the 2 groups, but the improvements in 1,5-anhydroglucitol in the miglitol group were significantly higher than in the voglibose group. Insulin resistance index, C-reactive protein, and percentage flow-mediated dilatation were also improved in the miglitol group but not in the voglibose group. In conclusion, 3-month repeated administration of miglitol improved vascular endothelial dysfunction by strongly suppressing postprandial hyperglycemia. Miglitol may have antiatherogenic effects in patients with type 2 diabetes and coronary artery disease.
Miglitol is a new α-glucosidase inhibitor (α-GI) that is absorbed rapidly and almost completely from the small intestine after oral administration, consequently suppressing postprandial blood glucose levels more effectively than other α-GIs. Hiki et al demonstrated that a single administration of miglitol significantly improved postprandial hyperglycemia and postprandial endothelial dysfunction in patients with diabetes and coronary artery disease (CAD). However, the effect of repeated administration of miglitol on vascular endothelial dysfunction is not clear. We hypothesized that repeated administration of miglitol for 3 months might improve vascular endothelial dysfunction by suppressing daily postprandial glucose levels in patients with diabetes and CAD. In the present study, we measured blood biochemistry and vascular endothelial function with flow-mediated dilatation (FMD), a noninvasive assessment of endothelial dysfunction, before and after 3-month administration of miglitol and compared these data with data from patients receiving the α-GI voglibose.
Methods
Fifty patients with type 2 diabetes and CAD were prospectively recruited from Hyogo Prefectural Awaji Hospital. Diabetes mellitus was diagnosed according to Japan Diabetes Society criteria (fasting blood glucose >126 mg/dl, blood glucose >200 mg/dl 2 hours after administration of 75 g glucose in an oral glucose tolerance test, glycosylated hemoglobin (HbA 1c ) ≥6.5%, or use of oral hypoglycemic antidiabetic medications oral hypoglycemic agents).
Inclusion criteria were age 40 to 90 years and documented CAD, defined as >50% diameter stenosis of a coronary artery observed on angiography, history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery. Exclusion criteria were type 1 diabetes mellitus; previous receipt of α-GI therapy; systemic disease including hepatic disease, renal disease (serum creatinine >2.5 mg/dl), collagen disease, and malignancy; HbA 1c >8.0%; and percentage change in FMD >7.0%. Patients with HbA 1c levels >8.0% were excluded, because previous studies have demonstrated that persistent glycosuria due to severe hyperglycemia may lead to depletion of the plasma level and pooling of 1,5-anhydroglucitol (1,5-AG). Patients with percentage changes in FMD >7.0% at the beginning of the study were also excluded, because this FMD change represents normal endothelial function, and the aim of the present study was to examine the effect of α-GIs on endothelial dysfunction. No subjects changed daily dietary habits during the examination period.
Researchers provided full verbal and written explanations of the nature and purpose of the study to all subjects, who subsequently provided written informed consent. The study was approved by the ethics committee of Hyogo Prefectural Awaji Hospital.
Subjects were randomly divided into 2 groups of 25 patients each. Patients in the miglitol group were administered miglitol 150 mg/day, and those in the voglibose group were administered voglibose 0.6 mg/day. If blood glucose levels were considered uncontrollable (HbA 1c >7.0% after 1 month of drug administration) by α-GI monotherapy, we administered additional antidiabetic agents, mainly sulfonylurea, to more adequately control glucose levels.
Blood samples were collected from all patients after overnight fasting at the beginning and end of the 3-month trial period. Plasma concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, fasting blood glucose, HbA 1c , 1,5-AG, serum creatinine, and C-reactive protein were measured. The homeostasis model assessment ratio ([immunoreactive insulin × fasting blood glucose]/405) was calculated as an index of insulin resistance.
Subjects were instructed to abstain from smoking, alcohol, caffeine, and antioxidant vitamins for ≥12 hours and to fast for ≥4 hours before FMD measurements in the morning. High-resolution ultrasound with a 10-MHz linear-array transducer probe (UNEXEF18G; Unex Company Ltd., Nagoya, Japan) was used to acquire images of the brachial artery. After baseline images of the brachial artery were recorded, a pediatric cuff was inflated to 50 mm Hg higher than the subject’s systolic blood pressure to occlude the brachial artery and was kept inflated for 5 minutes. The cuff was then deflated, and images of the brachial artery were recorded for 2 minutes. Images of the brachial artery diameters were captured in diastole (gated with the electrocardiographic R wave), and semiautomated readings (medial-adventitial interfaces to medial-adventitial interfaces) were recorded. Percentage FMD change in brachial artery diameter was computed from initial and maximum diameters as (maximum diameter − baseline diameter)/baseline diameter × 100%.
Measurements were taken by 2 experienced technicians blinded to patients’ data or test groups. The estimated limit of agreement for percentage FMD measurements was calculated using a Bland-Altman plot (intraobserver mean difference 0.05%, upper 2 SDs 0.51%, lower 2 SDs −0.39%, percentage disparity 4.3%; interobserver mean difference 0.06%, upper 2 SDs 0.82%, lower 2 SDs −0.72%, percentage disparity 4.2%).
Statistical analyses were conducted using MedCalc version 9.3 (MedCalc Software, Mariakerke, Belgium). Continuous variables are expressed as mean ± SD. Comparisons between groups were performed using unpaired Student’s t tests, Mann-Whitney U tests, or chi-square tests as indicated. Changes in biochemical data before and after treatment were compared using paired Student’s t tests.
The relation between change in FMD from the beginning of the trial and changes in other biologic variables was investigated using Pearson’s correlation coefficient and Spearman’s rank correlation coefficient in all cohorts. A multiple linear regression analysis was also performed to explore determinants of changes in FMD from baseline in all cohorts. Biologically plausible factors (age, gender, and concomitantly used drugs) were included in the original model. Two-tailed p values <0.05 were considered statistically significant.
Results
At the beginning of the trial, patient characteristics ( Table 1 ) and blood biochemistry ( Table 2 ) were similar between the 2 groups. In the voglibose group, 3 patients developed intestinal side effects and dropped out, and 1 patient was removed because of poor compliance. In the miglitol group, 1 patient developed intestinal side effects and dropped out. Concomitant use of sulfonylurea was higher in the voglibose group, but the difference was not significant.
| Variable | Voglibose Group | Miglitol Group | p Value |
|---|---|---|---|
| (n = 21) | (n = 24) | ||
| Age (years) | 70.4 ± 5.2 | 70.1 ± 10.4 | 0.90 |
| Men | 11 (52%) | 13 (54%) | 0.80 |
| Body mass index (kg/m 2 ) | 24.1 ± 4.3 | 23.5 ± 3.8 | 0.63 |
| Hypertension | 15 (71%) | 16 (66%) | 0.98 |
| Dyslipidemia | 15 (71%) | 18 (75%) | 0.90 |
| Diabetes mellitus | 21 (100%) | 24 (100%) | 0.99 |
| Smoking history | 4 (19%) | 9 (38%) | 0.30 |
| Previous percutaneous coronary intervention | 21 (100%) | 24 (100%) | 0.99 |
| Previous coronary artery bypass grafting | 2 (9.5%) | 1 (4%) | 0.90 |
| Old myocardial infarction | 4 (19%) | 10 (41%) | 0.18 |
| Concomitantly used drug | |||
| Statins | 16 (76%) | 18 (75%) | 0.42 |
| Angiotensin receptor blocker/angiotensin-converting enzyme inhibitor | 14 (66%) | 16 (66%) | 0.74 |
| Sulfonylurea agent | 11 (52%) | 6 (25%) | 0.11 |
| Peroxisome proliferator–activated receptor–γ agonist | 6 (28%) | 8 (33%) | 0.98 |
| Variable | Voglibose Group | Miglitol Group | p Value |
|---|---|---|---|
| (n = 21) | (n = 24) | ||
| Total cholesterol (mg/dl) | 182 ± 48 | 180 ± 30 | 0.87 |
| LDL cholesterol (mg/dl) | 110 ± 38 | 104 ± 25 | 0.54 |
| HDL cholesterol (mg/dl) | 49 ± 20 | 49 ± 15 | 0.94 |
| Triglyceride (mg/dl) | 131 ± 84 | 136 ± 78 | 0.84 |
| Fasting blood glucose (mg/dl) | 131 ± 55 | 136 ± 78 | 0.97 |
| HbA 1c (%) | 6.7 ± 0.7 | 6.7 ± 0.8 | 0.86 |
| 1,5-AG | 16.2 ± 8.3 | 14.5 ± 8.7 | 0.45 |
| Homeostasis model assessment ratio | 5.1 ± 5.3 | 4.7 ± 4.0 | 0.79 |
| C-reactive protein | 0.34 ± 0.47 | 0.29 ± 0.49 | 0.76 |
| Percentage FMD | 3.0 ± 1.9 | 2.8 ± 1.9 | 0.71 |
Although HbA 1c and 1,5-AG levels were similar between the groups after 3 months of treatment, the improvement in 1,5-AG levels was significantly higher in the miglitol group than in the voglibose group after 3 months (+6.8 μg/ml in the miglitol group vs +1.4 μg/ml in the voglibose group).
The index of insulin resistance (homeostasis model assessment ratio) and levels of C-reactive protein were improved in the miglitol group but not in the voglibose group after 3 months ( Table 3 ). Similarly, percentage FMD was improved in the miglitol group (+2.5%; p < 0.001) but not in the voglibose group (+0.2%; p = 0.36) after 3 months ( Table 3 , Figure 1 ) .
| Variable | Voglibose Group | Miglitol Group | ||
|---|---|---|---|---|
| Baseline | 3 Months | Baseline | 3 Months | |
| Total cholesterol (mg/dl) | 182 ± 48 | 172 ± 39 | 180 ± 31 | 171 ± 28 |
| Low-density lipoprotein cholesterol (mg/dl) | 110 ± 38 | 99 ± 30 | 104 ± 25 | 97 ± 19 |
| High-density lipoprotein cholesterol (mg/dl) | 49 ± 20 | 52 ± 22 | 49 ± 15 | 53 ± 17 |
| Triglyceride (mg/dl) | 131 ± 84 | 141 ± 96 | 136 ± 78 | 118 ± 51 |
| Fasting blood glucose (mg/dl) | 131 ± 55 | 116 ± 60 ⁎ | 136 ± 78 | 112 ± 34 ⁎ |
| HgA 1c (%) | 6.6 ± 0.7 | 6.1 ± 0.8 ⁎ | 6.6 ± 0.8 | 6.0 ± 0.7 ⁎ |
| 1,5-AG | 16.2 ± 8.3 | 17.6 ± 8.6 ⁎ | 14.5 ± 8.7 | 21.3 ± 9.8 ⁎ |
| Homeostasis model assessment ratio | 5.1 ± 5.3 | 8.2 ± 8.9 | 4.7 ± 4.0 | 2.5 ± 3.7 ⁎ |
| C-reactive protein | 0.34 ± 0.47 | 0.37 ± 0.61 | 0.29 ± 0.49 | 0.10 ± 0.18 ⁎ |
| Percentage FMD | 3.0 ± 1.9 | 3.2 ± 1.7 | 2.8 ± 1.9 | 5.3 ± 2.1 ⁎ |
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