Comparison of three a-glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type 2 diabetes

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1 Comparison of three a-glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type diabetes Hitoshi Sugihara, Mototsugu Nagao, Taro Harada,YasushiNakajima, Kyoko Tanimura-Inagaki,FumitakaOkajima, Hideki Tamura, Takeshi Inazawa, Takatoshi Otonari 3, Masanobu Kawakami 4, Shinichi Oikawa Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Division of Endocrinology and Metabolism, Department of Medicine, Kashiwa City Hospital, Kashiwa, 3 Otonari Medical Clinic, Fukuoka, and 4 Department of Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan Keywords Bodyweight, Type diabetes mellitus, a-glucoseidase inhibitor Correspondence Shinichi Oikawa Tel.: Fax: address: shinichi@nms.ac.jp J Diabetes Invest 4; 5: 6 doi:./jdi.35 ABSTRACT Aims/Introduction: a-glucosidase inhibitors (agis) are widely used for the primary treatment of type diabetes. We compared the clinical effects of three agis (miglitol, acarbose and voglibose) in patients with obese type diabetes. Materials and Methods: Japanese patients (n = 8) with obese type diabetes (body mass index [BMI] 5 kg/m ) were enrolled in this multicenter, open-label study. The participants were randomized into the miglitol (n = 8), acarbose(n = ), voglibose (n = 9) or control (n = ) groups. Glycemic control (fasting blood glucose and glycated hemoglobin [HbAc]), bodyweight, BMI, serum insulin, serum lipids (low-density lipoprotein and high-density lipoprotein cholesterol, and triacylglycerols) and adipocytokines (leptin and adiponectin) were evaluated every 4 weeks for weeks. Results: In the miglitol group, HbAc was improved significantly from the baseline at all points. The changes in HbAc at 8 and weeks from baseline were greater in the miglitol group than the control group. The voglibose group showed significant improvements in HbAc at weeks. Bodyweight and BMI were decreased significantly in the miglitol group. In addition, significant correlations were observed between the decrements in HbAc and bodyweights over weeks in the miglitol (r =.759, P <.) and voglibose groups (r =.667, P =.). Serum lipid and adipocytokine levels were not altered in any groups. Conclusions: agis, especially miglitol, can effectively control blood glucose and bodyweight in obese type diabetes. This study was registered with UMIN (no. UMIN6465). INTRODUCTION Type diabetes is a well-known risk factor for cardiovascular disease. Several experimental results suggest that postprandial hyperglycemic spikes contribute to the pathophysiology of diabetic cardiovascular complications. The suppression of postprandial hyperglycemia is therefore a promising approach for preventing cardiovascular disease in type diabetes. Received 5 December ; revised July 3; accepted 3 July 3 a-glucosidase inhibitors (agis) are widely used for the primary treatment of type diabetes. They inhibit maltase, sucrase and other disaccharide hydrolases (i.e., suppress the degradation of disaccharides to monosaccharides) in the brush border membrane of the small intestine. Therefore, agis can improve postprandial hyperglycemia by delaying carbohydrate absorption. The Study to Prevent Non-Insulin-Dependent Diabetes Mellitus trial 3 showed that treatment with an agi, acarbose, is associated with a significant risk reduction in cardiovascular 6 J Diabetes Invest Vol. 5 No. March 4 ª 3 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 Comparison of a-glucosidase inhibitors events in patients with impaired glucose tolerance or type diabetes. Subsequently, much attention has been focused on agis as therapeutic agents for type diabetes and its complications. Weightgainintypediabetesnotonlyworsensdiabeticcontrol, but also increases the risk of diabetes-associated cardiovascular complications 4. However, glycemic control with insulin or certain oral hypoglycemic agents (insulin secretagogues and thiazolidinediones) promotes weight gain 5. In contrast, biguanides and incretin-related drugs (glucagon-like peptide [GLP-] analogs and dipeptidyl peptidase 4 inhibitors) have beneficial effects on bodyweight. Meanwhile, the effects of agis on bodyweight control remain unclear. Whereas some studies suggest that agis can reduce bodyweight in type diabetes 3,6, a meta-analysis of randomized controlled trials with acarbose showed that it has minor effects for lowering bodyweight 7. Three agis are now clinically available in Japan: acarbose, miglitol and voglibose. However, to our knowledge, there have been no reports comparing these drugs head-to-head. In the present study, we evaluated the effects of these three agis on glycemic control, weight management and other clinical measures in the treatment of Japanese patients with obese type diabetes. MATERIALS AND METHODS The present study was a multicenter (Nippon Medical School Hospital; Saitama Medical Center, Jichi Medical University; Hachijo Municipal Hospital; Kashiwa City Hospital; and Otonari Medical Clinic), open-label, randomized study. The protocol was approved by each institutional ethics review board, and all participants were enrolled after being informed of the clinical trial and providing written consent. Participants The study included 8 outpatients (38 men and 43 women) with obese type diabetes (aged 4 years; glycated hemoglobin [HbAc] %; body mass index [BMI] 5 kg/m ). HbAc was measured by the latex agglutination method and expressed as a National Glycohemoglobin Standardization Program (NGSP) equivalent value (%) 8,9. Patients who had received insulin therapy or agi medication, or had a serious hepatic, renal, or cardiac disease were excluded. Study Design After the informed consent was obtained, an application form was sent to an external registration center by facsimile. Approved participants were allocated to one of four treatment groups using a random number list for miglitol (5 mg/day), acarbose (3 mg/day), voglibose (.9 mg/day) and control (no additive medication). The dose of miglitol was not the maximum dose approved in Japan (5 mg/day), whereas acarbose and voglibose were used at maximum doses, because these doses are generally used in practice. All patients underwent a -week therapy with the assigned regimen, and were instructed to maintain their usual diet and medications over the study period. Anthropometric measurements and blood sample tests were carried out after an overnight fast at baseline, and 4, 8 and weeks after the treatment. The primary end-points were HbAc,bodyweightandBMI,aswellastheirchangesfrom baseline after drug treatment. The secondary end-points included other glycemic parameters (fasting plasma glucose [FPG] and serum insulin), serum lipids (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triacylglycerols [TG]) and adipocytokines (leptin and adiponectin). All patients completed questionnaires about their digestive symptoms (borborygmus, abdominal distension, flatulence and fecal condition), appetite and drug compliance every 4 weeks. Statistical Analyses The clinical characteristics of patients were analyzed by the v -test or one-way analysis of variance (ANOVA). The changes over the study period were analyzed by two-way ANOVA with Bonferroni correction. Intergroup differences were analyzed by two-way repeated-measures ANOVA with Bonferroni correction. The questionnaire results were analyzed by the Friedman test with Bonferroni correction. The level of statistical significance was set at P <.5. Associations between changes in HbAc and bodyweight were evaluated by Pearson s correlation coefficient analysis. All statistical analyses were carried out using SPSS for Windows, Japanese version 6. (SPSS Institute Inc., Tokyo, Japan). RESULTS Of the 8 enrolled patients, 78 had sufficient baseline and follow-up data to evaluate the primary end-points (Figure ). Two patients in the control group and one in the acarbose group with insufficient data were excluded from the statistical analysis. The baseline characteristics of the study participants are shown in Table. There were no significant differences in the clinical characteristics among the four groups. Primary Endpoints Table shows HbAc, bodyweight, and BMI in the four groups. In the control group, HbAc increased significantly from baseline at weeks of treatment. In the miglitol group, HbAc decreased significantly from baseline at 4 weeks, and the decreased HbAc level was kept over the study period. In the voglibose group, a significant decrease was observed in HbAc after weeks of treatment. HbAc did not change significantly in the acarbose group over the study period (Table ). In addition, the changes in HbAc from baseline (DHbAc) in the miglitol group were greater than those in the control group at 8 and weeks of treatment (Figure a). The bodyweight of the miglitol group decreased significantly from baseline at 4, 8 and weeks of treatment, whereas no significant bodyweight changes were observed in any other groups over the study period (Table and Figure b). Conse- ª 3 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. 5 No. March 4 7

3 Sugihara et al. Participants (n = 8) Control group (n = ) Miglitol group (n = 8) Acarbose group (n = ) Voglibose group (n = 9) (n = ) (n = 8) (n = ) (n = 9) (n = 7) (n = 4) (n = 4) (n = 5) Figure Flow diagram of the study. Table Baseline characteristics of the participants Control Miglitol Acarbose Voglibose Significance No. of patients 8 9 Male/female 7/5 /8 3/9 8/ NS Age (years) NS Height (cm) NS Bodyweight (kg) NS BMI (kg/m ) NS HbAc, NGSP (%) NS FPG (mmol/l) NS Total cholesterol (mmol/l) NS LDL cholesterol (mmol/l) NS HDL cholesterol (mmol/l) NS TG (mmol/l) NS Concomitant medications, n (%) Oral hypoglycemic agents 9 (86.4) (66.7) 5 (68.) 6 (84.) NS Sulfonylurea 6 (7.3) 8 (44.4) 8 (36.4) 8 (4.) NS Glinide 8 (36.4) (.) 4 (8.) 3 (5.8) NS DPP-4 inhibitor (.) (.) (.) (5.3) NS Thiazolidinedione 3 (3.6) 3 (6.7) (4.6) 3 (5.8) NS Metformin (5.) 5 (7.8) (5.) 8 (4.) NS Hypotensive agents 8 (8.8) 4 (77.8) (5.) 5 (79.) NS Hypolipidemic agents (5.) 4 (.) 8 (36.4) (5.6) NS Data are expressed as mean standard deviation. BMI, body mass index; FPG, fasting plasma glucose; HbAc, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NGSP, National Glycohemoglobin Standardization Program; TG, triacylglycerols; DPP-4, dipeptidyl peptidase 4. NS, not significant (P.5). quently, BMI was decreased from baseline only in the miglitol group at 4, 8 and weeks (Table and Figure c). However, no significant differences were observed in the changes from baseline in bodyweight (DBW) or BMI (DBMI) among the four groups (Figure b,c). There were significant correlations between DHbAc and DBW at weeks in the miglitol (r =.759, P <.) and voglibose (r =.667, P =.) groups (Figure 3b,d). A similar correlation was observed between DHbAc and DBW at weeks in all participants (r =.476, P <.; Figure 3e). No significant correlations were observed in the control and acarbose groups (Figure 3a,c). Secondary End-points Over the study period, neither FPG nor serum insulin was changed significantly in any groups. In addition, no significant 8 J Diabetes Invest Vol. 5 No. March 4 ª 3 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd

4 Comparison of a-glucosidase inhibitors Table Changes in glycated hemoglobin, bodyweight and body mass index during the study period (primary end-points) Baseline 4 weeks 8 weeks weeks HbAc (%) Control Miglitol Acarbose Voglibose Bodyweight (kg) Control Miglitol Acarbose Voglibose BMI (kg/m ) Control Miglitol Acarbose Voglibose Data are expressed as mean standard deviation. BMI, body mass index; HbAc, glycated hemoglobin. P <.5, P <. vs baseline. P <.5 vs control group. changes were observed in serum lipid profiles or adipocytokines at any time-point in any groups (Table 3). Questionnaire The questionnaire data on digestive symptoms showed that the participants in the three agi-treated groups experienced some digestive symptoms. Participants in the acarbose group in particular reported increased incidences of persistent borborygmus, abdominal distension and flatulence (Table S). No distinct differences were observed among the groups with respect to drug compliance or appetite. DISCUSSION In the present study, we evaluated the effects of three agis on glycemic control and bodyweight reduction in Japanese patients with obese type diabetes. Miglitol and voglibose lowered HbAc, whereas only miglitol reduced bodyweight and BMI. agis retard carbohydrate digestion and absorption, and thus reduce postprandial hyperglycemia. Among the three agis, miglitol differs from acarbose and voglibose with respect to pharmacokinetics. After oral administration, acarbose and voglibose are practically not absorbed,. In contrast, miglitol presents at a high concentration in the upper small intestine and is subsequently absorbed. Such differences in pharmacokinetics could contribute to the superior therapeutic benefit of miglitol; that is, it can suppress the postprandial blood glucose elevation most effectively. Indeed, recent studies with continuous glucose monitoring showed that miglitol strongly reduces postprandial blood glucose levels in type diabetes 3,4. Although there were no concurrent changes in fasting plasma glucose or insulin levels, adequate suppression of postprandial hyperglycemia could con- (a) ΔBMI ΔBW ΔHbAc (b) (%) (kg) (c) (kg/m ) Baseline Baseline Baseline 4 8 Time (weeks) 4 8 Time (weeks) 4 8 Time (weeks) Figure Changes in (a) glycated hemoglobin (DHbAc), (b) bodyweight (DBW) and(c) body mass index(dbmi) from baseline. Data are expressed as mean standard error of the mean. P <.5, P <.vsbaseline. P <.5, P <. vs control group., Control;, miglitol;, acarbose;, voglibose. ª 3 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. 5 No. March 4 9

5 Sugihara et al. (a) r =.77 P =.37 (b) r =.759 P <. ΔHbAc (%) 6 4 ΔHbAc (%) 6 4 (c) r =.77 P =.5 (d) r =.667 P =. ΔHbAc (%) 6 4 ΔHbAc (%) 6 4 (e) r =.476 P <. ΔHbAc (%) 6 4 Figure 3 Correlations between changes in glycated hemoglobin (DHbAc) and bodyweight (DBW) over weeks. (a) Control, (b) miglitol, (c) acarbose, (d) voglibose group and (e) total participants., Control;, miglitol;, acarbose;, voglibose. tribute to the rapid and persistent reduction of HbAc in the miglitol group. Meanwhile, in the present study, HbAc did not show a significant decrease in the acarbose group. Most of the previous intervention studies with acarbose were carried out for much longer durations, and reported that acarbose treatment significantly reduced HbAc 7. Therefore, the relatively short study period ( weeks) might obscure the blood glucose-lowering effect of acarbose. Intensive diabetic therapies with insulin and its secretagogues increase the risk of weight gain in type diabetes 5,6. Weight gain and obesity could induce insulin resistance and increase the risk of cardiovascular diseases in such patients. In the present study, a weight-lowering effect was observed only in the miglitol group. The effects of miglitol on incretins might be one of the reasons for this result. Recent studies suggest that miglitol enhances the release of GLP- whilst it suppresses the release of glucose-dependent insulinotropic polypeptide (GIP) by increasing glucose absorption from the lower small intestine 7,8. Indeed, elevated GLP- contributes to appetite control by inhibiting gastrointestinal motility 9 and inducing satiety through the central nervous system. In fact, Arakawa et al. report that miglitol affects postprandial GLP- secretion more strongly than acarbose in patients with visceral obesity, and several reports suggest that miglitol increases GLP- and decreases GIP to greater extents than voglibose after a single or long-term 6 administration in type diabetes. Further analysis for the modulation of postprandial incretin levels with agis could explain the differences in the weight-lowering effects among agis. We did not find any changes in fasting plasma lipid profiles in the present study. However, a meta-analysis of acarbose showed a small tendency towards decreased fasting TG levels 7. In addition, some studies showed that postprandial TG decreased significantly in accordance with decreased insulin levels with acute 3,4 or long-term 4 acarbose treatment in type diabetes. These data suggest that the improvement of insulin resistance by agis might suppress postprandial TG elevation. Hence, postprandial insulin and TG levels should be assessed to further understand the lipid-lowering effect of each agi. J Diabetes Invest Vol. 5 No. March 4 ª 3 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd

6 Comparison of a-glucosidase inhibitors Table 3 Changes in fasting plasma glucose, serum insulin, serum lipids and adipocytokines during the study period (secondary endpoints) Baseline 4 weeks 8 weeks weeks FPG (mmol/l) Control Miglitol Acarbose Voglibose Serum insulin (pmol/l) Control Miglitol Acarbose Voglibose Total cholesterol (mmol/l) Control Miglitol Acarbose Voglibose LDL cholesterol (mmol/l) Control Miglitol Acarbose Voglibose HDL cholesterol (mmol/l) Control Miglitol Acarbose Voglibose TG (mmol/l) Control Miglitol Acarbose Voglibose Adiponectin (lg/ml) Control Miglitol Acarbose Voglibose Leptin (ng/ml) Control Miglitol Acarbose Voglibose Data are expressed as mean standard deviation. FPG, fasting plasma glucose; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triacylglycerols. After the -week agi treatment, a significant decrease in HbAc was observed in the miglitol and voglibose groups, but not in the acarbose group.in addition,a significant correlation was observed between DHbAc and DBW in the miglitol and voglibose groups. Thus, the improved glycemic control with these agis might be partly due to weight reduction. A few studies suggest that acarbose and miglitol increase plasma adiponectin levels 5,6. Although reductions in bodyweight and body fat mass by agis are speculated to modulate adipocytokine levels, adiponectin and leptin levels did not change in any groups of the present study. Other pathways, such as those involving incretins, could contribute to both the better glycemic control and bodyweight reduction by agis. Miglitol 7 and voglibose 7 have been reported to increase postprandial incretin levels in patients with type diabetes, whereas acarbose has not 8, in placebo-controlled studies. Further research into the underlying mechanisms of the different effects on glycemic control and bodyweight among agis is necessary for better understanding of the characteristics of these drugs. The present study had several limitations. First, this study was an open-label study with a small sample size, though the participants were randomized and a control group was included. Second, we did not evaluate postprandial levels of plasma glucose, insulin and incretins. These postprandial measures would provide direct information on the effects of agi.third,wedidnot select the maximum dose permitted in Japan in the miglitol group. If the maximum dose was selected, it could be preferable to the present dose for both blood glucose and bodyweight control in the miglitol group. However, as the dose of agi is increased, the side-effects such as abdominal symptoms might be likely to occur. It remains to be elucidated whether the maximum dose of miglitol would have superior efficacy with good tolerability. Fourth, we investigated only patients with obese type diabetes. Whether similar effects of miglitol are observed in other types of diabetes or individuals with impaired glucose tolerance is of particular interest. Further investigation is required to better understand these characteristics of each agi. In conclusion, the present findings show that miglitol and voglibose lowered HbAc in patients with obese type diabetes. In addition, miglitol reduced bodyweight within a short period (4 weeks of treatment). These results suggest that miglitol is a preferable agent for improving glycemic control with promoting bodyweight reduction. Further studies on the characteristics of each agi could provide better treatment options, not only for blood glucose control with bodyweight management, but also for preventing complications in type diabetes. ACKNOWLEDGEMENTS This study was supported by Sanwa Kagaku Kenkyusho Co., Ltd. There is no conflictofinterestforalltheauthorslisted. REFERENCES. Gallwitz B. Implications of Postprandial Glucose and Weight Control in People With Type Diabetes: understanding and implementing the International Diabetes Federation guidelines. Diabetes Care 9; 3: S3 S35.. Lebovitz HE. a-glucosidase inhibitors. Endocrinol Metab Clin North Am 997; 6: Hanefeld M, Cagatay M, Petrowitsch T, et al. Acarbose reduces the risk for myocardial infarction in type diabetic patients: meta-analysis of seven long-term studies. Eur Heart J 4; 5: 6. ª 3 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. 5 No. March 4

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