Efficacy of acarbose in Chinese subjects with impaired glucose tolerance

This multicentre, double-blind, placebo-controlled study investigated the efficacy of acarbose in Chinese individuals with impaired glucose tolerance (determined using a 75 g oral glucose tolerance test). Subjects were randomised to either placebo or acarbose 50 mg t.i.d. for a period of 16 weeks. Primary efficacy variables were the maximum postprandial plasma glucose value (C(max)) and the serum insulin profile. Secondary efficacy parameters included postprandial glucose profile, maximum postprandial insulin concentration (C(max)), changes in lipid profile and blood pressure and HbA(1c) and body weight and conversion to Type 2 diabetes. In the intention-to-treat analysis, acarbose treatment resulted in significantly higher reductions in postprandial glucose and serum insulin concentrations compared to placebo. Triglyceride concentration was the only lipid parameter to be significantly reduced in acarbose subjects. Loss of body weight was also significantly greater for acarbose than placebo subjects. Some 19 individuals converted to Type 2 diabetes (seven acarbose, 12 placebo), but this difference was not significant. Acarbose is efficacious in improving the metabolic state of individuals with impaired glucose tolerance indicating a potential benefit for the delay or prevention of onset of Type 2 diabetes in Chinese subjects.     

Cardiovascular benefits of acarbose in impaired glucose tolerance and type 2 diabetes

Impaired glucose metabolism is associated with an increased risk of cardiovascular events and cardiovascular-associated mortality. Postprandial hyperglycaemia is one of the earliest identifiable indicators of impaired glucose control. It contributes to the progression from impaired glucose tolerance to overt type 2 diabetes and exacerbates chronic hyperglycaemia in established diabetes. It is also an independent risk factor for cardiovascular disease in patients with impaired glucose tolerance and type 2 diabetes. Thus, an important strategy to reduce cardiovascular risk in patients with impaired glucose metabolism is to reduce postprandial glucose excursions. Acarbose, an alpha (alpha)-glucosidase inhibitor, reduces postprandial hyperglycaemia by delaying carbohydrate absorption from the small intestine. This mechanism of action provides glycaemic control without increasing insulin levels and exacerbating coexisting cardiovascular risk factors. The Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM) assessed the ability of acarbose to reduce cardiovascular risk. In this study of 1429 individuals with impaired glucose tolerance, acarbose therapy reduced the risk of any cardiovascular event by 49% (P=0.03), of an acute myocardial infarction by 91% (P=0.02) and of developing hypertension by 34% (P=0.006). Furthermore, a retrospective meta-analysis of randomised studies of acarbose in type 2 diabetes patients showed that acarbose therapy reduced the risk of any cardiovascular event by 35% (P=0.006) and the risk of a myocardial infarction by 64% (P=0.012). These results suggest that acarbose is useful in reducing the risk of cardiovascular events in patients with impaired glucose metabolism.     

Use of an alpha-glucosidase inhibitor to maintain glucose homoeostasis during postprandial exercise in intensively treated Type 1 diabetic subjects.

AIM: We evaluated the effects of an alpha-glucosidase inhibitor, acarbose, on glucose homoeostasis during postprandial exercise in Type 1 diabetic subjects. METHODS: Seven Type 1 diabetic subjects with good glycaemic control on ultralente-regular insulin were randomized in a single blind cross-over study to acarbose 100 mg or placebo taken with a mixed meal (600 kcal, 75 g carbohydrates), followed 90 min later by 30 min of exercise at 50% maximum aerobic capacity. Glucose turnover was measured by tracer (d-[6,6,2H2]glucose) methodology, and intestinal glucose absorption was quantified using carbohydrate polymers labelled with [13C]glucose. RESULTS: Acarbose resulted in a significant decrease in the postprandial glycaemic rise (mean +/- SEM 2.9 +/- 0.6 vs. 5.0 +/- 0.7 mmol/l; P < 0.005) and in the glycaemic nadir during exercise (- 0.8 +/- 0.6 vs. 0.9 +/- 1.3 mmol/l below baseline; P < 0.05). Total glucose appearance increased similarly under the two treatments during the postprandial (27.0 vs. 27.9 micromol per kg per min) and exercise (33.9 vs. 33.5 micromol per kg per min) periods. Mean glucose absorption was significantly delayed by acarbose (7.8 vs. 10.2 micromol per kg per min; P < 0.02), but was compensated by the lack of postprandial suppression of hepatic glucose production (106% of basal hepatic glucose production vs. 81%; P < 0.006). Episodes of hypoglycaemia were no different (three vs. six). CONCLUSION: These results indicate that, in Type 1 diabetic subjects, acarbose results in a better glycaemic profile during postprandial exercise and suggest that it could lead to a lower risk of exercise-induced hypoglycaemia due to delayed glucose absorption and less suppression of hepatic glucose production.     

Who should benefit from the use of alpha-glucosidase inhibitors?

Although most commonly used drugs such as biguanides, sulfonylureas, and more recently, thiazolidinediones, are effective in controlling fasting hyperglycemia, a high percentage of patients have sustained elevated hemoglobin A_1c because of persistent elevation of postprandial plasma glucose (PPPG). α-Glucosidase inhibitors (AGIs) specifically target PPPG. AGIs have been shown in several randomized controlled trials to be effective in controlling blood glucose, whether they are used as monotherapy or in combination with other antidiabetic medications. Among the AGIs, acarbose has also been shown to decrease the risk of progressing to diabetes in subjects with impaired glucose tolerance (IGT). Studies have also suggested that acarbose could decrease the risk of cardiovascular disease, both in IGT and in diabetes. Furthermore, AGIs are very safe and are nontoxic drugs. Their only side effects are gastrointestinal, such as flatulence and diarrhea; however, these can be minimized by the “start low, go slow” approach. AGIs should be considered whenever postprandial hyperglycemia is the dominant metabolic abnormality.     

The effect of acarbose on insulin resistance in obese hypertensive subjects with normal glucose tolerance: a randomized controlled study

Aim:  Acarbose, a glucose oxidase inhibitor, delays the absorption of glucose thus reducing post-prandial blood glucose level, haemoglobin A1c (HbA1c) and insulin resistance in patients with diabetes mellitus and in subjects with impaired glucose tolerance. The effect of acarbose in subjects with normal glucose tolerance (NGT) has hitherto not been examined. The aim of the present study was to examine the effect of acarbose in obese hypertensive subjects with NGT.
Methods:  A double-blinded, parallel group study was performed on 56 male subjects with hypertension, body mass index (BMI) 27–35 kg/m², fasting blood glucose ≤ 6 mmol/l and a normal oral glucose tolerance test. Blood pressure, HbA1c, lipid profile and insulin resistance [homeostasis model assessment (HOMA) index] were determined initially and following 24 weeks of acarbose, 150 mg/day or placebo. The primary end point was the change in insulin resistance. Anti-hypertensive treatment and diet were kept constant during the study.
Results:  Insulin resistance decreased in acarbose users but not on placebo. HOMA index declined from 5.36 ± 1.7 to 4.10 ± 1.6 (p = 0.001) on acarbose, the corresponding values on placebo were 5.44 ± 1.9 and 5.53 ± 1.7. A decrease in serum triglyceride values (2.16 ± 0.16 mmol/l to 1.76 ± 0.15 mmol/l, p = 0.02) took place on acarbose with no change on placebo. There was no change in BMI, low-density lipoprotein or high-density lipoprotein values in either group. Blood pressure declined equally in both the groups, probably due to better patient compliance.
Conclusions:  Acarbose may reduce insulin resistance and triglycerides also in obese hypertensive subjects with normal glucose tolerance.     

Acarbose improves fibrinolytic activity in patients with impaired glucose tolerance

Acarbose has been shown to ameliorate insulinemia, suggesting that it may exert favorable effects on the impaired fibrinolytic state in prediabetic patients. We therefore conducted a randomized controlled study to examine the effects of acarbose on fibrinolysis in patients with impaired glucose tolerance (IGT). The participants were randomized to receive (n = 20) or not (control, n = 20) 100 mg of acarbose before each meal (300 mg/d) for 3 months. A marked decrease in the plasma levels of plasminogen activator inhibitor 1 (by 42%) and fibrinogen (by 27%) was observed in the acarbose group at the end of the study, whereas no significant changes in the levels of these parameters were observed in the control group. We also conducted postprandial evaluation of insulin-related clinical markers and found ameliorated hyperinsulinemia in the subjects treated with acarbose. These results indicate that acarbose could improve fibrinolysis in patients with IGT, mainly by ameliorating insulinemia. Other favorable effects of acarbose, such as reduction in the plasma levels of oxidized low-density lipoprotein, glucose toxicity, and hyperglycemia, might also contribute, at least in part, to the beneficial effects of the drug on the fibrinolytic state in patients with IGT.     

餐后血糖与血管并发症

越来越多的证据表明糖尿病、糖耐量异常和非糖尿病患者的餐后血糖异常与动脉硬化的发生发展关系密切,且较空腹血糖和糖化血红蛋白为强,在校正了其他心血管危险因素后,这种关系仍存在。其机制可能与餐后高血糖时脂质过氧化增强、内皮功能障碍、高凝状态、黏附因子水平升高、炎症、氧化/氮化应激增强等有关。阿卡波糖及其他药物的干预治疗能明显减少糖尿病、糖耐量异常的心血管事件。     

Relationship of glucose and insulin levels to the risk of myocardial infarction: a case-control study

OBJECTIVE: To assess the relationship between dysglycemia and myocardial infarction in nondiabetic individuals. BACKGROUND: Nondiabetic hyperglycemia may be an important cardiac risk factor. The relationship between myocardial infarction and glucose, insulin, abdominal obesity, lipids and hypertension was therefore studied in South Asians-a group at high risk for coronary heart disease and diabetes. METHODS: Demographics, waist/hip ratio, fasting blood glucose (FBG), insulin, lipids and glucose tolerance were measured in 300 consecutive patients with a first myocardial infarction and 300 matched controls. RESULTS: Cases were more likely to have diabetes (OR 5.49; 95% CI 3.34, 9.01), impaired glucose tolerance (OR 4.08; 95% CI 2.31, 7.20) or impaired fasting glucose (OR 3.22; 95% CI 1.51, 6.85) than controls. Cases were 3.4 (95% CI 1.9, 5.8) and 6.0 (95% CI 3.3, 10.9) times more likely to have an FBG in the third and fourth quartile (5.2-6.3 and >6.3 mmol/1); after removing subjects with diabetes, impaired glucose tolerance and impaired fasting glucose, cases were 2.7 times (95% CI 1.5-4.8) more likely to have an FBG >5.2 mmol/l. A fasting glucose of 4.9 mmol/l best distinguished cases from controls (OR 3.42; 95% CI 2.42, 4.83). Glucose, abdominal obesity, lipids, hypertension and smoking were independent multivariate risk factors for myocardial infarction. In subjects without glucose intolerance, a 1.2 mmol/l (21 mg/dl) increase in postprandial glucose was independently associated with an increase in the odds of a myocardial infarction of 1.58 (95% CI 1.18, 2.12). CONCLUSIONS: A moderately elevated glucose level is a continuous risk factor for MI in nondiabetic South Asians with either normal or impaired glucose tolerance.     

Effects of the α‐glucosidase inhibitor acarbose on the development of long‐term complications in diabetic animals: pathophysiological and therapeutic implications

Short‐term studies with acarbose have demonstrated its efficacy in reducing postprandial blood glucose levels and glycated haemoglobin (HbA_1c) levels. These effects would be expected to translate into improvements in long‐term complications of diabetes, but such data are not yet available due to the long follow‐up times required. Animal models of diabetes have, however, demonstrated the efficacy of acarbose in combating the long‐term complications of the disease. The 18 animal studies reviewed here showed that acarbose treatment reduced postprandial blood glucose concentrations and decreased protein glycation. Through these actions, acarbose delayed or prevented the onset of renal, retinal, lens and neurological changes and the development of ischaemic myocardial lesions. Acarbose treatment can therefore be expected to benefit patients with Type 2 and, in combination with insulin, Type 1 diabetes. This is being investigated in ongoing clinical studies in patients with Type 2 diabetes and impaired glucose tolerance (IGT). Copyright © 1999 John Wiley & Sons, Ltd.     

Efficacy and safety of acarbose in the treatment of Type 1 diabetes mellitus: a placebo-controlled, double-blind, multicentre study.

AIMS: The aim of the study was to evaluate the efficacy and safety of acarbose in patients with Type 1 diabetes mellitus (DM). METHODS: A multicentre double-blind, randomized, placebo-controlled study was performed. After a 6-week run-in, 121 patients were randomized to acarbose or placebo and to high- or low-fibre diet for 24 weeks. Acarbose dose was 50 mg t.d.s. for the first 2 weeks and 100 mg t.d.s. for the subsequent weeks. RESULTS: At the end of 24 weeks of treatment the intention to treat analysis showed that acarbose compared with placebo decreased 2 h postprandial plasma glucose levels (12.23 +/- 0.83 vs. 14.93 +/- 0.87 mmol/l; F = 6.1, P < 0.02) (least square means +/- SEM). No significant effect of acarbose was recorded on HbA1c or on the number of hypoglycaemic episodes. The effect of acarbose on blood glucose control was not influenced by the amount of carbohydrate and/or fibre intake. The incidence of adverse events were 75% and 39% in acarbose and placebo groups, respectively; they were mild and confined to the gastrointestinal tract. CONCLUSIONS: The use of acarbose in combination with insulin reduces postprandial plasma glucose levels in Type 1 diabetic patients who are not satisfactorily controlled with insulin alone but without significant effect on HbA1c.     

阿卡波糖对冠心病糖耐量减低患者经皮冠状动脉介入治疗后心肌灌注的影响及其机制

目的观察阿卡波糖治疗冠状动脉粥样硬化性心脏病(冠心病)糖耐量减低(impaired glucose tolerance,IGT)行经皮冠状动脉介入(percutaneous coronary intervention,PCI)治疗后完全血运重建患者的血糖、血脂、血管内皮生长因子(vascular endothelial growth factor,VEGF)和心肌灌注的变化,探讨其改善心肌灌注的可能机制。方法选择2017年1月至2018年3月河北大学附属医院收治的冠心病合并IGT,PCI治疗完全血运重建,术后6个月均复查冠状动脉造影(coronary arterial angiography,CAG)示无支架内血栓、再狭窄、新发病变的患者123例。所有入组患者均严格遵循糖尿病饮食、运动控制、监测血糖并按相关指南坚持抗栓、降脂和降压等治疗。将入组患者按照随机化原则分为试验组:A组为阿卡波糖低剂量(50 mg/次,3次/d)、B组为阿卡波糖高剂量组(100 mg/次,3次/d);对照组(C组为)安慰剂。观察3组患者的血糖、血脂、VEGF、心肌灌注显像变化。结果3组患者基线血糖、血脂、VEGF、心肌灌注显像等比较,差异无统计学意义(P>0.05)。3组患者复查CAG均未见支架内血栓、再狭窄、新发病变。3组患者治疗前、后血脂比较,差异无统计学意义(P>0.05)。治疗后,阿卡波糖低剂量、高剂量治疗组患者血糖、VEGF较对照组患者的降低,心肌灌注显像改善,差异具有统计学意义(P<0.05),且高剂量组较低剂量组疗效更显著(P<0.05)。结论阿卡波糖可降低冠心病合并IGT患者行PCI治疗后的血糖、血浆VEGF因子浓度,抑制血管内皮过度增生和改善心肌微循环,改善心肌灌注,从而降低主要不良心血管事件的发生。     

Influence of treatment with acarbose or glibenclamide on insulin sensitivity in type 2 diabetic patients

Aim: The aim of our double-blind, placebo-controlled study was to compare the effect of acarbose and glibenclamide on the insulin sensitivity in type 2 diabetes.
Methods: We investigated 77 patients (mean age 58.7 years, mean BMI 27.3 kg/m²), treated by diet alone for at least 4 weeks. The subjects were randomized into three treatment groups for 16 weeks: 100 mg t.i.d. acarbose ( n  = 25) or 1 mg t.i.d. glibenclamide ( n  = 27) or one t.i.d. placebo ( n  = 25). Before and after therapy, the levels of fasting plasma glucose, glycosylated haemoglobin, fasting insulin, plasma glucose and insulin 1 h after a standardized breakfast were measured and insulin sensitivity determined by euglycaemic hyperinsulinaemic clamp test.
Results: After the treatment period, BMI in the acarbose and placebo group decreased significantly, whereas in the glibenclamide group a significant increase was observed. Fasting plasma glucose was only significant reduced under glibenclamide. The postprandial glucose decreased significantly after acarbose (13.8 vs. 11.4 mmol/l, p < 0.05) and glibenclamide treatment (14.6 vs. 11.4 mmol/l, p < 0.05) and was unchanged under placebo (13.8 vs. 13.7 mmol/l). The fasting insulin levels remained unchanged in all three groups, whereas postprandial insulin values increased significantly under glibenclamide. Neither acarbose nor glibenclamide significantly changed insulin sensitivity [acarbose: glucose disposal rate before treatment 2.3 mg/kg body weight/min/insulin, after treatment 3.2; glibenclamide 2.2 vs. 2.1; placebo 2.6 vs. 3.0].
Conclusions: Our results show a more substantial improvement of glucose control under glibenclamide than under acarbose which, however, was not associated with an increase of insulin sensitivity.     

Miglitol suppresses the postprandial increase in interleukin 6 and enhances active glucagon-like peptide 1 secretion in viscerally obese subjects

Visceral obesity and insulin resistance are regarded as risk factors for atherosclerosis. Epidemiologic studies have demonstrated long-term anti-atherosclerotic effects with administration of α-glucosidase inhibitors. α-Glucosidase inhibitors also have been reported to enhance glucagon-like peptide 1 (GLP-1) secretion. We compared the postprandial effects of a single administration of miglitol and acarbose on glucose and lipid metabolism, on insulin requirement, on GLP-1 secretion, and on inflammatory and endothelial markers in viscerally obese subjects. Twenty-four viscerally obese subjects with relative insulin resistance participated in this study. Subjects were given a single dose of miglitol (50 mg), acarbose (100 mg), or placebo blindly and randomly before a meal in a crossover design. The meal loads after drug administration were tested 3 times within 2 weeks. We measured glucose, insulin, lipids, lipoprotein lipase, interleukin 6, intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and active GLP-1 at before and various minutes after the meal. Single administration of both α-glucosidase inhibitors had several beneficial effects in improving postprandial hyperglycemia and reducing postprandial insulin requirement approximately 25% of placebo without adversely affecting lipid profiles. Although lipoprotein lipase levels within 2 hours after the meal did not show differences among miglitol, acarbose, and placebo administrations, miglitol significantly suppressed the increases in triglycerides, remnant-like particle triglycerides, and remnant-like particle cholesterol compared to acarbose and placebo in the early phase. Miglitol also significantly enhanced active GLP-1 secretion to a greater extent than acarbose (P < .01) and placebo (P < .001), and significantly suppressed the postprandial increase in interleukin 6 compared to placebo (P < .01). The results point to the potential suitability of miglitol as an anti-atherosclerotic effect in viscerally obese subjects, in preference to acarbose. Further studies are needed to elucidate the long-term effects on enhanced GLP-1 secretion and anti-atherosclerosis.     

天芪降糖胶囊预防2型糖尿病：一项在中国糖耐量减低患者中进行的随机、双盲、安慰剂对照研究

目的观察天芪降糖胶囊对预防糖耐量减低（IGT）患者向2型糖尿病（T2DM）发展的效果。方法216例IGT患者,随机分为2组,分别口服天芪降糖胶囊（TQ组,110例）和对照组（Con组,106例）,观察治疗后血糖变化及转化为正常血糖和T2DM的比例。结果天芪降糖胶囊治疗后服糖2h血糖（2htG）值明显低于基线值（P=0．000）,且2htG下降幅度大于Con组（P〈0．005）;与Con组相比,天芪降糖胶囊使T2DM发生风险下降56％。结论天芪降糖胶囊可显著降低IGT患者向T2DM发展的风险。     

Efficacy of 24-Week Monotherapy With Acarbose, Metformin, or Placebo in Dietary-Treated NIDDM Patients: The Essen-II Study

PURPOSE: To compare the therapeutic potential of acarbose, metformin, or placebo as first line treatment in patients with non-insulin-dependent diabetes mellitus (NIDDM).PATIENTS AND METHODS: Ninety-six patients with NIDDM (35–70 years of age, body mass index (BMI) ≤ 35 kg/m², insufficiently treated with diet alone, glycated hemoglobin (HbA_1C; 7% to 11%) were randomized into 3 groups and treated for 24 weeks with acarbose, 3 × 100 mg/day, or metformin, 2 × 850 mg/day, or placebo. Efficacy, based on HbA_1C (primary efficacy criterion), fasting blood glucose (BG) and insulin, 1 hour postprandial BG and insulin (after standard meal test), postprandial insulin increase, plasma lipid profile, and tolerability, based on subjective symptoms and laboratory values were determined every 6 weeks. Analysis of covariance was performed for endvalues with adjustment on baseline values. Ninety-four patients were valid for efficacy evaluation.RESULTS: Both active drugs showed the same improvement of efficacy criteria compared with placebo. Baseline adjusted means at endpoint were as follows: BG, fasting and 1 hour postprandial, 9.2 mM and 10.9 mM with placebo, 7.6 mM and 8.7 mM with acarbose, and 7.8 mM and 9.0 mM with metformin; HbA_1C was 9.8% with placebo, 8.5% with acarbose, and 8.7% with metformin. Comparisons: acarbose versus placebo and metformin versus placebo were statistically significant, but not acarbose versus metformin.No effect on fasting insulin could be observed. Relative postprandial insulin increase was 1.90 with placebo, 1.09 with acarbose, and 1.03 with metformin. Comparisons: acarbose versus placebo and metformin versus placebo were statistically significant, but not acarbose versus metformin.With respect to lipid profile, acarbose was superior to metformin. Low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol ratio increased by 14.4% with placebo, was unchanged with metformin, but decreased by 26.7% with acarbose. Comparisons: acarbose versus placebo and acarbose versus metformin were statistically significant, but not metformin versus placebo.Slight body weight changes were observed with acarbose (−0.8 kg) and metformin (−0.5 kg), but not with placebo. Acarbose led to mild or moderate intestinal symptoms in 50% of the patients within the first 4 weeks, but in only 13.8% of the patients within the last 4 weeks.CONCLUSIONS: Acarbose and metformin are effective drugs for the first line monotherapy of patients with NIDDM. With respect to plasma lipid profile, especially HDL cholesterol, LDL cholesterol and LDL/HDL cholesterol ratio, acarbose may be superior to metformin.     

Acarbose lowers serum triglyceride and postprandial chylomicron levels in type 2 diabetes

AIM: This study was designed to examine the therapeutic effect of acarbose on serum triglyceride (TG), free fatty acid (FFA), very low-density lipoprotein (VLDL) and chylomicron (CM) in the meal tolerance test (MTT) before and after acarbose treatment in type 2 diabetes mellitus (DM2). METHODS: Effects of acarbose on postprandial lipid metabolism were examined in DM2 patients. The subjects with normotriglyceridaemia (TG > or = 1.7 mmol/l, n = 60) were divided to three groups (A, B and C), and DM2 patients with hypertriglyceridaemia (TG > 1.7 mmol/l, n = 20) were designated group D. Group A was a control, and group B was designed to examine the one-dose effect of acarbose (100 mg) on lipid levels in MTT using the balanced food of 400 kcal. In groups C and D, acarbose 300 mg/day was administered for 8 weeks, and MTT with the one-dose acarbose administration was performed. We determined the levels of fasting and postprandial levels of glucose, insulin, FFA and TG-rich lipoproteins such as CM and VLDL. RESULTS: Acarbose treatment lowered plasma glucose levels and insulin secretion. In comparison among study groups A, B and C, acarbose significantly lowered serum TG levels in postprandial state. In group D, after the 8-week acarbose administration, fasting or postprandial FFA, TG and VLDL levels were also lowered. Interestingly, postprandial increase in CM was suppressed by acarbose administration in group B, C or D. CONCLUSIONS: Acarbose lowers postprandial TG and CM levels in DM2 with either normotriglyceridaemia or hypertriglyceridaemia. Improvement of insulin resistance with acarbose may also reduce fasting TG levels in DM2 with hypertriglyceridaemia. Acarbose is a beneficial therapeutic agent to reduce TG levels in DM2 patients, thereby leading to suppression of cardiovascular events.     

Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults

BACKGROUND: Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, promotes weight loss, and may reduce the risk of developing impaired glucose tolerance and type 2 diabetes in obese subjects. OBJECTIVE: To test the hypothesis that orlistat combined with dietary intervention improves glucose tolerance status and prevents worsening of diabetes status more effectively than placebo. METHODS: We pooled data from 675 obese (body mass index, 30-43 kg/m2) adults at 39 US and European research centers in 3 randomized, double-blind, placebo-controlled multicenter clinical trials. Subjects received placebo plus a low-energy diet during a 4-week lead-in period. On study day 1, the diet was continued, and subjects were randomized to receive placebo 3 times a day (n=316) or treatment with orlistat, 120 mg 3 times a day (n=359), for 104 weeks. A standard 3-hour oral glucose tolerance test was performed on day 1 and at the end of treatment. MAIN OUTCOME MEASURES: The categorical assessment of glucose tolerance status (normal, impaired, diabetic) and changes in status from randomization to end of treatment were the primary efficacy measures. The secondary measures were fasting and postchallenge glucose and insulin levels. RESULTS: The mean length of follow-up was 582 days. Subjects who were treated with orlistat lost more weight (mean +/- SEM, 6.72 +/- 0.41 kg from initial weight) than subjects who received placebo (3.79+/-0.38 kg; P<.001). A smaller percentage of subjects with impaired glucose tolerance at baseline progressed to diabetic status in the orlistat (3.0%) vs placebo (7.6%) group. Conversely, among subjects with impaired glucose tolerance at baseline, glucose levels normalized in more subjects after orlistat treatment (71.6%) vs placebo (49.1%; P=.04). CONCLUSIONS: The addition of orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of progression to the development of impaired glucose tolerance and type 2 diabetes.     

Acarbose for the prevention of Type 2 diabetes,hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM Trial data

The STOP-NIDDM Trial has shown that acarbose treatment in subjects with impaired glucose tolerance is associated with a significant risk reduction in the development of diabetes, hypertension and cardiovascular complications. Kaiser and Sawicki have accused the investigators of the STOP-NIDDM Trial of major biases in the conduct of the study, of manipulating the data and of conflict of interest. The aim of this paper is to present data and explanations refuting these allegations.In the STOP-NIDDM Trial, 61 subjects were excluded from the efficacy analysis before unblinding for legitimate reasons: failure to satisfy major entry criteria (n=17) and lack of post-randomisation data (n=44). Blinding and randomisation were carried out by an independent biostatistician. Titration of placebo/acarbose is well described in the protocol and in the study design paper.Of the study population, 9.3% had a fasting plasma glucose of 7.0 mmol/l at screening and could have been diabetic according to the new diagnostic criteria. However, even if these subjects are excluded, patients having acarbose treatment still saw a significant risk reduction in the development of diabetes (p=0.0027). The changes in weight are consistent in different publications and are related to different times of follow-up and assessment. Weight change does have an effect on the development of diabetes, but acarbose treatment is still effective even after adjusting for this (p=0.0063). The cardiovascular endpoints were a clearly designated assessment in the original protocol, and only those defined in the protocol and ascertained by the independent Cardiovascular Event Adjudication Committee were used in the analysis. Hypertension was defined according to the most recent diagnostic criteria.The STOP-NIDDM Trial results are scientifically sound and credible. The investigators stand strongly behind these results demonstrating that acarbose treatment is associated with a delay in the development of diabetes, hypertension and cardiovascular complications in a high-risk population with IGT.Abbreviations BID two times a day - FPG fasting plasma glucose - OD once a day - STOP-NIDDM Study to Prevent Non-Insulin-Dependent Diabetes Mellitus - TID three times a day     

Acarbose, an alpha-glucosidase inhibitor, attenuates postprandial hypotension in autonomic failure

Postprandial hypotension is an important clinical condition that predisposes to syncope, falls, angina, and cerebrovascular events. The magnitude of the fall in blood pressure after meals depends on enteric glucose availability. We hypothesized that acarbose, an alpha-glucosidase inhibitor that decreases glucose absorption in the small intestine, would attenuate postprandial hypotension. Acarbose or placebo was given 20 minutes before a standardized meal in 13 patients with postprandial hypotension in the setting of autonomic failure (age: 65+/-2.64 years; body mass index: 25+/-1.08 kg/m(2); supine plasma norepinephrine: 110+/-26.6 pg/mL). Four patients were studied in a single-blind protocol and 9 patients in a double-blind, randomized, crossover fashion. Patients were studied supine, and blood pressure, heart rate, and neuroendocrine parameters were obtained at baseline and for 90 minutes after meal intake. After adjusting for potential confounders, acarbose significantly attenuated the postprandial fall in systolic and diastolic blood pressures by 17 mm Hg (95% CI: 7 to 28; P=0.003) and 9 mm Hg (95% CI: 5 to 14; P=0.001), respectively. Furthermore, acarbose effectively reduced plasma levels of insulin, a known vasodilator, by 11 microU/mL (95% CI: 5 to 18; P=0.001) compared with placebo. After adjusting for insulin levels, the attenuation of postprandial hypotension by acarbose remained significant, indicating that additional mechanisms contribute to this effect. In conclusion, 100 mg of acarbose successfully improved postprandial hypotension in patients with severe autonomic failure. This effect is not explained solely by a reduction in insulin levels.     

Cardiovascular disease and oral agent glucose-lowering therapies in the management of type 2 diabetes

Although glucose-lowering oral agents have been available for clinical use for over 60 years, the formal evidence base supporting their advantage and safety in regard of cardiovascular (CV) outcomes remains less than optimal. However, a synthesis of the evidence results in a high probability of benefit. For metformin, the United Kingdom Prospective Diabetes Study (UKPDS) substudy is convincing for a definite effect in reducing myocardial infarction (MI), but the quantitative extent of that is uncertain. For sulfonylureas, support for reduction in MI comes from the UKPDS extension study, where the central estimate for risk reduction remains the same as in the original planned end to the study, but the greater number of events was statistically significant for the sulfonylurea/insulin arm. Other studies do not support the view that metformin and sulfonylureas differ with respect to MI or indeed CV outcomes more generally. The data available for acarbose, an α-glucosidase inhibitor, are weak but not of concern, although some positive substudy data are available for people with impaired glucose tolerance. For peroxisome proliferator-activated receptor-γ agonists the CV data are more controversial, but the purpose-designed randomized controlled trials are clear that pioglitazone is advantageous to placebo (except for heart failure [HF]), whereas rosiglitazone is indistinguishable from metformin/sulfonylureas (even when including HF data). Lower-quality data do, however, lead to significant concerns for MI with rosiglitazone. Early and somewhat low-quality data for the dipeptidyl peptidase inhibitors show they are safe and hold promise for cardiovascular advantage, with major randomized controlled trials being underway. Preliminary CV data are available for one sodium/glucose cotransporter 2 inhibitor and look reassuring.