Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes

OBJECTIVE: To demonstrate the efficacy, tolerability, and safety of acarbose compared with placebo in patients with type 2 diabetes inadequately controlled with diet and metformin (2,000 or 2,500 mg/day in divided doses). RESEARCH DESIGN AND METHODS: This study had a multicenter randomized double-blind placebo-controlled parallel-group comparison design. The trial lasted 31 weeks and consisted of a 1-week screening period, a 6-week placebo pretreatment period, and a 24-week period of acarbose or placebo, with a forced titration from 25-50 mg t.i.d. and a titration of 50-100 mg tid that was based on glucose control. The primary efficacy variable was the mean change from baseline in HbA1c. Secondary efficacy variables included mean changes from baseline in fasting and postprandial plasma glucose, serum insulin, and triglyceride levels. RESULTS: The addition of acarbose to patients on background metformin and diet therapy showed a statistically significant reduction in mean HbA1c of 0.65%. There were statistically significant reductions in fasting and postprandial plasma glucose and serum insulin levels compared with placebo. Gastrointestinal side effects were more frequently reported in the acarbose-treated patients. No significant differences in liver transaminase elevations were observed between patients treated with acarbose and those treated with placebo. CONCLUSIONS: The results of this study demonstrate that the addition of acarbose to patients with type 2 diabetes who are inadequately controlled with metformin and diet is safe and generally well tolerated and that it significantly lowers HbA1c and fasting and postprandial glucose and insulin levels.     

A double-blind placebo-controlled trial evaluating the safety and efficacy of acarbose for the treatment of patients with insulin-requiring type II diabetes

OBJECTIVE: To determine whether a forced titration of acarbose (from 50 to 300 mg three times daily) administered over a 24-week period, in conjunction with diet and insulin therapy, improves glycemic control and reduces daily insulin requirements in insulin-requiring type II diabetes. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial was 36 weeks in duration. The trial consisted of a 6-week pretreatment period, a 24-week double-blind treatment period, and a 6-week post-treatment follow-up period. The primary efficacy variables were the mean change from baseline in HbA1c levels and the mean percentage change from baseline in total daily insulin dose. RESULTS: Treatment with acarbose was associated with significant reductions in HbA1c levels of 0.40% (P = 0.0001) and in total daily insulin dose of 8.3% (P = 0.0015). There were also significant reductions in all plasma glucose variables measured, including a 0.9 mmol/l reduction in fasting glucose (P = 0.0440), a 2.6 mmol/l reduction in glucose Cmax (P = 0.0001) and a 270 mmol.min-1.l-1 reduction in glucose area under the curve (P = 0.0002). Although acarbose treatment was associated with a greater incidence of adverse events than was placebo treatment, primarily flatulence and diarrhea, these events did not generally prevent patients from completing the study. CONCLUSIONS: The results of this study suggest that acarbose is a safe and effective adjunct to diet and insulin therapy for the management of insulin-requiring type II diabetes.     

Post-transplant hyperlipidaemia: low-dose lovastatin lowers atherogenic lipids without plasma accumulation of lovastatin

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) < or = 35 kg/m2, insufficiently treated with diet alone, glycated hemoglobin (HbA1c; 7% to 11%) were randomized into 3 groups and treated for 24 weeks with acarbose, 3 x 100 mg/day, or metformin, 2 x 850 mg/day, or placebo. Efficacy, based on HbA1c (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; HbA1c 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.     

The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone

OBJECTIVE: To compare the therapeutic effects of the alpha-glucosidase inhibitor miglitol (BAY m 1099), the sulfonylurea glibenclamide, and placebo on parameters of metabolic control and safety in patients with NIDDM that is inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS: After a 4-week placebo run-in period, 201 patients in 18 centers in 4 countries were randomized in a double-blind manner to miglitol (50 mg t.i.d., followed by 100 mg t.i.d.), glibenclamide (3.5 mg q.d/b.i.d.), or placebo for 24 weeks. Efficacy criteria were changes from baseline of HbA1c, fasting and postprandial blood glucose and insulin levels, body weight, and serum triglycerides. RESULTS: Efficacy was assessed in 119 patients who completed the full protocol, and the results were similar to those obtained in 186 patients who fulfilled the validity criteria for analysis. Compared with placebo, mean baseline-adjusted HbA1c decreased by 0.75% (P = 0.0021) and 1.01% (P = 0.0001) in the miglitol and glibenclamide treatment groups, respectively. Blood glucose decreased slightly in the fasting state and considerably in the postprandial state in both treatment groups but not in the placebo group. Fasting insulin levels increased slightly (NS) in all treatment groups; however, postprandial insulin levels decreased with miglitol, while increasing markedly with glibenclamide (P = 0.0001 between all treatment groups). Gastrointestinal side effects (flatulence and diarrhea) occurred mostly in the miglitol-treated patients, while some glibenclamide-treated patients had symptoms suggestive of hypoglycemia. CONCLUSIONS: Miglitol monotherapy is effective and safe in NIDDM patients. Compared with glibenclamide, it reduced HbA1c less effectively and caused more gastrointestinal side effects. On the other hand, glibenclamide, unlike miglitol, tended to cause hypoglycemia, hyperinsulinemia, and weight gain, which are not desirable in patients with NIDDM.     

Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study

OBJECTIVE: To determine the efficacy of acarbose, compared with placebo, on the metabolic control of NIDDM patients inadequately controlled on maximal doses of conventional oral agents. RESEARCH DESIGN AND METHODS: In this three-center double-blind study, 90 Chinese NIDDM patients with persistent poor glycemic control despite maximal doses of sulfonylurea and metformin were randomly assigned to receive additional treatment with acarbose 100 mg thrice daily or placebo for 24 weeks, after 6 weeks of dietary reinforcement. Efficacy was assessed by changes in HbA1c, fasting and 1-h postprandial plasma glucose and insulin levels, and fasting lipid levels. RESULTS: Acarbose treatment was associated with significantly greater reductions in HbA1c (-0.5 +/- 0.2% vs. placebo 0.1 +/- 0.2% [means +/- SEM], P = 0.038), 1-h postprandial glucose (-2.3 +/- 0.4 mmol/l vs. placebo 0.7 +/- 0.4 mmol/l, P < 0.001) and body weight (-0.54 +/- 0.32 kg vs. placebo 0.42 +/- 0.29 kg, P < 0.05). There was no significant difference between the two groups regarding changes in fasting plasma glucose and lipids or fasting and postprandial insulin levels. Flatulence was the most common side effect (acarbose vs. placebo: 28/45 vs. 11/44, P < 0.05). One patient on acarbose had asymptomatic elevations in serum transaminases that normalized in 4 weeks after acarbose withdrawal. Another patient on acarbose developed severe hypoglycemia; glycemic control was subsequently maintained on half the baseline dosage of sulfonylurea. CONCLUSIONS: In NIDDM patients inadequately controlled on conventional oral agents, acarbose in moderate doses resulted in beneficial effects on glycemic control, especially postprandial glycemia, and mean body weight. Additional use of acarbose can be considered as a useful alternative in such patients if they are reluctant to accept insulin therapy.     

New imidazoles as probes of the active site topology and potent inhibitors of beta-glucosidase

OBJECTIVE: To evaluate the long-term efficacy, safety, and tolerability of the alpha-glucosidase inhibitor miglitol in the treatment of African-American patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 345 African-American type 2 diabetic patients (mean age 55.6 years, BMI 31.9 kg/m2, duration of diabetes 4.9 years, baseline HbA1C 8.7%) treated with either diet alone or sulfonylurea were randomized to 1 year of double-blind treatment with either placebo (n = 117) or miglitol (n = 228) at doses of 50 or 100 mg t.i.d., titrated based on tolerability. The primary efficacy criterion was change from baseline in HbA1C at the 6-month visit. Secondarily efficacy parameters included changes from baseline in plasma glucose and serum insulin (both fasting and 120 min after a standardized test meal), fasting lipids, and urinary albumin-to-creatinine ratio. Safety and tolerability evaluations were primarily based on reporting of adverse events and symptoms and on periodic laboratory analyses. RESULTS: Miglitol treatment was associated with a mean placebo-subtracted reduction in HbA1C from baseline of 1.19% at 6 months. Fasting and 120-min postprandial plasma glucose levels were reduced in parallel to HbA1C, in association with miglitol treatment. Significant reductions versus placebo in 120-min postprandial insulin levels, in LDL cholesterol, and in fasting triglycerides, were also seen in the miglitol group at individual study time points. Softer, more frequent stools and flatulence were significantly more common in the miglitol group. Urinary tract infections, hematuria, and herpes simplex infections were significantly more common in the placebo group. CONCLUSIONS: Miglitol treatment appears to be at least as efficacious in the African-American type 2 population as in the U.S. type 2 population at large, with comparable tolerability. alpha-Glucosidase treatment may be an important therapeutic option in these patients in view of their greater risk for microvascular complications and the accumulating body of evidence that better glucose control reduces the risk of these complications.     

The genetic basis of "Scarsdale Gourmet Diet" variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene

Elevated serum triglyceride levels may be related to the following clinical features: increased blood coagulation and viscosity, increased serum fibrinogen levels, decreased fibrinolysis, and for serum levels over 1000 mg/dl, a strong increase of acute pancreatitis rate. Pharmacological choice among the numerous drugs to treat hypertriglyceridemias is currently debated. Our study was aimed to assess the therapeutic efficacy of acarbose in the treatment of non-diabetic subjects, affected by familiar hypertriglyceridemia (FH). We studied 18 non-diabetic patients (10 males, 8 females; mean age 57.61+/-6.85 years) without family history of diabetes mellitus affected by familiar hypertriglyceridemia. The study protocol planned a treatment period of 20 weeks, divided into five 4-week courses and made up as follows: diet plus acarbose therapy (4 weeks); diet therapy alone (4 weeks) alternatively. In the second and fourth 4-week courses diet plus acarbose were administered, while diet therapy alone was administered in the first, third, and fifth 4-week courses. Acarbose doses consisted of 50 mg (1/2 pill) twice daily. Mean serum triglyceride levels, after first month of dietary treatment, underwent a significant reduction from 481.5 +/- 67.1 mg/dl to 389.5 +/- 62.7 mg/dl, even if they did not reach the optimal levels to keep on the dietary therapy alone. After the first month of treatment with acarbose associated to diet, we observed a further reduction of serum triglycerides levels (p = 0.02). When diet alone was administered, mean triglyceride serum levels underwent a significant enhancement (p = 0.003). Restarting for the second time the association treatment, we observed a noteworthy reduction of mean serum triglyceride levels (p = 0.0001). Acarbose acts on the pathogenesis of FH, lowering the production of endogenous triglycerides. Our data suggested that acarbose can be considered a valid therapeutic tool in the treatment of familiar hypertriglyceridemias, also in non-diabetic patients.     

Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Glimepiride Study Group

OBJECTIVE: To compare the efficacy and safety of two daily doses of the new sulfonylurea, glimepiride (Amaryl), each as a once-daily dose or in two divided doses, in patients with NIDDM. RESEARCH DESIGN AND METHODS: Of the previously treated NIDDM patients, 416 entered this multicenter randomized double-blind placebo-controlled fixed-dose study. After a 3-week placebo washout, patients received a 14-week course of placebo or glimepiride 8 mg q.d., 4 mg b.i.d., 16 mg q.d., or 8 mg b.i.d. RESULTS: Fasting plasma glucose (FPG) and HbA1c values were similar at baseline in all treatment groups. The placebo group's FPG value increased from 13.0 mmol/l at baseline to 14.5 mmol/l at the last evaluation endpoint (P < or = 0.001). In contrast, FPG values in the four glimepiride groups decreased from a range of 12.4-12.9 mmol/l at baseline to a range of 8.6-9.8 mmol/l at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change [vs. placebo] from baseline). Two-hour postprandial plasma glucose (PPG) findings were consistent with FPG findings. In the placebo group, the HbA1c value increased from 7.7% at baseline to 9.7% at endpoint (P < or = 0.001), whereas HbA1c values for the glimepiride groups were 7.9-8.1% at baseline and 7.4-7.6% at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change from baseline). There were no meaningful differences in glycemic variables between daily doses of 8 and 16 mg or between once- and twice-daily dosing. Adverse events and laboratory data demonstrate that glimepiride has a favorable safety profile. CONCLUSIONS: Glimepiride is an effective and well-tolerated oral glucose-lowering agent. The results of this study demonstrate maximum effectiveness can be achieved with 8 mg q.d. of glimepiride in NIDDM subjects.     

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.     

Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial

PURPOSE: To study the efficacy and safety of various dosages of metformin as compared with placebo in patients with type II diabetes mellitus. PATIENTS AND METHODS: A 14-week, multicenter, double-blind, dose-response study was conducted. After a 3-week, single-blind, placebo-controlled washout, 451 patients with fasting plasma glucose levels of at least 180 mg/dL were randomized to receive an 11-week course of placebo or metformin given at 500, 1000, 1500, 2000, or 2500 mg daily. RESULTS: Metformin improved glucose variables as compared with placebo. The adjusted mean changes in fasting plasma glucose from baseline associated with each metformin group at week 7, 11, or at endpoint exceeded those associated with placebo by 19 to 84 mg/dL at dosages of 500 to 2000 mg daily, respectively. The corresponding between-group differences in glycated hemoglobin (HbA1c) ranged from 0.6% to 2.0% at dosages of 500 to 2000 mg daily, respectively. All between-group differences were significant (P < 0.05) for both fasting plasma glucose and HbA1c at week 7, week 11, and endpoint, except for the difference between placebo and metformin 500 mg in fasting plasma glucose at endpoint (P = 0.054). Treatment-related adverse events occurred in 15% of patients in the placebo group and in 28% in the metformin group (P = 0.02); these were primarily manifested as digestive disturbances, such as diarrhea. CONCLUSIONS: Metformin lowered fasting plasma glucose and HbA1c generally in a dose-related manner. Benefits were observed with as little as 500 mg of metformin; maximal benefits were observed at the upper limits of the recommended daily dosage. All dosages were well tolerated. Metformin appears to be a useful therapeutic option for physicians who wish to titrate drug therapy to achieve target glucose concentrations.     

Does suppression of postprandial blood glucose excursions by the alpha-glucosidase inhibitor miglitol improve insulin sensitivity in diet-treated type II diabetic patients?

OBJECTIVE: Insulin sensitivity is impaired in patients with type II diabetes and is exacerbated by high mean blood glucose (BG). Potentially, large postprandial swings in BG could result in further decrements of insulin sensitivity. Because alpha-glucosidase inhibitors cause a marked reduction in the amplitude of BG changes, the aim of this study was to determine if such a BG-smoothing effect improves insulin sensitivity in well-controlled type II diabetic subjects treated with diet alone. RESEARCH DESIGN AND METHODS: Patients received either miglitol (BAY m 1099) (50 mg three times daily) or placebo for 8 weeks in a randomized double-blind parallel study. The miglitol (9 men, 2 women) and placebo (7 men, 3 women) groups were well matched (mean +/- SD) for age, weight, and blood glucose control (fasting BG, 6.4 +/- 1.0 vs. 6.9 +/- 1.6 mmol/l; HbA1, 7.7 +/- 1.0 vs. 7.9 +/- 0.4%; fructosamine, 0.99 +/- 0.08 vs. 1.07 +/- 0.17 mmol/l). The glucose metabolic clearance rate was calculated during the last 30 min of a 150 min glucose/insulin sensitivity test (glucose, 6 mg . kg-1 . min-1; insulin, 0.5 U . kg-1 . min-1). RESULTS: There was no significant improvement in metabolic clearance rate (0.21 +/- 0.27 vs. 0.16 +/- 0.35 l . kg-1 . min-1) for the miglitol- and placebo-treated groups, respectively. There were no statistically significant differences between miglitol and placebo for changes from baseline in BG (0.1 +/- 0.1 vs. -0.1 +/- 0.2 mmol/l), HbA1 (0.1 +/- 0.1 vs. 0.3 +/- 0.1%), and fructosamine (-0.06 +/- 0.02 vs. -0.03 +/- 0.02 mmol/l). CONCLUSIONS: Alpha-glucosidase-induced improvement in postprandial hyperglycemia does not result in increased insulin sensitivity.     

No relationship between carbohydrate intake and effect of acarbose on HbA1c or gastrointestinal symptoms in type 2 diabetic subjects consuming 30-60% of energy from carbohydrate

OBJECTIVE: To determine the relationship between carbohydrate intake and the effect of acarbose on HbA1c in subjects with type 2 diabetes treated with acarbose alone, acarbose plus sulfonylurea, acarbose plus metformin, or acarbose plus insulin. RESEARCH DESIGN AND METHODS: We conducted a double-blind randomized placebo-controlled study in which subjects with diabetes in four treatment strata (77 on diet alone, 83 treated with metformin, 103 treated with sulfonylurea, and 91 treated with insulin) were randomized to treatment with placebo or acarbose for 12 months. Before randomization, and 3, 6, 9, and 12 months after randomization, fasting blood was obtained for HbA1c, and 3-day diet records were collected. Subjects who completed at least 6 months of acarbose therapy and provided at least three 3-day diet records were included. RESULTS: In the 114 subjects included in this analysis, carbohydrate intake varied from approximately 30-60% of energy There was no significant relationship between carbohydrate intake and change in HbA1c in any of the four treatment strata (diet: n=26, r=0.35, P=0.076; metformin: n=27, r=0.26, P=0.19; sulfonylurea: n=35, r=0.24, P=0.16; insulin: n=25, r=-0.27, P=0.19). In the 80 subjects consuming <50% of energy from carbohydrate, the fall in HbA1c (7.83 +/-0.17% at baseline to 6.72+/-0.13% on acarbose, P < 0.001) was no different from that of the 34 subjects consuming >50% of energy from carbohydrate (7.55+/-0.25% at baseline to 6.66+/-0.23% on acarbose, P < 0.001). There was no difference in carbohydrate intake between those who dropped out of the study because of gastrointestinal side effects and those who did not, and there was no relationship between severity of symptoms and the composition of the diet. CONCLUSIONS: In subjects with type 2 diabetes consuming 30-60% of energy from carbohydrate, the effect of acarbose on HbA1c and gastrointestinal symptoms was not related to carbohydrate intake. Because most people consume at least 30% of energy from carbohydrate, we conclude that no special diet is needed for acarbose to be effective in improving blood glucose control in the treatment of type 2 diabetes.     

Relationship between gastric emptying and an alpha-glucosidase inhibitor effect on postprandial hyperglycemia in NIDDM patients

OBJECTIVE: The purpose of the study was to examine the relationship between gastric emptying and the efficacy of an alpha-glucosidase inhibitor in NIDDM patients. RESEARCH DESIGN AND METHODS: Sixteen NIDDM patients (4 patients treated with diet therapy alone and 12 receiving a sulfonylurea) were given 0.6 mg of voglibose daily for 4 weeks. The efficacy of voglibose was assessed by measurement of HbA1c, fasting plasma glucose, and 45- and 120-min postprandial plasma glucose (PPG) and serum insulin concentrations before and after the 4 weeks of voglibose therapy. Gastric emptying was evaluated using the proportional cumulative area under the absorption curve (% AUC) of plasma acetaminophen concentration at 60 min after ingestion of a liquid test meal containing 20 mg/kg of acetaminophen. These measurements were also taken before and after the therapy. RESULTS: The change in the 45-min PPG levels from the fasting state correlated significantly with the % AUC of the plasma acetaminophen concentrations (r = 0.625, P = 0.0096) before the voglibose administrations. The mean 45-min and 2-h PPG levels were reduced significantly after 4 weeks of voglibose (P < 0.05 and P < 0.01, respectively). Two-hour postprandial serum insulin concentrations were also significantly reduced at the end of the treatment period (P < 0.05). The changes in the PPG levels between pre- and posttreatment periods correlated significantly with the % AUC of the plasma acetaminophen concentrations before the treatment period (r = 0.499, P = 0.0490; r = 0.713, P = 0.0019, respectively). There was no significant difference in the plasma acetaminophen concentrations between pre- and posttreatment periods. CONCLUSIONS: The rate of gastric emptying affects the efficacy of voglibose therapy in NIDDM patients. Voglibose did not however alter the rate of gastric emptying.     

Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. The Troglitazone Study Group

To assess the effects of troglitazone monotherapy on glycemic control in patients with type 2 diabetes mellitus, we carried out a 6-month, randomized, double-blind, placebo-controlled study in 24 hospital and outpatient clinics in the United States and Canada. Troglitazone 100, 200, 400, or 600 mg or placebo once daily with breakfast was administered to 402 patients with type 2 diabetes with fasting serum glucose (FSG) > 140 mg/dL, glycosylated hemoglobin (HbA1c) > 6.5%, and fasting C-peptide > or = 1.5 ng/mL. Prior oral hypoglycemic therapy was withdrawn in patients who received it before the study. FSG, HbA1c, C-peptide, and serum insulin were evaluated at baseline and the end of the study. Analysis was performed on two subsets of patients based on prestudy therapy: Patients treated with diet and exercise only before the study (22% of patients), and those who had been receiving sulfonylurea therapy (78% of patients). Patients treated with 400 and 600 mg troglitazone had significant decreases from baseline in mean FSG and HbA1c at month 6 compared with placebo-treated patients (FSG: -51 and -60 mg/dL, respectively; HbA1c: -0.7 and -1.1%, respectively). In the diet-only subset, 600 mg troglitazone therapy resulted in a significant (P < 0.05) reduction in HbA1c (-1.35%) and a significant reduction in FSG (-42 mg/dL) compared with placebo. Patients previously treated with sulfonylurea therapy had significant (P < 0.05) decreases in mean FSG with 200-600 mg troglitazone therapy compared with placebo (-48, -61, and -66 mg/dL, respectively). Significant (P < 0.05) decreases in mean HbA1c occurred with 400 and 600 mg troglitazone therapy at month 6 (-0.8 and -1.2%, respectively) compared with placebo in this same subset. Significant (P < 0.05) decreases in triglycerides and free fatty acids occurred with troglitazone 400 and 600 mg, and increased high-density lipoprotein occurred with 600 mg troglitazone. We conclude that troglitazone monotherapy significantly improves HbA1c and fasting serum glucose, while lowering insulin and C-peptide in patients with type 2 diabetes. Troglitazone 600 mg monotherapy is efficacious for patients who are newly diagnosed and have never received pharmacological intervention for diabetes.     

BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model

We previously demonstrated that chronic dietary treatment with acarbose, an alpha-glucosidase inhibitor, improves glucose homeostasis in the streptozotocin (STZ)-induced diabetic rat. In this study we evaluated the effects of 4 weeks of acarbose treatment on glucose homeostasis in STZ-diabetic rats for both meal-fed (three times daily) and ad libitum feeding conditions. Sprague Dawley male rats (n = 58) were started on a daily meal-feeding paradigm consisting of three 2-h feeding periods: 0700 to 0900 hours, 1300 to 1500 hours, and 1900 to 2100 hours. Following 2 weeks of adaptation, half of the animals were switched to ad libitum feeding. The feeding paradigm itself (meal fed versus ad lib.) affected neither body weight nor daily food intake. Twenty animals from each feeding group then received STZ (60 mg/kg i.v.), whereas control animals received vehicle injections only. Two days later, the diet of 10 STZ-treated animals from each paradigm was supplemented with acarbose (40 mg of BAY G 5421/100-g diet), and the groups were treated for 4 weeks. Untreated diabetic rats had lower body weight than vehicle-injected control rats at all time points after STZ treatment. Acarbose treatment delayed this effect on body weight. STZ treatment induced hyperphagia regardless of feeding paradigm, which was significantly attenuated by acarbose only for the first week of treatment. Untreated diabetic rats had fasting blood glucose values 4 times those of vehicle-injected controls in both the meal-fed and ad libitum-fed conditions. Acarbose significantly lowered fasting blood glucose in the treated STZ groups. Blood glucose was also assessed 0, 90, and 180 min following the start of a meal. The postprandial rise in blood glucose was significantly reduced in acarbose-treated meal-fed diabetic rats, to values not significantly different from those of vehicle-injected control rats. During the fourth week of treatment glycated hemoglobin levels were significantly higher in untreated diabetic groups compared to vehicle-injected control groups. Acarbose treatment significantly reduced this rise, regardless of the feeding paradigm. Collectively, the results demonstrate that acarbose reduces diabetes-induced increases of blood glucose and glycated hemoglobin and that the glycemic effects of acarbose are most apparent during the absorptive period. Feeding paradigm (ad lib. versus meal fed) has little or no influence on acarbose's metabolic effects, indicating that large meals are not required to realize the beneficial effects of the drug. The meal-fed STZ-diabetic rat may be a good model with which to test meal-based diabetes treatments.     

A risk-benefit appraisal of acarbose in the management of non-insulin-dependent diabetes mellitus

Acarbose is an alpha-glucosidase inhibitor proposed for the treatment of diabetic patients. It acts by competitively inhibiting the alpha-glucosidases in the intestinal brush border. The principal action of these enzymes is to convert nonabsorbable dietary starch and sucrose into absorbable monosaccharides (e.g. glucose). Enzyme inhibitors delay this conversion, slowing the formation and consequently the absorption of monosaccharides, and thus reducing the concentration of postprandial blood glucose. Both starch and sucrose are influenced, whereas lactose and glucose are not. Many studies in experimental animals, healthy volunteers and patients with non-insulin-dependent diabetes mellitus (NIDDM) have shown that acarbose decreases postprandial blood glucose, with a lesser reduction of fasting blood glucose, plasma triglycerides and postprandial insulin levels. In long term studies in NIDDM patients, acarbose significantly reduced glycosylated haemoglobin levels. Acarbose is only minimally absorbed from the gut and no systemic adverse effects have been demonstrated after long term administration. The drug allows undigested carbohydrates to pass into the large bowel where they are fermented causing flatulence, bloating and diarrhoea. These symptoms, which occur in approximately 30 to 60% of patients, tend to decrease with time and seem to be dose-dependent. They are minimised by starting therapy with low doses (such as 50mg 3 times daily) which may be effective in many patients. An increase in serum hepatic transaminases observed in earlier studies in the US, where doses of acarbose up to 900mg daily were used, has been not reported with the lower doses of the drug actually recommended [150 to 300mg (up to 600mg) daily]. In conclusion, acarbose may be useful in patients with NIDDM when diet alone is no longer able to maintain satisfactory blood glucose control. Furthermore, it may be a valid alternative to sulphonylurea or biguanide therapy when these drugs are contraindicated and insulin administration may be delayed. Acarbose seems also to be a useful adjunct to hypoglycaemic oral agents but its precise role in this field has not been fully clarified.     

Clinical experience with an alpha glucosidase inhibitor (acarbose) in the treatment of non-insulin-dependent diabetes. Multicenter study

BACKGROUND: Acarbose, an alpha glucosidase inhibitor is a drug used in the treatment of non insulin dependent diabetes mellitus, that interferes with the intestinal absorption of monosaccharides. AIM: To study the effect of acarbose in non insulin dependent diabetic patients that had an inadequate metabolic control with diet and sulphonylureas. PATIENTS AND METHODS: Diabetic patients received acarbose, 150 mg/day during four weeks and this dose was increased to 300 mg/day during 3 months. Afterwards, patients were followed for a period of 12 weeks without acarbose. Fasting and post-prandial blood glucose and glycosilated hemoglobin were measured sequentially during the study. RESULTS: Eighty five patients were recruited for the study but 64 complied with the treatment protocol. The age of these patients was 56 +/- 8.8 years old, their diabetes duration was 7.8 +/- 8.8 years and their body mass index was 27.6 +/- 3.6 kg/m2. During acarbose treatment, glycosilated hemoglobin decreased from 8.36 +/- 1.33 to 7.71+ 1.7% (p < 0.001), fasting blood glucose decreased from 173 +/- 48 to 159 +/- 59 mg/dl (p < 0.03) and post-prandial blood glucose decreased from 254 +/- 80 to 241 +/- 80 mg/dl (NS). After discontinuing acarbose glycosilated hemoglobin and blood glucose levels returned to basal levels. Body weight and blood pressure did not change during the treatment period. Fifty nine patients had gastrointestinal symptoms (meteorism, flatulence and abdominal distention) that were mild in 59% and moderate in 39%. Episodes of hypoglycemia were not observed. CONCLUSIONS: Acarbose, associated to sulphonylureas is an effective drug to reduce blood glucose and glycosilated hemoglobin levels in patients with non insulin dependent diabetes.     

Effect of herbimycin A on hsp30 and hsp70 heat shock protein gene expression in Xenopus cultured cells

Glucose intolerance and diabetes mellitus are both prevalent in patients with chronic liver diseases. We examined the efficacy and systemic safety of therapy with an alpha-glucosidase inhibitor, acarbose, in diabetes mellitus associated with chronic liver diseases. Twenty patients with chronic hepatitis or liver cirrhosis and overt diabetes mellitus received acarbose (taken orally) for 8 weeks. The initial dosage of acarbose was 50 mg three times daily, taken before meals; this was increased to 100 mg three times daily after 2 weeks. The mean fasting plasma glucose level was 173.7 +/- 18.6 mg/dl (mean +/- SE) at entry, and was significantly decreased to 132.9 +/- 7.5 mg/dl (P < 0.05) after 8 weeks of acarbose treatment. The improved glycemic control was reflected by a significant decrease in glycosylated hemoglobin (HbA1c) from 7.2 +/- 0.3% at entry to 6.3 +/- 0.2% (P < 0.05) after 8 weeks. Serum levels of both aspartate and alanine aminotransferases fluctuated during acarbose treatment, probably due to the natural course of chronic liver diseases, but the mean values had decreased after 8 weeks of treatment. Plasma ammonia levels increased, from 61.3 +/- 10.7 micrograms/dl to 71.1 +/- 9.6 micrograms/dl after 8 weeks of acarbose treatment but the increase was not significant. Clinically significant elevation of plasma ammonia concentration was seen in 2 cirrhotic patients (121 and 124 micrograms/dl); this was asymptomatic and gradually returned to the normal range despite continuous acarbose treatment in one patient, and was reversed after the withdrawal of acarbose with the concomitant administration of lactulose in the other patient. No other blood tests results, including albumin, cholinesterase, and prothrombin time, or lipid profile and nutritional status, in terms of rapid turnover proteins, prealbumin, retinol binding protein, and transferin, were altered throughout the study period. These results indicate that diabetes mellitus associated with chronic liver diseases may be safely and effectively treated with acarbose. However, clinicians must be aware of the possibility of hyperammonemia when they prescribe acarbose for patients with diabetes mellitus and advanced liver cirrhosis.     

The effect of pindolol on carbohydrate and fat metabolism in diabetes mellitus

Twenty-seven diabetic patients, nine treated with insulin, nine treated with tolbutamid, and nine placed on diet, were given either pindolol or placebo 5 mg, three times daily during a 6-week period. The following 6-week period those receiving pindolol in the first 6 weeks received placebo and vice versa. Pindolol had no influence on the concentration of blood glucose, free fatty acids, triglycerides, or total cholesterol. The effect of pindolol on carbohydrate and fat metabolism appears to be of no clinical relevance in diabetic patients receiving their usual therapy.     

Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group

OBJECTIVE: To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone. RESEARCH DESIGN AND METHODS: There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed. RESULTS: Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy CONCLUSIONS: Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.