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.     

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.     

Efficacy and safety of acarbose in insulin-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 insulin. RESEARCH DESIGN AND METHODS: A multicenter randomized double-blind placebo-controlled parallel-group comparison study was conducted. The trial was 26 weeks with a 2-week screening period and a 24-week period of treatment with acarbose or placebo, with forced titration from 25 mg t.i.d. to 50 mg t.i.d. after 4 weeks, and titration of 50 mg t.i.d. to 100 mg t.i.d. after 12 weeks based on glucose control. The dosage of insulin was to remain stable. The primary efficacy variable was mean change from baseline in HbA1c, and secondary efficacy variables included mean changes in fasting and postprandial plasma glucose and triglyceride levels. RESULTS: The addition of acarbose to the treatment of patients receiving background insulin and diet therapy resulted in a statistically significant reduction in mean HbA1c of 0.69% compared with placebo. There were statistically significant reductions in postprandial plasma glucose and glucose area under the curve, and in postprandial serum triglyceride levels in the acarbose-treated patients. Gastrointestinal side effects were more frequently reported in the acarbose-treated patients. There were no significant differences in hypoglycemic events or liver transaminase elevations between groups. CONCLUSIONS: This study demonstrated that the addition of acarbose to patients with type 2 diabetes who are inadequately controlled with insulin and diet is safe and generally well tolerated and that it significantly lowers HbA1c and postprandial glucose levels.     

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.     

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.     

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.     

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.     

Alterations in glucose metabolism in the elderly patient with diabetes

OBJECTIVE: To determine the alterations in glucose metabolism in elderly patients with NIDDM. RESEARCH DESIGN AND METHODS: We studied 9 healthy elderly control subjects (73 +/- 1 yr of age; body mass index 25.7 +/- 0.4 kg/m2) and 9 untreated elderly NIDDM patients (72 +/- 2 yr of age; BMI 25.9 +/- 0.5 kg/m2). Each subject underwent a 3-h oral glucose tolerance test (40 g/m2); a 2-h hyperglycemic glucose clamp study (glucose 5.4 mM above basal); and a 4-h euglycemic insulin clamp (40 mM.m2.min-1). Tritiated glucose methodology was used to measure glucose production and disposal rates during the euglycemic clamp. RESULTS: Patients with NIDDM had a higher fasting glucose (9.3 +/- 0.3 vs. 5.1 +/- 0.1 mM in control subjects vs. NIDDM patients, respectively, P < 0.001) and a greater area under the curve for glucose during the OGTT (16.0 +/- 0.6 vs. 6.7 +/- 0.3 mM in control subjects vs. NIDDM patients, respectively, P < 0.01) than the healthy control subjects. During the hyperglycemic clamp, patients with NIDDM had an absent first-phase insulin response (112 +/- 6 vs. 250 +/- 31 pM in control subjects vs. NIDDM patients, respectively, P < 0.01), and a blunted second-phase insulin response (159 +/- 11 vs. 337 +/- 46 pM in control subjects vs. NIDDM patients, respectively, P < 0.01). Before the euglycemic clamp, fasting insulin (99 +/- 5 vs. 111 +/- 10 pM in control subjects vs. NIDDM patients, respectively) and hepatic glucose production (11.8 +/- 0.7 vs. 11.5 +/- 0.5 mumol.kg-1-min-1 in control subjects vs. NIDDM patients, respectively) were similar. Steady-state (180-240 min) glucose disposal rates during the euglycemic clamp were slightly, but not significantly, higher in the normal control subjects (36.5 +/- 1.1 vs. 33.1 +/- 1.9 mumol.kg-1-min-1 in control subjects vs. NIDDM patients, respectively, NS). CONCLUSIONS: We conclude that NIDDM in nonobese elderly subjects is characterized by a marked impairment in insulin release. This may be attributable to the toxic effects of chronic hyperglycemia on the beta-cell. When compared with age-matched control subjects, the NIDDM patients showed no increase in fasting insulin or hepatic glucose production, and insulin resistance was mild.     

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.     

1,5-Anhydro-D-glucitol evaluates daily glycemic excursions in well-controlled NIDDM

OBJECTIVE: To evaluate the usefulness of plasma 1,5-anhydro-D-glucitol (1,5-AG) as a possible marker for daily glycemic excursion, we measured plasma 1,5-AG, HbA1c, fasting plasma glucose (FPG) level, and daily excursion of glycemia, from which the M-value (after Schlichtkrull) was calculated as an index of daily glycemic excursion. RESEARCH DESIGN AND METHODS: The subjects were 76 patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) treated with diet therapy only (diet, n = 17), oral hypoglycemic agents (OHA, n = 28), conventional insulin therapy (CIT, n = 16), or multiple insulin injection therapy (MIT, n = 15). RESULTS: HbA1c values were similar among all the groups (diet, 6.9 +/- 0.6; OHA, 7.2 +/- 0.5; CIT, 7.1 +/- 0.6; MIT, 7.2 +/- 0.5%). The MIT group showed a significantly higher 1,5-AG concentration (11.5 +/- 5.3 micrograms/ml), a significantly lower M-value (9.2 +/- 5.2), and little risk of hypoglycemia ( < 4 mmol/l) and hyperglycemia ( > 10 mmol/l) (1.3 +/- 1.1 times/24 h) compared with the CIT group (6.9 +/- 3.3 micrograms/ml, 15.7 +/- 8.9, 2.2 +/- 1.6 times/24 h, respectively). Insulin doses (22.4 +/- 4.5 vs. 22.0 +/- 8.9 U/day), FPG (6.6 +/- 2.2 vs. 7.4 +/- 2.4 mmol/l), and HbA1c concentrations were not significantly different between the CIT and MIT groups. M-values significantly correlated with 1,5-AG concentrations (r = 0.414, P < 0.05), but not with HbA1c concentrations. CONCLUSIONS: The findings suggest that the plasma 1,5-AG concentration can be a useful index of the daily excursion of blood glucose, especially in patients with well-controlled NIDDM.     

Quantitative, competitive PCR assay for HIV-1 using a microplate-based detection system

OBJECTIVE: Amylin, a secretory peptide of beta-cells, is the constituent peptide of islet amyloid, which is characteristic of NIDDM, and changes in amylin secretion in response to therapies may influence the rate of production of islet amyloid. The primary objective of this study was to determine whether therapy with sulfonylurea or basal insulin in NIDDM would alter amylin secretion in a way that might affect the formation of islet amyloid. RESEARCH DESIGN AND METHODS: In a randomized crossover design, eight subjects with NIDDM underwent three 8-week periods of therapy with diet alone, sulfonylurea, or exogenous basal insulin, with evaluation of amylin, amylin-like peptide (ALP), and glucose and C-peptide concentrations, both during fasting and after a standard breakfast. Changes in beta-cell function (% beta) were assessed, in the basal state by homeostasis model assessment (HOMA) and in the stimulated state by hyperglycemic clamps. Seven nondiabetic control subjects each underwent a meal profile and hyperglycemic clamp. RESULTS: Both sulfonylurea and insulin therapy reduced basal glucose concentrations compared with diet alone, but neither reduced the increased postprandial glucose increments. Both sulfonylurea and insulin therapy increased basal % beta, assessed by HOMA, but only sulfonylurea increased the second-phase C-peptide responses to the hyperglycemic clamp. Sulfonylurea increased time-averaged mean postprandial amylin and ALP concentrations compared with diet alone (geometric mean [1-SD range] for amylin, 4.9 [2.0-11.8] vs. 3.0 [1.4-6.2] pmol/l, P = 0.003; for ALP, 16.4 [8.5-31.7] vs. 10.1 [4.9-20.8] pmol/l, P = 0.001). Insulin therapy reduced basal ALP concentrations compared with diet alone (2.9 [1.5-5.6] vs. 6.0 [2.6-13.6] pmol/l, P = 0.03), but had no effect on postprandial concentrations of amylin (3.0 [1.3-6.5] pmol/l) or ALP (10.0 [5.5-18.1] pmol/l). CONCLUSIONS: By increasing postprandial concentrations of the constituent peptides of islet amyloid, sulfonylurea therapy might increase the rate of deposition of islet amyloid and thereby accelerate the decline of % beta in NIDDM, compared with diet therapy alone.     

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.     

Small weight loss on long-term acarbose therapy with no change in dietary pattern or nutrient intake of individuals with non-insulin-dependent diabetes

OBJECTIVES: To see if the long-term treatment of non-insulin dependent diabetes (NIDDM) with the alpha-glucosidase inhibitor acarbose affects food intake and body weight. DESIGN: Randomized, double-blind, placebo-controlled, parallel design clinical trial of 12 months duration. SUBJECTS: Subjects with NIDDM in four treatment strata: 77 on diet alone, 83 also treated with metformin, 103 also treated with sulfonylurea and 91 also treated with insulin. MEASUREMENTS: Two 3 day diet records were obtained before randomization to acarbose or placebo therapy, and additional 3 day diet records were obtained at 3, 6, 9 and 12 months after randomization. Body weight was also measured at these times. RESULTS: Of the 354 subjects randomized, 279 (79%) completed at least 9 months of therapy and, of these, 263 (94%) provided at least one diet record during the baseline period and two diet records during the treatment period. After one year, subjects on acarbose had lost 0.46 +/- 0.28 kg, which differed significantly from the 0.33 +/- 0.25 kg weight gain on placebo (P = 0.027). The difference in weight change between acarbose and placebo did not differ significantly in the different treatment strata. Being in the study had significant effects on diet, including a reduction in energy intake from 1760-1700 Kcal/d (P < 0.05), a reduction in simple sugars intake from 18.5-17.4% of energy (P < 0.001), and reductions in the number of different foods consumed (33-30, P < 0.001) and the number of meals eaten per day (4.7-4.3, P < 0.001). However, compared to placebo treatment, acarbose had no effect on energy intake, nutrient intakes, or dietary patterns. CONCLUSIONS: In subjects with NIDDM on weight-maintaining diets, long-term acarbose therapy results in a small weight loss, but has no effect on energy or nutrient intakes. The weight loss induced by acarbose may be due partly to reduced doses of concomitant oral agents and insulin and partly to energy loss due to increased colonic fermentation.     

Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study

OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.     

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.     

Neural network subtyping of depression

OBJECTIVE: To examine the mechanisms by which weight loss improves glycemic control in overweight subjects with NIDDM, particularly the relationships between energy restriction, improvement in insulin sensitivity, and regional and overall adipose tissue loss. RESEARCH DESIGN AND METHODS: Hyperinsulinemic glucose clamps were performed in 20 subjects (BMI = 32.0 +/- 0.5 [SEM] kg/m2, age = 48.4 +/- 2.7 years) with normal glucose tolerance (NGT) (n = 10) or mild NIDDM (n = 10) before and on the 4th (d4) and 28th (d28) days of a reduced-energy (1,100 +/- 250 [SD] kcal/day) formula diet. Body composition changes were assessed by dual energy x-ray absorptiometry and insulin secretory changes were measured by insulin response to intravenous glucose before and after weight loss. RESULTS: In both groups, energy restriction (d4) reduced fasting plasma glucose (FPG) (delta FPG: NGT = -0.4 +/- 0.2 mmol/l and NIDDM = -1.1 +/- 0.03 mmol/l, P = 0.002), which was independently related to reduced carbohydrate intake (partial r = 0.64, P = 0.003). There was a marked d4 increase in percent of insulin suppression of hepatic glucose output (HGO) in both groups (delta HGO suppression: NGT = 28 +/- 15% and NIDDM = 32 +/- 8%, P = 0.002). By d28, with 6.3 +/- 0.4 kg weight loss, FPG was further reduced (d4 vs. d28) in NIDDM only (P = 0.05), and insulin sensitivity increased in both groups (P = 0.02). Only loss of abdominal fat related to improvements in FPG (r = 0.51, P = 0.03) and insulin sensitivity after weight loss (r = 0.48, P = 0.05). In contrast to insulin action, there were only small changes in insulin secretion. CONCLUSIONS: Both energy restriction and weight loss have beneficial effects on insulin action and glycemic control in obesity and mild NIDDM. The effect of energy restriction is related to changes in individual macronutrients, whereas weight loss effects relate to changes in abdominal fat.     

Different change in lipoprotein(a) levels from lipid levels of other lipoproteins with improved glycemic control in patients with NIDDM

OBJECTIVE: To evaluate change both in lipoprotein(a) [Lp(a)] and lipid levels in other lipoproteins in non-insulin-dependent diabetes mellitus (NIDDM) after short-term improvement of glycemic control. RESEARCH DESIGN AND METHODS: We compared Lp(a) levels in 210 NIDDM patients with those in 46 control subjects and evaluated the relationship between glycemic control and Lp(a) levels in diabetic patients. In addition, changes in Lp(a) levels and lipid levels were assessed after the improvement of glycemic control in 54 poorly controlled NIDDM patients. RESULTS: In NIDDM, Lp(a) levels in all patients, 62 patients with HbA1c < 6.0%, and 75 patients with HbA1c between 6.0 and 8.0%, were significantly higher than those in control subjects (19.1 [1.7-106.6], 19.2 [6.0-106.6], and 20.3 [2.7-75.3] vs. 15.4 [2.0-61.7] mg/dl, median [range], P < 0.05). Lp(a) levels in 73 patients with HbA1c of > or = 8.0% (18.7 [1.7-58.8] mg/dl) were not significantly different from those in control subjects. After glycemic control, lipid levels in plasma and in other lipoproteins fell significantly, but Lp(a) did not change (from 18.3 [1.7-58.8] to 18.4 [6.6-95.3] mg/dl). Changes in lipid levels, including Lp(a), did not correlate with those in fasting plasma glucose or HbA1c. CONCLUSIONS: These results suggest that elevated Lp(a) levels do not reflect poor glycemic control and that Lp(a) levels are independent of lipid levels in other lipoproteins after improved glycemic control in NIDDM.     

Effects of glycemic control on plasma 3-deoxyglucosone levels in NIDDM patients

OBJECTIVE: To clarify the effects of glycemic control on the level of 3-deoxyglucosone (3-DG), a reactive dicarbonyl compound, in plasma from diabetic patients. RESEARCH DESIGN AND METHODS: Fasting plasma samples were collected from 15 healthy volunteers and 27 patients with NIDDM. Samples were collected from six poorly controlled patients before and after improved glycemic control for at least 2 months. Plasma 3-DG was determined by high-performance liquid chromatography (HPLC) as a 2,3-diaminonaphthalene derivative. We observed the relationship of 3-DG levels with plasma glucose or HbA1c levels and examined changes in 3-DG levels after glycemic control in the six patients. RESULTS: Plasma 3-DG was significantly more increased in diabetic patients than in nondiabetic control subjects (31.8 +/- 11.3 vs. 12.8 +/- 5.2 ng/ml, means +/- SD, P < 0.001), but there was an approximately threefold difference in 3-DG levels among diabetic patients. 3-DG levels were well correlated with plasma glucose (r = 0.56, P < 0.005) and HbA1c levels (r = 0.74, P < 0.001) in diabetic patients. The improvement of hyperglycemia in six patients resulted in a significant decrease in 3-DG (35.2 +/- 13.2 vs. 21.3 +/- 3.4 ng/ml, P < 0.05). CONCLUSIONS: The results indicate that the plasma glucose level is a predominant determinant of the plasma 3-DG level in diabetic patients and good glycemic control would be important to reduce this reactive metabolite.