In patients with inadequate glycemic control despite established glyburide/metformin therapy, the addition of rosiglitazone improves glycemic control, allowing more patients to achieve an HbA1C level <7% and perhaps delaying the need for insulin treatment.
A total of 1856 patients from three randomized, double-blind, multicentre, parallel-group clinical trials were stratified at baseline according to HbA1C (< 8% or > or = 8%), age (< 65 years or > or = 65 years) and body mass index (BMI; < 28 kg/m2 or > or = 28 kg/m2). The effects of study treatments on HbA1C and the incidence of hypoglycaemic symptoms were determined in each subgroup.
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Type 2 diabetes mellitus is characterized by both insulin deficiency and insulin resistance. Effective treatment often requires therapy directed at both abnormalities. Patients on monotherapy might benefit from a combination agent such as glyburide/metformin, which increases insulin secretion and reduces insulin resistance.
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After 24 weeks, therapy with glyburide/metformin plus rosiglitazone resulted in a greater reduction in HbA1C levels (-1.0%, P<0.001) compared with combination therapy that included placebo, and in a larger proportion of patients (42% vs. 14%) who attained levels <7%. The difference in fasting plasma glucose levels between groups was -48 mg/dL (P<0.001), favoring glyburide/metformin plus rosiglitazone. The adverse event profile in the rosiglitazone-treated group included mild-to-moderate edema (8%), hypoglycemia (22%), and weight gain of 3 kg. No patient experienced hypoglycemia requiring third-party assistance.
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Although hyperaemic MBF did not differ significantly between the patients and controls (1.81 (0.38) v 1.97 (0.43) ml/min/g; mean (SD)), the CPT-induced MBF increase (DeltaMBF) was significantly less in diabetic patients than in controls (0.07 (0.07) v 0.25 (0.12) ml/min/g; p<0.001). Treatment with glyburide and metformin significantly decreased plasma glucose concentrations from 207 (76) to 134 (52) mg/dl (p<0.001). This decrease in plasma glucose was paralleled by a significant increase in DeltaMBF in response to CPT (0.20 (0.16) from 0.07 (0.07) ml/min/g; p<0.001), which tended to be lower than in controls at baseline (0.20 (0.16) v 0.25 (0.12) ml/min/g; p = NS). The decrease in plasma glucose concentrations correlated significantly with the improvement in DeltaMBF in response to CPT (r = 0.67, p<0.01).
The subjects of the study were individuals prescribed metformin or sulfonylurea or both before July 2000, who were prescribed both metformin and sulfonylurea concurrently (either separately or FDC) after August 2000.
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Adherence was measured by medication possession ratio; the proportion of days on which a patient had medication available.
The combination treatments were more effective than either monotherapy irrespective of baseline HbA1C, age or BMI in each trial. Antihyperglycaemic effects were greater in patients with HbA1C > or = 8% at baseline, especially with the combinations. The majority of hypoglycaemic symptoms with glibenclamide-containing treatments occurred in patients with HbA1C < 8% at baseline. Neither age nor BMI had a marked effect on the efficacy of the combination treatments, and there was no increase in hypoglycaemic symptoms in older patients.
To evaluate the efficacy and safety of glyburide/metformin combined tablet compared to glyburide or metformin alone in patients with type 2 diabetes.
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Oral antidiabetic combination therapy is a proven means of establishing glycaemic control in the hyperglycaemic, Type 2 diabetic patient, but co-administering two oral antidiabetic agents separately may hinder compliance with therapy. A new single-tablet of glyburide/metformin combination therapy (Glucovance), Bristol-Myers Squibb, Inc.) has recently been developed, which addresses the primary defects of Type 2 diabetes: beta-cell dysfunction and insulin resistance. The glyburide/metformin tablet, taken with meals, is designed to optimise the absorption of glyburide and to address the postprandial glucose rise. Glyburide/metformin tablets are more effective in controlling fasting and postprandial glycaemia than its component monotherapies, at lower doses of metformin and glyburide compared with monotherapy because of the synergy between its glyburide and metformin components. Moreover, a double-blind study showed that glyburide/metformin tablets are more effective than a free combination of glyburide co-administered with metformin in controlling postprandial glucose. Retrospective analyses suggested that glyburide/metformin tablets control glycated haemoglobin (A1C) more effectively than a free combination of glyburide co-administered with metformin, at lower mean doses of glyburide and metformin. The incidence of side effects is lower than separate component therapy for any given A1C. Glyburide/metformin tablets are an effective option for optimising the control of blood glucose in Type 2 diabetic patients and appear to enhance adherence to therapy.
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The study sample comprised 2,275 diabetic patients, aged 45-74 years, with proven CAD, who were screened but not included in the bezafibrate infarction prevention study. In addition, 9,047 nondiabetic patients with CAD represented a reference group. Diabetics were divided into four groups on the basis of their therapeutic regimen: diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a combination of the latter two (n = 253).
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All patients taking a glyburide/metformin preparation at the Carl T. Hayden VAMC were identified from pharmacy records. Patients with documented hemoglobin A values within 31 weeks prior and between 3 and 33 weeks after initiation of therapy (92 subjects) were examined.
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This exploratory double-blind, randomised, 20-week study evaluated the mechanism of action of metformin-glibenclamide combination tablets (Glucovance) vs. metformin and glibenclamide in 50 type 2 diabetes patients inadequately controlled by diet and exercise. A glycaemic target of HbA1C 7.0% was used. Final HbA(1C), fasting glucose and post-oral glucose tolerance test (OGTT) glucose were similar between groups, although average doses of metformin and glibenclamide from combination tablets (708 and 3.5 mg) were lower than monotherapy doses (1500 and 6.6 mg). Second-phase insulin during a hyperglycaemic clamp increased by 93% with combination tablets, 36% with metformin and 46% with glibenclamide. The insulin response post-OGTT was more rapid with the combination tablets vs. glibenclamide. First-phase insulin responses improved modestly in all groups, possibly due to reduced glucotoxicity. Changes in insulin sensitivity were minor. Larger beta-cell responses between combination tablets and glibenclamide may reflect more rapid glibenclamide absorption.
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Type 2 diabetes is a chronic and progressive disease. Oral antidiabetic monotherapies directly address only one defect as their primary mechanism of action, and do not control blood glucose sufficiently well to meet current glycaemic targets. In consequence, most patients need combination therapy within a few years. However, the co-administration of two or more oral antidiabetic drugs may render treatment regimens difficult to follow. Combining oral antidiabetic agents into a single tablet provides a means of intensifying antidiabetic therapy while supporting good patient compliance. An insulin sensitiser and an insulin secretagogue represent a rational oral antidiabetic combination, as they address the dual endocrine defects of insulin resistance and impaired beta-cell function in type 2 diabetes. Nevertheless, the components of a combination tablet must be carefully chosen. Metformin (an insulin sensitiser) and glibenclamide (an insulin secretagogue) are well supported by decades of clinical evidence, and the pharmacokinetics of these agents support twice-daily co-administration. The final technical challenge is to optimise their delivery within a single-tablet combination. A recently-introduced metformin-glibenclamide combination tablet (Glucovance) has been extensively studied in well-designed clinical trials, where it has been shown to be more effective than its component monotherapies in controlling fasting and postprandial glycaemia. This treatment provides a case study in the development of a single-tablet oral antidiabetic combination, in terms of the pharmacokinetic issues facing the development of this preparation, and the implications of the pharmacokinetic properties of the components of the combination tablet on their pharmacodynamic actions and risk-benefit profile.
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In this 16-week, double-blind, multicentre, parallel-group trial, 411 patients were randomized to receive metformin 500 mg, glibenclamide 5 mg, metformin-glibenclamide 500 mg/2.5 mg or metformin-glibenclamide 500 mg/5 mg, titrated with the intention to achieve fasting plasma glucose (FPG) < or = 7 mmol/l.
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From a 12-year-old diabetes registry of members of Kaiser Permanente Northwest, a large group-model HMO, we tracked the glycemic control histories of all 570 registrants who, in 1998, added metformin therapy to sulphonylurea monotherapy.
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Final HbA(1c) values were lower for repaglinide/metformin treatment than for nateglinide/metformin (7.1 vs. 7.5%). Repaglinide/metformin therapy showed significantly greater mean reductions of HbA(1c) (-1.28 vs. -0.67%; P < 0.001) and of fasting plasma glucose (FPG) (-39 vs. -21 mg/dl; P = 0.002). Self-monitoring of blood glucose profiles were significantly lower for repaglinide/metformin before breakfast, before lunch, and at 2:00 A.M. Changes in the area under the curve of postprandial glucose, insulin, or glucagon peaks after a test meal were not significantly different for the two treatment groups during this study. Median final doses were 5.0 mg/day for repaglinide and 360 mg/day for nateglinide. Safety assessments were comparable for the two regimens.
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Due to the poor flow properties of metformin hydrochloride, in order to attain the dose uniformity, a wet granulation based manufacturing process was used. The prepared tablets were evaluated for the release of metformin hydrochloride and glibenclamide using validated HPLC methods. The similarity factor was calculated, taking into consideration as reference profile the mean in vitro dissolution data of Glucovance. The formulation process was undertaken using a reproducible DoE generated model, attained by the variation of each of the formulation factors on two levels, followed by the filling of the data resulted from the analytical testing of the tablets.
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The diabetic groups presented similar clinical characteristics upon recruitment. Crude mortality rate after a 7.7-year follow-up was lower in nondiabetics (14 vs. 31.6%, p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%), 324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients (43.9%) on combined treatment (p<0.000001). Time-related mortality was almost equal for patients on metformin and on combined therapy over an intermediate follow-up period of 4 years (survival rates 0.80 and 0.79, respectively). The group on combined treatment presented the worst prognosis over the long-term follow-up, with a time-related survival rate of 0.59 after 7 years, versus 0.68 and 0.70 for glyburide and metformin, respectively. After adjustment to variables for prognosis, the use of the combined treatment was associated with an increased hazard ratio (HR) for all-cause mortality of 1.53 (95% confidence interval [CI] 1.20-1.96), whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02-1.45) and HR 1.26 (95% CI 0.81-1.96), respectively.
Compared to 2-pill therapy, a FDC resulted in important increases in patient adherence. Economic analyses are warranted to determine whether the clinical benefits attributable to the adherence gains are worth the incremental cost of a FDC.
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An 18-year-old Spanish Mustang mare was referred for evaluation of progressive weight loss and persistent hyperglycemia. Clinicopathologic abnormalities included marked hyperglycemia and glycosuria. Serum cortisol concentration was appropriately decreased following administration of dexamethasone, indicating that the horse did not have pituitary pars intermedia dysfunction. Serum insulin and plasma C-peptide concentrations were low, suggesting that hyperglycemia was a result of decreased secretion of insulin by pancreatic beta cells. In addition, glucose concentration did not return to the baseline concentration until 5 hours after i.v. administration of a glucose bolus, suggesting that insulin secretion, insulin effect, or both were reduced. However, i.v. administration of insulin caused only a slight decrease in the plasma glucose concentration, giving the impression that the action of insulin was impaired. Within 5 hours after administration of a combination of glyburide and metformin, which is used to treat diabetes mellitus in humans, the glucose concentration was within reference limits. The horse was euthanized, and a postmortem examination was done. Immunohistochemical staining of sections of the pancreas revealed attenuation of the pancreatic islet beta-cell population, with beta cells that remained generally limited to the periphery of the islets. These findings indicate that, albeit rare, pancreatic beta-cell failure may contribute to the development of diabetes mellitus in horses.
Three methods were developed for simultaneous determination of metformin hydrochloride and glyburide in an antihyperglycemic binary mixture without previous separation. In the first method, a reversed-phase HPLC column with acetonitrile-water (60 + 40, v/v) mobile phase at 0.9 mL/min flow rate was used to separate both compounds, with UV detection at 254 nm. Linearity was obtained in the concentration range of 0.06--0.24 microg/mL for glyburide and 1.5-6.0 microg/mL for metformin hydrochloride. The second method depended on first- and second-derivative UV spectrometry with zero-crossing measurements. The first-derivative amplitude at 261 nm was selected for the assay of glyburide, and the second-derivative amplitude at 235 nm was selected for the assay of metformin hydrochloride. The third method depended on measuring the first derivative of the ratio-spectra at 241 nm for glyburide and 227 nm for metformin hydrochloride. For the second and third methods, Beer's law was obeyed in the range of 10-55 microg/mL for glyburide and 20-200 microg/mL for metformin. The proposed methods were extensively validated and applied for the analysis of some pharmaceutical formulations containing binary mixtures of the mentioned drugs.
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Treatment with glibenclamide/metformin resulted in a significantly smaller mean PPGE than was attained by treatment with glibenclamide plus metformin, according to measurements taken after the day 14 afternoon standardised meal (89.5 vs 117.4 mg/dl, p = 0.011). The mean glibenclamide peak concentration (C(max)) was significantly greater (approximately 16%) after glibenclamide/metformin treatment on both days 1 and 14. Glibenclamide/metformin treatment was associated with a 2-fold greater area under the concentration-time curve to 3 hours for glibenclamide (AUC(3)) [p < 0.001], although the AUC over the administration interval was equivalent for both formulations.
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Both glyburide/metformin 2.5 mg/500 mg and glyburide/metformin 5.0 mg/500 mg combination therapy were efficacious and well tolerated in the treatment of Chinese patients with type 2 diabetes mellitus.
Longitudinal data from a large claims database were used to assess adherence from January 1, 2000, to December 31, 2001. Propensity scoring methods were used to mitigate concerns related to non-random assignment of patients to treatments.
To evaluate the change in hemoglobin A1C (A1C) in patients with type 2 diabetes switched from coadministration of a sulfonylurea (SU), glyburide or glipizide, and metformin (SU+Met) to a single glyburide-metformin tablet.
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Intensive management of Type 2 DM with a new metformin-glibenclamide combination tablet improved glycaemic control and facilitated the attainment of glycaemic targets at lower doses of metformin or glibenclamide compared with the respective monotherapies, without compromising tolerability.
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The results have shown that the experimental responses match the statistical generated model and that the investigation is reproducible.
Single-tablet metformin-glibenclamide combination treatment is more effective than metformin or glibenclamide monotherapy, and is well tolerated in patients with hyperglycaemia inadequately controlled by diet and exercise or antidiabetic monotherapy, irrespective of their severity of hyperglycaemia at baseline, age or weight.