The contribution of extrapancreatic effects of sulfonylureas to the blood glucose-decreasing activity was reevaluated in vivo and in vitro with several conventional sulfonylureas and with the new one glimepiride. In vivo, in dogs, after single approximately equipotent blood glucose-decreasing doses, the sulfonylureas were tested for a ranking in the ratios of mean plasma insulin-increasing and blood glucose-decreasing activity. Studies were also performed in hyperglycemic hyperinsulinemic KK-Ay mice under once daily treatment for 8 weeks. In vitro, glimepiride and glibenclamide were tested for the ranking of their extrapancreatic activity with respect to the stimulation of glucose transport and glucose metabolizing processes in normal and insulin-resistant fat cells as well as in the isolated diaphragm. Furthermore, in vitro studies were performed, especially with glimepiride, in order to characterize the molecular mechanism for the extrapancreatic activity. The dog studies revealed a marked ranking in the ratios of plasma insulin-increasing and blood glucose-decreasing activity between the different sulfonylureas (glimepiride < glipizide < gliclazide < glibenclamide). In the hyperglycemic hyperinsulinemic KK-Ay mice, glimepiride reduced blood glucose by 40%, plasma insulin by 50% and HBA1c by 33%, whereas glibenclamide and gliclazide had no effect on these parameters. In vitro, glimepiride and glibenclamide had extrapancreatic effects within the lower microM range, with glimepiride exhibiting 2-3-fold lower ED50 values than glibenclamide. In the absence of insulin, both stimulated glucose transport--up to 60% of the maximum insulin response in the rat diaphragm and up to 35% in 3T3 adipocytes. Glycogenesis was stimulated in the rat diaphragm--up to 55% of the maximum insulin effect; lipogenesis in 3T3 adipocytes--up to 40%. The studies on the molecular mechanism of extrapancreatic activity with rat adipocytes and diaphragm suggest that these direct insulin-mimetic effects rely on the induction of GLUT4 translocation from internal stores to the plasma membrane and on the activation of the key metabolic enzymes, glycogen synthase and glycerol-3-phosphate acyltransferase. These processes occur within the same drug concentration range and with the same ranking between glimepiride and glibenclamide as observed for glucose utilization and transport. The direct effects of sulfonylureas may ultimately be regulated by a glycosyl-phosphatidylinositol-specific phospholipase C, shown to be activated by glimepiride in rat adipocytes. Lipolytic cleavage products thereby generated from glycolipidic structures may in turn stimulate specific protein phosphatases which activate key regulatory proteins/enzymes of glucose and lipid metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)
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Daily insulin dose (units/kg BW), weight gain, and number of hypoglycemic events were significantly lower (p < 0.01) in subjects receiving sulfonylureas in comparison with placebo. However, the daily insulin dose alone was significantly lower (p < 0.05) with glimepiride (0.49 +/- 0.10; mean +/- SE) than with other sulfonylureas (tolazamide 0.58 +/- 0.12, glyburide 0.59 +/- 0.12, glipizide GITS 0.59 +/- 0.14). Finally, a significant correlation (r = 0.68; p < 0.001) was noted between suppression of plasma C-peptide level and the daily insulin dose among all participants.
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Vildagliptin-metformin treatment provided blood glucose control efficacy comparable to that of glimepiride-metformin treatment and resulted in better adverse event profiles with lower risks of hypoglycemia and weight gain.
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Our results conclude that Ramadan fasting affects metabolic parameters in type 2 diabetes and hypoglycemia should be kept in mind especially in patients using sulfonylurea treatment. Ramadan fasting is not advised for type 2 diabetics while taking medical therapy. If the patient wants Ramadan fasting, these patients using Repaglinide can reduce the frequency of hypoglycemia.
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Glimepiride (Hoe 490) is a new sulfonylurea. After oral administration of Hoe 490 to rabbits, blood glucose was lowered 3.5 times more than after glibenclamide (HB 419) and after intravenous administration, 2.5 times more. This superiority in efficacy was demonstrated by onset, maximum and duration of action. In rats, intravenous and oral Hoe 490 has a much shorter effect on blood glucose than HB 419, but the initial effect of Hoe 490 orally was up to 6 times and i.v. up to 2 times stronger than that of HB 419. In dogs, oral and intravenous Hoe 490 had a considerably longer blood glucose-lowering effect than HB 419. However, the effect of intravenous Hoe 490 was only half as intense as that of HB 419 in the first hours after treatment and the effect of oral Hoe 490 was initially stronger and thereafter temporarily distinctly weaker than that of HB 419. The more rapid decrease in blood glucose in the dog after oral administration of Hoe 490 was accompanied by a correspondingly earlier and higher plasma insulin increase. In accordance with the less intense initial blood glucose decrease in the dog after intravenous Hoe 490 there was a weaker and slower rise and faster drop of plasma insulin. The long action of oral and intravenous Hoe 490 in the dog can, however, not be sufficiently explained by the plasma insulin values. In the isolated rat pancreas perfused with glucose-free medium, HB 419 released glucagon beside insulin and somatostatin. The threshold concentration for the glucagon secretion was lower as those for the insulin and somatostatin release.(ABSTRACT TRUNCATED AT 250 WORDS)
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A stability-indicating high-performance liquid chromatography (HPLC) procedure was developed for the determination of metformin HCl (MTH), atorvastatin calcium (AC) and glimepiride (GP) in combination and their main degradation products. The separation and quantization were achieved on a 5-µm Qualisil gold, C18 column (4.6 mm × 250 mm). The mobile phase selected was phosphate buffer (pH 2.9)-organic phase in proportion of 70:30. Organic phase consisted of methanol-acetonitrile (90:10) at a flow rate of 1 mL/min and detection of analytes was carried out at 230 nm. The method exhibited good linearity over the range of 10-60 µg/mL for MTH, 2-20 µg/mL for AC and 5-30 µg/mL for GP. Square of the correlation coefficients was found to be >0.999. Various stress degradation studies were carried out in combination as per International Conference of Harmonization (ICH) guidelines for 4 h. The recovery and precision were determined in terms of intraday and interday precisions and expressed as relative standard deviations. These were <1 and <2%, respectively. Finally, the applicability of the method was evaluated in nanoparticle analysis of MTH, AC and GP as well as in stability studies of nanoformulation.
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The current study demonstrates that glimepiride improves both first and second phases of insulin secretion, but not insulin sensitivity, in individuals with type 2 diabetes.
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This single-centre, 12-week, double-blind, placebo-controlled trial assessed how the human glucagon-like-peptide 1 analogue liraglutide impacted endothelial function in adult patients (n = 49) with type 2 diabetes and no overt cardiovascular disease. Patients were randomized to liraglutide, placebo or glimepiride. At baseline and Week 12, venous occlusion plethysmography was used to measure forearm blood flow (FBF) in response to acetylcholine (ACh) and sodium nitroprusside (SNP) before and after (L)-N(G)-monomethyl arginine (L-NMMA) infusion. At Week 12, ACh-mediated FBF increased with liraglutide and decreased with placebo; however, the between-treatment difference was not significant (p = 0.055). Inhibition of ACh-mediated FBF after L-NMMA infusion increased with liraglutide and decreased with placebo; this between-treatment difference was also not significant (p = 0.149). No change in FBF was observed with SNP. Liraglutide did not significantly impact endothelium-dependent vasodilation after 12 weeks; however, additional investigations looking at the effect of liraglutide on endothelial function in alternative vasculature and during the postprandial period are warranted.
To assess the efficacy, safety, and dose-response relationship of glimepiride in patients with NIDDM.
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To observe the efficacy and safety of adding glimepiride to established insulin therapy in poorly controlled type 2 diabetes (T2D) and to assess the relationship of changes in the serum high-molecular weight (HMW) adiponectin levels and glycemic control after glimepiride treatment.
Activation of free fatty acid receptor 1 (FFAR1; also known as G-protein-coupled receptor 40) by fatty acids stimulated glucose-dependent β-cell insulin secretion in preclinical models. We aimed to assess whether selective pharmacological activation of this receptor by TAK-875 in patients with type 2 diabetes mellitus improved glycaemic control without hypoglycaemia risk.
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To investigate the efficacy and safety of linagliptin, a dipeptidyl peptidase-4 inhibitor, in type 2 diabetes mellitus (T2DM) patients for whom metformin was inappropriate.
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The optimum oral pharmacological treatment of diabetes mellitus to reduce cardiovascular disease and mortality following myocardial infarction has not been established. We therefore set out to investigate the association between individual oral glucose-lowering drugs and cardiovascular outcomes following myocardial infarction in patients with diabetes mellitus not treated with emergent percutaneous coronary intervention.
Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.
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TAK-875 significantly improved glycaemic control in patients with type 2 diabetes with minimum risk of hypoglycaemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes.
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The data suggest that there is a correlation between fibrinogen levels and relaxin expression. Relaxin may exert its cardioprotective properties after pathologic fibrinogen increase. This regulation may be affected by diabetes. As a consequence, cardiovascular risk may increase in women with aberrant relaxin functionality.
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Irrespective of treatment, reductions in A1C levels were generally greater in groups with higher baseline A1C values. After 26 weeks of treatment, liraglutide produced the greatest reductions in A1C values across all baseline categories, ranging from 0.7% to 1.8% (baseline A1C categories ≤7.5% to >9.0%, respectively), followed by insulin glargine (0.3% to 1.5%) and then by glimepiride (0.4% to 1.3%). Generally, larger percentages of patients achieved the A1C target of ≤6.5% with liraglutide therapy across all baseline categories (from 62% of patients with A1C values ≤7.5% to 10% of patients with A1C values >9.0%) in comparison with other treatments (ranging from 49% to 0% of patients, respectively). Similarly, greater proportions of patients also reached the A1C target of <7.0% with liraglutide therapy across all baseline categories (from 83% of patients with A1C values ≤7.5% to 25% of patients with A1C values >9.0%) versus comparators (from 74% to 5% of patients, respectively).
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We report a patient with neuropsychiatric systemic lupus erythematosus (NPSLE) complicated by diabetes mellitus (DM) who showed pneumatosis cystoides intestinalis (PCI) while being treated with prednisolone (PSL) and an alpha-glucosidase inhibitor (αGI). The PCI was ameliorated with the cessation of the αGI and tapering of PSL in addition to transient fasting. Multiple factors, including NPSLE, DM, and medications, may have been involved in the pathogenesis of PCI in this patient.
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No significant effects of the CYP2C9*2 and CYP2C9*3 alleles were found. However, a trend towards a lower stable glimepiride dose for carriers of the CYP2C9*3 allele was observed.
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Using the DMM data from the LAPTOP study, simulations based on both therapies showed that the BOT regimen provides better glycemic control and reduction in HbA1c thereby leading to a reduction in the long-term complications of diabetes and mortality.
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5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55-1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43-2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68-1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients.
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Comparable HbA1c reduction was observed with a mean±standard deviation change from baseline to the 32-week endpoint of -0.94±1.15% in the vildagliptin group and -1.00±1.32% in the glimepiride group. A similar reduction in 2h-PPG (vildagliptin group 3.53±4.11 mmol/L vs. the glimepiride group 3.72±4.17 mmol/L) was demonstrated, and the decrements in FPG (vildagliptin group 1.54±2.41 mmol/L vs. glimepiride group 2.16±2.51 mmol/L) were not different between groups. The proportion of patients who achieved an HbA1c less than 7% at week 32 was 50.1% in the vildagliptin group and 56.0% in the glimepiride group. An average body weight gain of 2.53±1.21 kg in the glimepiride group was observed in contrast with the 0.23±0.69 kg weight gain noted in the vildagliptin group. A 10-fold lower incidence of hypoglycemia was demonstrated in the vildagliptin group, in addition to an absence of severe hypoglycemia.