Glimepiride

Glimepiride is a sulfonylurea compound and is used to control blood sugar levels in individuals with type 2 diabetes.

When cultured cells in the presence of a physiological insulin dose and glimepiride (10 μM), 2-deoxyglucose uptake was increased to 186% of control. Glimepiride also increased 2-deoxyglucose uptake in the absence of insulin. At the same time, glimepiride increased the expression of both GLUT1 and GLUT4 to 164% and 148% of control, respectively. These results suggested glimepiride increased cardiac glucose uptake in an insulin-independent pathway [1].

In diabetic-prone (DP) BB rats, Glimepiride (200 mg/kg/day) reduced the incidence of diabetes by 23% compared with the control group [2]. In the hyperinsulinemic hyperglycemic KK-Ay mice, glimepiride reduced blood glucose by 40%, HBA1c by 33% and plasma insulin by 50%. In the absence of insulin, glimepiride caused glucose transport up to 60% and 35% of the maximum insulin response in the rat diaphragm and in 3T3 adipocytes, respectively [3].

References:
[1].  B?hr M, von Holtey M, Müller G, et al. Direct stimulation of myocardial glucose transport and glucose transporter-1 (GLUT1) and GLUT4 protein expression by the sulfonylurea glimepiride. Endocrinology, 1995, 136(6): 2547-2553.
[2].  Pan J, Chan EK, Cheta D, et al. The effects of nicotinamide and glimepiride on diabetes prevention in BB rats. Life Sci, 1995, 57(16): 1525-1532.
[3].  Müller G, Satoh Y, Geisen K. Extrapancreatic effects of sulfonylureas--a comparison between glimepiride and conventional sulfonylureas. Diabetes Res Clin Pract, 1995, 28 Suppl: S115-37.

Efficacy and safety of sitagliptin as compared with glimepiride in Japanese patients with type 2 diabetes mellitus aged >/= 60 years (START-J trial).[Pubmed:28294488]

Diabetes Obes Metab. 2017 Aug;19(8):1188-1192.

The aim of this study was to evaluate the efficacy and safety of sitagliptin administered to elderly patients with type 2 diabetes mellitus (T2DM) for 1 year as compared with Glimepiride. Patients aged >/=60 years with T2DM and inadequately controlled blood glucose were randomly assigned to sitagliptin 50 mg once daily or Glimepiride 0.5 mg once daily for 52 weeks. The primary efficacy endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 52. Secondary efficacy endpoints included self-monitored blood glucose and weight. Safety endpoints were adverse events including hypoglycaemia. Administration of sitagliptin or Glimepiride to elderly patients with T2DM resulted in a significant decrease in HbA1c change from baseline. At 52 weeks, the least squares mean difference between the treatments was 0.11% (95% confidence interval [CI] -0.02 to 0.24; P = .087) (1.2 mmol/mol [-0.2 to 2.6]). The upper limit of the CI was below the predefined non-inferiority margin (0.3% [3.3 mmol/mol]), demonstrating non-inferiority of sitagliptin to Glimepiride for the primary endpoint. Sitagliptin resulted in a significantly lower incidence rate of non-serious hypoglycaemia than Glimepiride during the 52 weeks (4.7% vs 16.1%; P = .002); thus, sitagliptin is a useful therapeutic option for elderly patients with T2DM.

Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions?[Pubmed:28260863]

Drug Des Devel Ther. 2017 Feb 23;11:503-512.

To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take Glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both Glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to Glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration-time curve during the dose interval at steady state (AUCtau,ss) for Glimepiride in combination with rosuvastatin than those for Glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to Glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism.

Formulation and Evaluation of New Glimepiride Sublingual Tablets.[Pubmed:28261517]

J Pharm (Cairo). 2017;2017:3690473.

Oral mucosal delivery of drugs promotes rapid absorption and high bioavailability, with a subsequent immediate onset of pharmacological effect. However, many oral mucosal deliveries are compromised by the possibility of the patient swallowing the active substance before it has been released and absorbed locally into the systemic circulation. The aim of this research was to introduce a new Glimepiride formula for sublingual administration and rapid drug absorption that can be used in an emergency. The new sublingual formulation was prepared after five trials to prepare the suitable formulation. Two accepted formulations of the new sublingual product were prepared, but one of them with disintegration time of 1.45 min and searching for preferred formulation, the binder, is changed with Flulac and starch slurry to prepare formula with disintegration time of 21 seconds that supports the aim of research to be used in an emergency. The five formulations were done, after adjusting to the binder as Flulac and aerosil with disintegration time of 21 seconds and accepted hardness as well as the weight variation. The assay of a new product (subGlimepiride) is 103% which is a promising result, confirming that the formula succeeded. The new product (subGlimepiride) is accepted in most quality control tests and it is ready for marketing.

Enhanced oral bioavailability and sustained delivery of glimepiride via niosomal encapsulation: in-vitro characterization and in-vivo evaluation.[Pubmed:28330377]

Drug Dev Ind Pharm. 2017 Aug;43(8):1254-1264.

This study was designed to investigate the potency of niosomes, for Glimepiride (GLM) encapsulation, aiming at enhancing its oral bioavailability and hypoglycemic efficacy. Niosomes containing nonionic surfactants (NIS) were prepared by thin film hydration technique and characterized. In-vitro release study was performed using a dialysis technique. In-vivo pharmacodynamic studies, as well as pharmacokinetic evaluation were performed on alloxan-induced diabetic rats. GLM niosomes exhibited high-entrapment efficiency percentages (E.E. %) up to 98.70% and a particle size diameter ranging from 186.8 +/- 18.69 to 797.7 +/- 12.45 nm, with negatively charged zeta potential (ZP). Different GLM niosomal formulation showed retarded in vitro release, compared to free drug. In-vivo studies revealed the superiority of GLM niosomes in lowering blood glucose level (BGL) and in maintaining a therapeutic level of GLM for a longer period of time, as compared to free drug and market product. There was no significant difference between mean plasma AUC0-48 hr of GLM-loaded niosomes and that of market product. GLM-loaded niosomes exhibited seven-fold enhancement in relative bioavailability in comparison with free drug. These findings reinforce the potential use of niosomes for enhancing the oral bioavailability and prolonged delivery of GLM via oral administration.

Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K(ATP) channels.[Pubmed:12086984]

Br J Pharmacol. 2002 Jul;136(5):746-52.

1. We have investigated the effects of the sulphonylurea, Glimepiride, currently used to treat type 2 diabetes, on ATP-sensitive K(+) (K(ATP)) currents of rat cardiac myocytes and on their cloned constituents Kir6.2 and SUR2A expressed in HEK 293 cells. 2. Glimepiride blocked pinacidil-activated whole-cell K(ATP) currents of cardiac myocytes with an IC(50) of 6.8 nM, comparable to the potency of glibenclamide in these cells. Glimepiride blocked K(ATP) channels formed by co-expression of Kir6.2/SUR2A subunits in HEK 293 cells in outside-out excised patches with a similar IC(50) of 6.2 nM. 3. Glimepiride was much less effective at blocking K(ATP) currents activated by either metabolic inhibition (MI) with CN(-) and iodoacetate or by the K(ATP) channel opener diazoxide in the presence of inhibitors of F(0)/F(1)-ATPase (oligomycin) and creatine kinase (DNFB). Thus 10 microM Glimepiride blocked pinacidil-activated currents by >99%, MI-activated currents by 70% and diazoxide-activated currents by 82%. 4. In inside-out patches from HEK 293 cells expressing the cloned K(ATP) channel subunits Kir6.2/SUR2A, increasing the concentration of ADP (1 - 100 microM), in the presence of 100 nM Glimepiride, lead to significant increases in Kir6.2/SUR2A channel activity. However, over the range tested, ADP did not affect cloned K(ATP) channel activity in the presence of 100 nM glibenclamide. These results are consistent with the suggestion that ADP reduces Glimepiride block of K(ATP) channels. 5. Our results show that Glimepiride is a potent blocker of native cardiac K(ATP) channels activated by pinacidil and blocks cloned Kir6.2/SUR2A channels activated by ATP depletion with similar potency. However, Glimepiride is much less effective when K(ATP) channels are activated by MI and this may reflect a reduction in Glimepiride block by increased intracellular ADP.