Comparison of the micro‐ and macro‐vascular effects of glimepiride and gliclazide in metformin‐treated patients with Type 2 diabetes: a double‐blind, crossover study

Abstract

Aims To compare the metabolic and vascular effects of two sulphonylureas (SU), gliclazide (specific for the pancreatic [SUR1] receptor) and glimepiride (a nonspecific agent that also binds to vascular and cardiac [SUR2] receptors), during chronic administration in metformin-treated patients with Type 2 diabetes (T2DM). Methods A randomized, double-blind, crossover study of gliclazide 80 mg BID and glimepiride 2 mg OD, each for 4 weeks as add-on therapy to metformin, with a 4-week washout period. Patients attended four study mornings after first dose and 4 weeks' SU treatment for measurements of arterial distensibility (Ax), pressor responsiveness to i.v. angiotensin II (ANGII), and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Results Glycaemic responses were similar (e.g. serum fructosamine was 315 vs 329 m mol l -1 after 4 weeks), and there was no change in augmentation index during treatment with either SU (9.1 vs 9.8 mmHg after 4 weeks [95% confidence interval -8.1, 10.5]). Similarly, there were no differences between treatments in pressor responsiveness (e.g. PD 10 [dose of agonist required to increase mean BP by 10 mmHg] for ANGII was 1.37 vs 1.68 ng kg -1 min -1 [ -4.3, 6.9]) or cutaneous microvascular vasodilator responses (peak ACh response 68 ± 36 vs 63 ± 34 perfusion units [ -82.7, 79.1]). Conclusions There is no evidence that SUR1-specific and nonspecific SUs have differential effects on arterial distensibility, endothelial function or vasodilator mechanisms in metformin-treated patients with T2DM.

Consensus recommendations on sulfonylurea and sulfonylurea combinations in the management of Type 2 diabetes mellitus – International Task Force

“…A randomized, double-blind, crossover study of GLIC 80 mg twice daily and GLIM 2 mg once daily, each for 4 weeks as add-on therapy to metformin, found no evidence between SUR1-specific (GLIC) and nonspecific SU (GLIM) in differential effects on arterial distensibility, endothelial function, or vasodilator mechanisms. [ 102 ]…”

Metabolic syndrome therapy: Prevention of vascular injury by antidiabetic agents

“…This effect is not shared by other SUs, including glibenclamide, glimepiride, glipizide, and tolbutamide, as demonstrated by Jennings [18]. A recent study did not show differential effects on arterial distensibility, endothelial function, or vasodilator mechanisms in diabetic patients treated with glimepiride or gliclazide [20]; however, both groups of patients were already treated with metformin, and the effect of this drug in both groups cannot be excluded.…”

Multiple Drug Resistance Associated with Function of ABC-Transporters in Diabetes Mellitus: Molecular Mechanism and Clinical Relevance

“…Studies on recombinant K-ATP channels have shown that e.g. gliclazide [68,72,73,74,75], and tolbutamide [10,14,68,76,77] inhibit Kir6.2/SUR1 currents with high affinity, but show low-affinity block of Kir6.2/SUR2 currents [12,68,73]. By contrast, glibenclamide, glimepiride, meglitinide (a molecule corresponding to the nonsulfonylurea half of glibenclamide), and repaglinide block both Kir6.2/SUR1 and Kir6.2/SUR2 channels with similar high affinity [68,69].…”

“…Target # Drugname Mechanism Literature Sur1/ABCC8 (4) Ambutonium binding [88] (5) Carbutamide receptor binding [72], [89] (6) Chlorpropamide receptor binding [72], [73], [78] (7) Dexamethasone binding [90] (8) Droperidol binding [69] (9) FOXA2 binding [91], [92] (10) Glibornuride binding [93], [94], [95], [96] (11) Gliclazide binding [68], [72], [73], [74], [75] (12) Glimepiride receptor binding [68], [72], [73], [74], [79], [80] (13) Glipizide receptor binding [72], [73], [79], [80] (14) Gliquidone binding [93], [97], [98], [70], [99], [100] (15) Glisoxepide receptor binding [72], [101] (16) Glucocorticoid binding [90], [102] (17) Glyburide binding [14], [68], [76] (18) KCNJ11 binding [103] (19) Meglitinide receptor binding [72], [89] (20) Metformin receptor binding …”