Cardiovascular Effects of Conventional Sulfonylureas and Glimepiride

Abstract

Sulfonylureas have, in the past, been reported to have adverse cardiovascular effects. Glimepiride is a new sulfonylurea. In spite of stimulating less insulin secretion, it has, depending on the species, equal or higher blood glucose decreasing activity and according to preliminary studies less cardiovascular activity than glibenclamide. Further studies were performed to confirm the lower cardiovascular activity of glimepiride. The IC50 for inhibition of rilmakalim-activated KATP channel currents in isolated ventricular myocytes was 31.6 nM for glimepiride and 6.8 nM for glibenclamide. In endotoxin shock-rats at a dose of 1 x 2 mg/kg i.v., glibenclamide induced a significantly higher blood pressure increase than glimepiride. At two i.v. doses of 20 mg/kg 4 min apart, in normal rats, glibenclamide produced signs of ischemia in the ECG in nearly all animals, glimepiride almost none, in diabetic rats, glibenclamide produced in all animals a lethal cardiogenic shock preceeded by serious ECG changes, glimepiride only in one fifth of the animals. In open-chest dogs, on intracoronary infusion of equieffective blood glucose-lowering doses, glibenclamide, gliclazide and glimepiride all reduced coronary blood flow, increased coronary resistance, depressed the mechanical activity of the heart, enhanced myocardial O2-extraction, reduced the serum potassium level and induced a moderate endocardial ST-segment elevation, but glimepiride to a significantly less extent than glibenclamide and gliclazide. The presented data confirm that glimepiride at equivalent blood glucose decreasing doses has less cardiovascular activity than conventional sulfonylureas.

Glimepiride, a Novel Sulfonylurea, Does Not Abolish Myocardial Protection Afforded by Either Ischemic Preconditioning or Diazoxide

“…1 Glimepiride, a second-generation sulfonylurea, has been shown to be more specific to the pancreas than to other tissues, especially the myocardium. 4 Furthermore, glimeperide was shown to have a more rapid as well as longer duration of action, and despite stimulating less insulin secretion in comparison with glibenclamide, it has been shown to have higher glucose-decreasing activity. 13,21 This characteristic may be as a consequence of its having a direct effect on the expression of glucose transporters, such as Glut-1 and Glut-4.…”

“…1 However, it has been suggested that classic sulfonylureas such as tolbutamide and glibenclamide (also known as glyburide) may have adverse effects on the cardiovascular system, mainly because they also close mitochondrial K ATP channels, thought to play a central role in ischemic preconditioning (IP) protection. [1][2][3] Glimepiride is a newer sulfonylurea derivative demonstrated to have fewer cardiac actions than other sulfonylureas in both animal 4 and human 5 studies. For example, Geisen et al 4 showed that glimepiride blocked K ATP currents in isolated rat cardiomyocytes at a concentration 5-fold higher than glibenclamide.…”

“…[1][2][3] Glimepiride is a newer sulfonylurea derivative demonstrated to have fewer cardiac actions than other sulfonylureas in both animal 4 and human 5 studies. For example, Geisen et al 4 showed that glimepiride blocked K ATP currents in isolated rat cardiomyocytes at a concentration 5-fold higher than glibenclamide. There are also data providing indirect evidence that glibenclamide, but not glimepiride, prevents preconditioning in humans subjected to balloon angioplasty.…”

Treatment of Type 2 Diabetes With Combined Therapy

“…Glibenclamide treatment affects ischemic preconditioning, exposing a possible higher risk of cardiovascular mortality in sulfonylurea-treated type 2 diabetic patients with myocardial infarction (44). In addition, myocardial function during ischemic challenge was found to be altered to a higher degree in glibenclamide-treated compared with insulintreated type 2 diabetic subjects (45).…”

ATP-Dependent K+ Channels Contribute to Local Metabolic Coronary Vasodilation in Experimental Diabetes

“…The IC 50 for glibenclamide is ϳ4 nmol/l in pancreatic ␤-cells and ϳ27 nmol/l in cardiac myocytes (35,36). Its lower potency in cardiac myocytes suggests that glibenclamide could possibly affect pancreatic insulin release without influencing coronary vasomotor tone at clinically administered doses.…”