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Metabolism: clinical and experimental

Vascular benefits of gliclazide beyond glycemic control.


PMID 11078471

Abstract

Advanced glycolysation end products (AGEs) and the free radicals generated in this process can both be implicated in the accelerated atherosclerosis and vascular and prothrombotic microangiopathic changes typified by diabetes. The rate of formation of free radicals is dependent on the rate of protein glycosylation and therefore the level and duration of hyperglycemia. Glycation and oxidation are inextricably linked. Increased oxidative stress due to excess free radical activity may be central to diabetic vascular disease, since endothelial cell damage, lipoprotein oxidation, and modification of platelet reactivity and the arachidonic acid cascade are all properties of free radicals and their reaction products, lipid peroxides. The importance of the demonstration of the mechanism whereby hyperglycemia contributes to vascular damage opens the possibility of scavenging free radicals, which will have effects independently of improving diabetic control. Over the past 15 years, studies have shown that gliclazide not only lowers blood glucose but also confers beneficial effects on the hemorrheologic abnormalities seen in diabetic vascular disease. Clinically, gliclazide reduces platelet reactivity and stimulates endothelial prostacyclin synthesis; it also increases fibrinolysis by its effects on tissue plasminogen activator. These effects, seen both in vitro and in vivo, are independent of glycemic control and are not seen with other sulfonylureas. In clinical studies, the beneficial effects of gliclazide on platelets have been related to a reduction in oxidative stress. This property is due to gliclazide's free radical scavenging ability that relates to the unique aminoazabicyclo-octane ring grafted onto the sulfonylurea. It is fully maintained by the gliclazide modified-release preparation. In diabetes, therefore, where increased glycation and oxidation are fundamental to the pathogenesis of diabetic vascular disease, agents such as gliclazide with its antioxidant activities may have an enhanced therapeutic role.