Clinical interest of PPARs ligands -: Particular benefit in type 2 diabetes and metabolic syndrome

Cardiovascular disease is significantly increased in patients with metabolic syndrome and type 2 diabetes. Several factors such as chronic hyperglycemia, lipid abnormalities, endothelium dysfunction, inflammation, oxidative stress, increased thrombosis and decreased fibrinolysis are likely to promote cardiovascular events in these patients. Because of positive effects on glucose homeostasis, lipid metabolism, proteins involved in all stages of atherogenesis, endothelium function, inflammation, thrombosis and fibrinolysis, PPARS alpha (fibrates) and PPARs gamma (glitazones) agonists are good candidates to reduce cardiovascular disease, more precisely in subjects with metabolic syndrome or type 2 diabetes. PPARS a agonists (fibrates) are potent hypolipidemic agents increasing plasma HDL-cholesterol and reducing free fatty acids, triglycerides, LDL-cholesterol and the number of small dense LDL particles. Moreover, they reduce vascular inflammation and thrombosis, promote fibrinolysis and inhibit the production of the vasoconstrictor factor, endothelin-1, by the endothelium. They have been shown, in clinical trials, to reduce cardiovascular disease, more particularly in patients displaying lipid abnormalities typical of metabolic syndrome and type 2 diabetes (high triglycerides, low HDL-cholesterol). PPARS gamma agonists (glitazones) have not only beneficial effects on glucose homeostasis, by increasing insulin sensitivity and reducing blood glucose level but also on lipid metabolism by elevating plasma HDL-cholesterol, decreasing free fatty acids and the number of small dense LDL particles, and for pioglitazone by reducing plasma triglycerides. Furthermore, they diminish vascular inflammation and vasoconstriction, inhibit monocyte chemotaxis, proliferation and migration of smooth muscle cells, in the vascular wall and decrease the production of adhesion molecules and metalloproteinases. PPARs gamma agonists (glitazones) have been shown to reduce the development of atherosclerotic lesions in rats. The potential clinical benefit of PPARs gamma agonists on the reduction of cardiovascular disease, in type 2 diabetic patients, will be specified by the ongoing intervention studies.