Clinical Thiazolidinediones as PPARγ Ligands with the Potential for the Prevention of Cardiovascular Disease in Diabetes

Stephanie   T.   de Dios; Richard   C.   O'Brien; Peter   J.   Little

Abstract

Thiazolidinediones (TZDs) are PPARγ ligands and the newest class of agents in routine clinical practice for the treatment of hyperglycemia in type 2 diabetes. The prime reason for treating hyperglycemia and related aspects of the metabolic syndrome is to prevent accelerated cardiovascular disease (CVD) in diabetes. The formation and subsequent rupture of atherosclerotic "plaques", establishes CVD as the major cause of premature mortality in diabetes. Metabolically, TZDs act as insulin sensitizers resulting in improved glucose uptake, lower blood glucose and reduced hyperinsulinemia, however, they also appear to have beneficial direct vascular actions. TZDs have a range of actions directly on vascular cells and the predominance of the reported actions is potentially beneficial. TZDs inhibit vascular smooth muscle cell proliferation, inhibit the expression of adhesion molecules and modify the structure of vascular proteoglycans in a manner that results in reduced lipid binding. These actions manifest as reduced lipid deposition in the vessels of animals with experimental diabetes and atherosclerosis. Early clinical data indicates that TZDs may prevent or delay CVD including atherosclerosis and restenosis following coronary angiography. TZDs may be the first class of oral hypoglycemic agents with significant anti-atherogenic effects to combat one of the major complications of diabetes.

Keywords: Thiazolidinediones, Cardiovascular Disease, Type 2 Diabetes, PPARγ, Glucose, Atherosclerosis