Effects of thiazolidinediones beyond glycaemic control

The incidence of type 2 diabetes continues to increase in the western world over the past decade. Consequently, complications of this disease have reached crisis proportions. In addition to the classical oral hypoglycaemic agents, i.e. sulfonylureas, newer classes have emerged that work by different mechanisms such as insulin sensitizers. One such class are the thiazolidinediones (rosiglitazone and pioglitazone). These agents act as ligands for the gamma peroxisome proliferator-activated receptors (PPARs) and result in a lower glucose. Data from animal and human studies supports the concept that thiazolidinediones exert several other beneficial metabolic and vascular effects, in addition to glycaemic control, including improvement in lipid profile, blood pressure lowering, redistribution of body fat away from the central compartment, anti-inflammatory effects such as reduction in hs-CRP and microalbuminuria as well as subclinical vascular inflammation, improvement in endothelial function. Conversely, thiazolidinediones have well-established side effects, most important of which are fluid retention leading to weight gain and development of heart failure as well as an increased incidence of bone fractures. Moreover, evidence from clinical trials suggests that these agents do not reduce cardiovascular risk. This article discusses the pleiotropic effects of thiazolidinediones focusing on clinical cardiovascular outcomes as well as other potential therapeutic uses in the context of their side-effect profile.