Thiazolidinediones: Beyond glycemic control

Our knowledge and understanding of the role played by peroxisome proliferator-activated γ receptors in physiology and pathophysiology has expanded dramatically over the past 5 years. Originally described as having important functions in adipogenesis and glucose homeostasis, their pharmacologic agonists, the thiazolidinediones, were introduced as antihyperglycemic, insulin-sensitizing agents for the management of type 2 diabetes mellitus. However, it was to some degree inevitable that the thiazolidinediones would be rapidly recognized as having vasculoprotective properties beyond glycemic control that might also be beneficial. First, diabetic complications are vascular in nature, the earliest feature of these is endothelial dysfunction. Second, it is being increasingly appreciated that these complications develop through inflammatory and procoagulant pathways in which increased oxidative stress is considered a major etiologic mechanism, and which are closely linked to the presence of insulin resistance, visceral obesity, and hyperglycemia. Early appreciation that the thiazolidinediones have antioxidant, anti-inflammatory, anti-procoagulant, and antiproliferative properties in addition to their insulin-sensitizing, anti-lipotoxic properties created a marriage of investigative pathways that has not only led to a very large body of literature on the pleiotropic effects of thiazolidinediones, but also to the development of new understandings of the connections between insulin resistance, obesity, and hyperglycemia and the onset of vascular disease. Understandably, most of the focus has been directed at the macrovascular complications of diabetes, since these are the major causes of morbidity and mortality in this population. However, there is evidence that these agents may have benefits for the microvascular complications as well, and their potential role for cardiovascular disease prevention in non-diabetic patients with the metabolic syndrome is a logical extension of the work performed in diabetes. The recently reported results of the effects of pioglitazone versus placebo on cardiovascular events in patients with type 2 diabetes support the contention that these agents have vasculoprotective effects.