Thiazolidinediones

Abstract

Editor’s note: This commentary was originally solicited as part of a Point-Counterpoint feature, but the author of the Counterpoint failed to provide the promised manuscript. Thiazolidinediones (TZDs), or “glitazones,” were first introduced for the treatment of type 2 diabetes in 1996, when troglitazone (Rezulin; Parke-Davis/Warner-Lambert) was approved by the Food and Drug Administration. Since the introduction of this unique class of compounds, many clinicians have embraced their use, whereas others have debated the role of insulin-sensitizing therapy for the management of type 2 diabetes. While troglitazone was withdrawn from the market in 2000 due to idiosyncratic hepatoxicity, two other glitazones, pioglitazone (Actos; Takeda Chemical Industries) and rosiglitazone (Avandia; GlaxoSmithKline), continue to be widely used by clinicians. Before the introduction of glitazones, conventional management of type 2 diabetes involved stepwise addition of medical nutrition therapy, sulfonylureas, and metformin. Despite broader use of early drug therapy, many patients do not achieve adequate blood glucose control (1). Even in those who do achieve treatment targets, a gradual deterioration in blood glucose control is often seen (2). These observations have prompted clinicians to use newer therapies, such as the glitazones, and have increased the use of early combination therapy to achieve glycemic targets Glitazones uniquely target insulin resistance—a core physiologic defect in those with type 2 diabetes—and by so doing significantly improve glucose control. Glitazones improve insulin action in muscle, adipose, and hepatic tissue by acting as agonists of peroxisome proliferator–activated receptor-γ (PPAR-γ) nuclear receptors. Activation of PPAR-γ results in a myriad of both metabolic and vascular effects by upregulating and downregulating expression of numerous genes, including genes known to regulate lipid and glucose metabolism, vascular function, thrombotic function, and the inflammatory response. Glitazones increase nonoxidative glucose disposal, increase triglyceride synthesis, and improve free fatty acid (FFA) metabolism (3). Glitazones also lower blood pressure, …