Progress with thiazolidinediones in the management of type 2 diabetes mellitus

Background: Much progress has been made in the field of medicine within the past 20 years; however, cardiovascular outcomes in patients with diabetes mellitus have not improved to a corresponding degree. Although numerous treatments are available for the management of type 2 diabetes, current approaches appear to address the spectrum of the disease and its complications insufficiently Objectives: This article reviews evidence for the minimal effects of standard antidiabetic treatments on the macrovascular complications associated with type 2 diabetes, discusses the improvements in markers of cardiovascular risk seen with the thiazolidinediones (TZDs), and explores the rationale for their earlier use. Methods: Relevant articles and guidelines on the use of oral antidiabetic agents in the treatment of type 2 diabetes were identified through a search of MEDLINE for the past 15 years using the terms cardiovascular, insulin resistance, metabolic syndrome, metformin, sulfonylurea, type 2 diabetes, and thiazolidinediones. The reference lists of selected articles also were searched. Articles chosen for review were required to assess clinically important outcomes or surrogate markers that have been shown to have a direct link to clinically important outcomes. Results: The data reviewed suggest that the sulfonylureas and/or metformin are able to reduce microvascular complications associated with type 2 diabetes but do not substantially affect macrovascular complications. In contrast, the TZDs demonstrate insulin-sensitizing effects attributable to their novel mechanism of action on the peroxisome proliferator-activated receptor gamma. The resulting reduction in insulin resistance appears to improve many of the metabolic and cardiovascular pathways influenced by insulin activity Blood pressure, vascular and coagulation defects, lipid abnormalities, and beta-cell function have been found to improve in patients receiving TZD treatment. For example, there are reports of significant reductions in levels of C-reactive protein (P < 0.01); small, dense low-density lipoprotein cholesterol particles (P < 0.05); and circulating free fatty acids (P < 0.003), in addition to improvements in the proinsulin-to-insulin ratio (P < 0.05). Conclusions: In this review of the literature, use of TZDs as monotherapy or as part of combination therapy has been associated with effective glycemic control and reductions in markers of various macrovascular complications of type 2 diabetes. Although outcomes trials are ongoing, the preliminary effects of TZD therapy are promising and suggest that earlier use of TZDs in the pharmacologic management of type 2 diabetes has the potential to minimize severe disease sequelae.