Evaluating the cardiovascular effects of the thiazolidinediones and their place in the management of type 2 diabetes in relation to the metabolic syndrome.

BACKGROUND: The aim of this work was to review evidence on the contribution of the metabolic syndrome to diabetes and atherosclerosis, to evaluate the effects of the thiazolidinediones (TZDs) on cardiovascular risk, and to assess the clinical use of TZDs and their associated risks and benefits. METHODS: Participants were a multidisciplinary panel of experts in endocrinology, cardiology, and nephrology. Available studies on hyperglycemia, hyperinsulinemia, beta-cell function, dyslipidemia, obesity, hypertension, inflammation, endothelial dysfunction, and vascular reactivity were reviewed through presentations by the experts. Assessments were made regarding the associations between characteristics of the metabolic syndrome, type 2 diabetes, and cardiovascular disease, along with the place of TZDs in therapy and management of related adverse clinical events. A panel was convened in November 2002 to develop conclusions based on scientific evidence presented during the meeting. Summary statements were evaluated based on strength and clinical relevance of the data and approved by all panel members. RESULTS AND CONCLUSIONS: Many characteristics of the metabolic syndrome are present before diabetes develops that greatly contribute to the cardiovascular disease burden associated with the progression of diabetes, such as atherosclerosis and coronary artery disease. Insulin resistance is a fundamental component of the metabolic syndrome, and interventions to improve insulin sensitivity are associated with positive cardiovascular effects. From current experimental and clinical data, TZDs appear to reduce risk factors for future cardiovascular events in patients with type 2 diabetes. Study data up to 2 years have demonstrated that TZDs effectively maintain glycemic control in patients with type 2 diabetes, which is attributed to their insulin-sensitizing effects and preservation of beta-cell function. Potential adverse events of TZDs include weight gain and edema, which are generally manageable. Aside from improving insulin sensitivity, TZDs improve lipid profiles, favorably alter deposition of adipose tissue to the periphery rather than visceral areas, decrease markers of inflammation and endothelial dysfunction, and restore vascular reactivity. These pleiotropic effects have the potential to improve cardiovascular outcomes in patients with type 2 diabetes. Trials are underway to confirm this potentially beneficial addition to proven therapies for hypertension, dyslipidemia, and atherosclerosis.

Lessons learned from landmark trials of type 2 diabetes mellitus and potential applications to clinical practice.

Landmark studies have demonstrated that diabetes is a significant risk factor for cardiovascular disease and mortality. Strong relationships exist between insulin resistance/hyperglycemia and mortality, microvascular complications, and cardiovascular complications. Lipid abnormalities frequently associated with type 2 diabetes and insulin resistance include low high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride levels. Lowering low-density lipoprotein cholesterol levels has been shown to improve the prognosis of patients with diabetes, and increasing HDL-C levels will significantly reduce the incidence of major coronary events. Higher levels of insulin sensitivity are associated with thinner intimal-medial thickness of the carotid artery, which indicates less atherosclerosis. Thiazolidinediones increase insulin sensitivity, decrease intimal-medial thickness, and appear to have inhibitory effects on the progression of atherosclerotic lesions. It is hoped that by preventing the onset of diabetes in high-risk individuals--and improving insulin sensitivity with lifestyle changes or pharmacologic treatment--the profound complications of type 2 diabetes will be prevented or delayed, as well.

Constructing an algorithm for managing type 2 diabetes. Focus on role of the thiazolidinediones.

With the understanding of type 2 diabetes mellitus constantly evolving, and with the introduction of many new agents during the past few years, it is often difficult to keep up to date with the management of type 2 diabetes. This article reviews the pathophysiology of type 2 diabetes, oral pharmacologic treatment, and proposed diabetes treatment algorithms, which aim to guide clinicians in the use of thiazolidinediones (TZDs) earlier in the course of diabetes. This is important because studies indicate that sulfonylureas, biguanides, and insulin do not protect the beta cell and cannot provide sustainable glycemic control. The basis for TZD use earlier in diabetes is 2-fold: to preserve beta-cell function while maintaining appropriate glycemic control for a longer duration than is usually attained through monotherapy with a secretagogue or biguanide, and to prevent or reverse the insulin resistance phenomenon of reduced insulin utilization that appears even prior to the clinical diagnosis of diabetes. Notably, decreasing insulin resistance also may reduce the incidence of adverse atherosclerotic consequences.