Introduction and summary statements

Abstract

It is estimated that diabetes mellitus affects nearly 17 million adults in the United States, and the prevalence of diabetes continues to rise at an alarming rate. Diabetes is a disease associated with considerable microvascular complications, including diabetic retinopathy, nephropathy, and neuropathy. Additionally, patients with diabetes are at significant risk for macrovascular complications, and cardiovascular disease (CVD) is the leading cause of death in individuals with type 2 diabetes. Increasingly, there is evidence to suggest that the presence of insulin resistance increases cardiovascular risk in patients with type 2 diabetes, and the metabolic syndrome (insulin resistance syndrome) is now recognized as a risk factor for coronary heart disease (CHD). Several studies have shown that decreasing insulin resistance improves cardiovascular outcomes. The thiazolidinediones (TZDs) have been shown to increase insulin sensitivity, maintain long-term glycemic control, and provide beneficial cardiovascular effects in patients with diabetes. In light of these findings, a multidisciplinary panel of experts in the fields of endocrinology, cardiology, and nephrology was convened in November 2002 to evaluate the use of TZDs in the management of type 2 diabetes. The contents of this supplement to The American Journal of Medicine are derived from that meeting and provide a comprehensive, stateof-the-art summary of a wide range of topics relating to the management of diabetes, particularly addressing the beneficial effects of the TZDs on characteristics of the metabolic syndrome and CVD. During the meeting, the panelists reviewed data generated from basic science and clinical studies evaluating hyperglycemia, hyperinsulinemia, -cell function, dyslipidemia, obesity, hypertension, inflammation, endothelial function, and vascular reactivity as well as cardiovascular effects and safety issues associated with the use of the TZDs. This supplement highlights the fact that many characteristics of the metabolic syndrome are both present before the diagnosis of clinical diabetes and contribute significantly to the CVD burden in patients with diabetes. Each article in this supplement, written by a member of the panel, provides background and support for the summary statements that were agreed upon during the meeting. The TZDs, selective and potent agonists of peroxisome proliferator-activated receptor– (PPAR), directly target insulin resistance by increasing insulin sensitivity in adipose, muscle, and hepatic tissue. Aside from improving peripheral glucose disposal and lowering blood glucose concentrations in patients with diabetes, these agents have generated increasing interest regarding their insulin-sensitizing effects and potential cardiovascular benefits. Activation of PPARmay influence atherosclerosis by both indirect (e.g., lowered glucose, decreased insulin resistance, improved lipid parameters) and direct (e.g., decreased vascular wall inflammation) effects. Various studies indicate that the TZDs have an impact on elements of the metabolic syndrome and may delay or prevent the development of type 2 diabetes in individuals at high risk as well as prevent development or progression of atherosclerotic disease in patients with type 2 diabetes. The TZDs exert beneficial effects on lipid abnormalities, endothelial function, hemostasis, and inflammation. Numerous studies have demonstrated that the TZDs change the dyslipidemia commonly associated with insulin resistance to a less atherogenic profile. Treatment with TZDs increases blood levels of high-density lipoprotein (HDL) cholesterol, changes the size of lowdensity lipoprotein (LDL) cholesterol particles from small and dense to large and buoyant (less atherogenic) particles, and decreases triglyceride blood levels in individuals with high baseline triglyceride levels. Studies also have shown that TZDs alter the distribution of fat from intrahepatic and visceral fat stores to subcutaneous compartments, changes associated with improved insulin sensitivity and reduced cardiovascular risk. These agents appear to prevent atherosclerotic processes: patients with type 2 diabetes were observed to have reduced intimal hyperplasia following implantation of coronary stents and decreased intimal-medial thickness of the carotid arteries on B-mode ultrasonography. The TZDs also lower blood pressure and reduce microalbuminuria in patients with type 2 diabetes. TZDs have been shown to decrease plasminogen activator inhibitor–1 (PAIand C-reactive protein (CRP) levels, which may reflect improved hemostatic function and decreased arterial inflammation. Taken together, these data suggest that the TZDs exert many promising effects that may translate to clinical benefit in terms of CVD prevention, both in de novo disease and in patients with established CVD. Despite the wealth of accumulating data emphasizing the positive glycemic and cardiovascular effects of the TZDs, some concerns have been raised regarding potential safety issues associated with these agents, including From the Lahey Clinic, Burlington, Massachusetts, USA (RWN), and Mount Sinai Medical Center and Mount Sinai Diabetes Center, New York, New York, USA (AJD). Correspondence should be addressed to either Andrew J. Drexler, MD, 345 East 37th St, Suite 313, New York, New York 10016 or to Richard W. Nesto, MD, Lahey Clinic, 41 Mall Road, Burlington, Massachusetts, USA 01805.