Thiazolidinedione Drugs and Cardiovascular Risks

The purpose of this science advisory is to summarize the currently available data concerning thiazolidinediones and cardiovascular risk, with a focus on ischemic heart disease (IHD) events, and to provide practical recommendations to healthcare workers seeking to minimize the burden of cardiovascular disease (CVD) and other complications in their patients with type 2 diabetes mellitus. On May 21, 2007, the US Food and Drug Administration (FDA) released a safety alert concerning a possible increased risk of ischemic cardiovascular events in patients prescribed the thiazolidinedione rosiglitazone. This safety alert was prompted by the results of a large meta-analysis that reported that treatment with rosiglitazone resulted in a 43% increase in risk for myocardial infarction (MI) and a possible increase in risk for cardiovascular death.1 These data were particularly alarming because the metabolic effects of thiazolidinediones were widely presumed, although not proven, to reduce the risk for IHD. Subsequently, a number of additional reports using alternative meta-analytic techniques,2,3 new metaanalyses,4–10 recently published results of new clinical trials,11–15 and observational studies of both rosiglitazone and pioglitazone16–24 have provided variable evidence regarding an adverse cardiovascular effect of these agents. On November 14, 2007, after a specially convened FDA Advisory Panel meeting on July 30, 2007, the FDA decided not to withdraw rosiglitazone from the market. They issued new prescribing information that included a new boxed warning regarding the potential risk for myocardial ischemia, particularly in patients with heart disease taking nitrates, and in patients for whom rosiglitazone was added to established insulin therapy.25 Diabetes mellitus is increasing in prevalence in the United States and worldwide. An estimated 23.6 million people in the United States, 7.8% of the population, had diabetes in 2007, with more than 90% of cases being type 2 diabetes mellitus. Diabetes increases the risk of CVD events by 2to 4-fold, and CVD accounts for nearly two thirds of deaths among diabetic patients.26 Among people who experience CVD events, diabetes is highly prevalent: 45% of those hospitalized for acute MI have known or previously undiagnosed diabetes.27 Diabetes is also an independent predictor of secondary adverse events, such as reinfarction, heart failure, and death.28,29 Similar trends have been observed in the global incidence of diabetes and its consequences. Improving care for diabetic patients has therefore become a global health priority.30,31 The pathophysiology of type 2 diabetes mellitus involves both insulin resistance and progressive loss of the insulin-secretory capacity of pancreatic beta cells. Prior to the late 1990s, pharmacological therapy for type 2 diabetes mellitus was directed at stimulating or replacing endogenous insulin secretion. Insulin resistance precedes the clinical manifestation of diabetes and has been shown to be associated with other cardiovascular risk factors and with increased cardiovascular risk.32 The thiazolidinedione class of drugs, ligands of the peroxisome-prolif-