Darren K. McGuire
Cardiovascular Effects of Rosiglitazone versus Placebo

My research focuses on the generation and application of evidence for the treatment of diabetes specifically in the area of cardiovascular risk modification. Research projects include analyses of existing clinical trial and epidemiologic databases, and participation in the execution of prospective registries and randomized clinical trials.
Under the support of the Donald W. Reynolds Cardiovascular Clinical Research Center at UT Southwestern Medical Center, we are executing a 150 patient randomized double-blind placebo controlled trial, presently just over 1/2 way enrolled. The project is anticipated to complete enrollment around June 2006 with study activities completing around December 2006. A Doris Duke fellow would have the opportunity to participate in all aspects of the project, with opportunity to explore the dataset and perform studies on the plasma/serum bank collected in the study.
The primary objectives of the study are: 1) to determine if rosiglitazone treatment improves integrated cardiovascular performance in patients at risk for CHF (congestive heart failure) 2) to determine if treatment with rosiglitazone decreases intracellular (ectopic) triglyceride (TG) deposition in cardiomyocytes using nuclear magnetic resonance (NMR) techniques, and how changes in intra-myocardial lipid content relate to changes in cardiac structure and function.
BACKGROUND: Cardiovascular disease (CVD), including congestive heart failure (CHF), accounts for over 75% of deaths among patients with diabetes. Thus, it is imperative to rigorously evaluate existing and emerging hypoglycemic therapies with regard to their cardiovascular consequences. The thiazolinedione (TZD) class of drugs, which includes rosiglitazone, are potent and selective agonists for the peroxisome proliferator-activated receptor (PPAR) and have emerged as a safe, effective and widely used treatment of hyperglycemia in type 2 diabetes. Through their effects on PPAR , TZDs have been shown to decrease hepatic gluconeogenesis, increase insulin sensitivity and lead to a transition of fat distribution from visceral to subcutaneous depots, a pattern that has been associated with lower cardiovascular risks. TZDs have also been shown to decrease ectopic, and possibly toxic, deposition of triglycerides in skeletal muscle and myocardium of animals and in skeletal muscle of humans that is associated with obesity and insulin resistance. Both in vitro and in vivo studies have revealed favorable pleiotropic effects of TZD on myocyte and ventricular structure and function. However, approximately 10% of patients taking TZDs develop peripheral edema, although it is unclear if this is related to impaired cardiac function. In addition, case reports exist of patients who have developed heart failure decompensation on the drug. These observations have led to a FDA warning regarding the use of TZDs in patients with or at high risk of developing CHF. Despite the high prevalence of CVD in patients with type 2 diabetes, the exact effects of TZDs on cardiac function remains unclear, and additional studies are needed to evaluate the effect of TZDs on cardiovascular performance, cardiac structure and myocardial triglyceride content in humans.

CONCISE SUMMARY OF PROJECT: This study is a prospective, randomized, double-blind, placebo-controlled, parallel-group study. Subjects will be randomized in a 1:1 fashion to receive rosiglitazone 4mg or matching placebo once daily for one month followed by rosiglitazone 8 mg or matching placebo once daily for 5 months. One hundred fifty subjects will be enrolled in this study. Study participation will last 6 months, and involve visits on months 1, 2, 3 and 6. Vital signs, physical exam and blood work (3-4 tablespoons) will be performed at each visit. At visits 1 and 5, skin-fold thickness, cardiopulmonary exercise testing, cardiac MRI, and magnetic resonance spectroscopy will be performed; SF-36 and Physical Activity Recall (PAR) surveys will be administered; and blood samples ( 3 tablespoons) will be collected, processed and stored for subsequent analysis of biomarkers related to metabolism, diabetes, and cardiovascular disease.
CRITERIA FOR INCLUSION OF SUBJECTS: The inclusion criteria includes: type 2 diabetes mellitus not treated with a TZD within the last six months, with a prior diagnosis of cardiovascular disease (CVD) or at least one additional CVD risk factor (smoking, hypertension, hypercholesterolemia, microalbuminuria, family history of premature coronary artery disease (CAD), or documented hsCRP >3). Diabetes will be defined by a prior clinical diagnosis and current use of hypoglycemic medical therapy.
CRITERIA FOR EXCLUSION OF SUBJECTS: The exclusion criteria includes: treatment with TZD (thiazolidinediones) within prior 6 months; documented intolerance to TZD; history or evidence of CHF; or AST/ALT >3x upper limit of normal (ULN).

RECRUITMENT OF SUBJECTS: Subjects will be recruited through the Dallas Heart Study and from the outpatient cardiology, endocrinology, and primary care clinics at Parkland Health and Hospital System, and by posted and published ads.