CARDIOVASCULAR DISEASE RISK IN INSULIN RESISTANT DYSLIPIDEMIC INDIVIDUALS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance (IR) is known to be associated with an increased risk for cardiovascular disease (CVD). Approximately 1/4 of the US population is IR and has the IR syndrome (IRS). IRS is associated with a high plasma triglyceride (TG) and a low high-density lipoprotein cholesterol (HDL-C). This atherogenic lipoprotein pattern also includes postprandial lipemia and is associated with an increased risk for CVD. It is unclear whether the CVD risk associated with IR is merely a function of the associated lipid and lipoprotein abnormalities, but increasing evidence suggests that this is not the case. Treatment options beyond lifestyle interventions to prevent CVD in IR individuals include fibric acid compounds that target the lipid/lipoprotein disturbances via activation of the nuclear hormone receptor PPAR-alpha, and more recently, the thiazolidenedione class of drugs that directly reverse the IR via activation of the related nuclear hormone receptor, PPAR-gamma. Interestingly, the latter class of drugs does not appear to have a major effect on TG and HDL-C concentrations despite the fact that they lower insulin, glucose, and free fatty acids, all of which contribute to hepatic VLDL production. However, prior studies have been limited in that they have measured only fasting lipid/lipoproteins, and they have not specifically targeted individuals with high TG and/or low HDL-C. Furthermore, while the thiazolidenediones have been studied with respect to markers of early CVD such as pro-inflammatory cytokines, C-reactive protein and adhesion molecules, there is little data on the effect of fibrates on these variables. The planned study will compare the effect of these two classes of drugs on CVD risk in IR individuals who have high TG and low HDL-C. Primary endpoints will include fasting and postprandial lipids and atherogenic remnant lipoproteins, along with surrogate markers of CVD such as C-reactive protein, asymmetric dimethylarginine, and adhesion molecules. Covariates will include change in IR, glucose, insulin, and free fatty acid concentrations. We hypothesize that while the fibrate will have a relatively greater effect on the fasting and postprandial lipid/lipoprotein profile, and the thiazolidenedione will have a relatively greater effect on insulin and glucose metabolism, circulating markers of early CVD (inflammation and endothelial dysfunction) will be reduced with both drugs.