Mechanisms of Atheroprotection by Fenofibric Acid (ABT 335) Added to a Statin in Subjects With Insulin Resistance (Hypertriglyceridemia and Low HDL-C)

The field of lipid treatment for atheroprevention, and of HDL-raising in particular, was shaken by the unexpected finding of a net adverse clinical effect of torcetrapib, a Cholesteryl ester transfer protein (CETP) inhibitor with HDL-raising effects far more dramatic than that of niacin or fenofibrate.

Trilipix (ABT 335, choline fenofibrate, or fenofibric acid) is approved by the FDA (12/2008) for treatment of dyslipidemia and may act as a new fibrate for treatment of dyslipidemia and atheroprevention. It is the first fibrate with sufficient evidence for safety in combination use with a statin to receive an FDA indication for that combination use. Thus, there is minimal safety risk to prospective research subjects, who in any case will have the very dyslipidemia for which this combination is approved and recommended. With the ongoing development of this agent through a time of great scientific controversy regarding torcetrapib and HDL, it is urgent to explore the HDL-related mechanisms by which Trilipix may be atheroprotective, with special attention to changes in HDL composition and function.

Novel methods have been developed for measuring HDL composition and function and have been added to state-of-the-art technologies to assemble the uniquely comprehensive panel of HDL parameters in this study. Such methods can now be employed in exploring potentially beneficial effects of promising HDL-active agents such as Trilipix. In addition, improvements in HDL with fibrates appear to be related to other favorable lipoprotein changes, such as reduced remnant levels and increased LDL particle size, and these likely help explain arterial benefits with these agents.

The recent advent and validation of many non-invasive methods for measuring arterial function allows characterization of arterial effects of lipid agents in a time- and cost-effective way, alternative to standard event-driven trials. This study offers a uniquely comprehensive panel of these arterial parameters in order to characterize the likely atheropreventive effects of Trilipix.

This study will investigate changes in both panels of endpoints (state-of-the-art measures of HDL and related lipoproteins, and of arterial function) with Trilipix, which will more clearly and broadly define the benefits of this agent than has been done for any other lipid therapy. In addition, analyses of the intercorrelations of the changes among these several parameters should strongly suggest mechanisms of atheropreventive benefits of Trilipix.