Comparing Tricor, Avandia, or Weight Loss to Lower Cardiovascular Risk Factors in People With High Triglycerides.

It has been estimated that approximately ¼ of the US population has the Insulin Resistant
Syndrome (IRS). The notion that insulin resistance and compensatory hyperinsulinemia lead to
a cluster of abnormalities that increase CVD risk was first introduced in 1988, and central
to the changes identified was a dyslipidemia characterized by a high plasma triglyceride
(TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. The atherogenic
lipoprotein pattern associated with the IRS has grown to include enhanced postprandial
lipemia and smaller and denser low-density lipoprotein (LDL) particles. In addition to being
associated with insulin resistance and compensatory hyperinsulinemia, these changes in
lipoprotein metabolism have been identified as increasing CVD risk. The power of the
dyslipidemia associated with the IRS is reinforced by reports that the plasma TG/HDL-C
concentration ratio is as powerful a predictor of CVD, if not more so, than the more
conventional total plasma cholesterol/LDL-C concentration ratio, and evidence from the
Copenhagen Male Study of the interaction between the plasma TG and HDL-C concentrations,
“conventional” CVD risk factors, and CVD events. Specifically, these latter investigators
were able to show in a prospective study (11) that CVD events were substantially attenuated
in: 1) smokers; 2) patients with high blood pressure; 3) individuals with a high LDL-C
concentration; and 4) subjects who were sedentary; as long as they were in the lowest 1/3rd
of the population with the lowest TG/HDL-C concentration ratio and presumably insulin
sensitive. Conversely, if they were in the tertile with the highest plasma TG/HDL-C
concentration ratio, and presumably insulin resistant, they had a significant increase in
CVD events in the absence of the four conventional CVD risk factors evaluated.

An obvious alternative therapeutic approach to decreasing CVD risk in patients with the IRS
would be to administer a thiazolidinedione (TZD) compound in an effort to directly treat the
basic defect of the syndrome. However, based upon our own results with rosiglitazone (ROSI)
in several different patient populations, improvements in insulin sensitivity were not
associated with a significant improvement in dyslipidemia. For example, in a recent study
(unpublished) of ROSI-treated patients with type 2 diabetes, neither plasma TG (358 to 347
mg/dL) nor HDL-C (40 to 42 mg/dL) concentrations improved, and both total (215 to 239 mg/dL
and LDL-C (118-142mg/dL) concentrations actually increased. Since the patients in this study
became more insulin sensitive with treatment, and had lower daylong plasma glucose, insulin,
and free fatty acid concentrations, the reason for the lack of a beneficial effect of ROSI
on lipoprotein metabolism is not clear. On the other hand, given evidence of the importance
of dyslipidemia in increasing CVD risk in insulin resistant individuals, it seems reasonable
to question the notion that TZD compounds provide the most beneficial approach to decreasing
CVD risk in the dyslipidemic patient with the IRS.

With this background in mind, we propose to initiate a study in which insulin resistant
individuals with the dyslipidemia characteristic of the IRS will be randomized to treatment
with fenofibrate,ROSI, or weight loss and the effect of these three treatments on CVD risk
factors compared. It is postulated that although insulin resistance will improve to a
greater degree with ROSI treatment, the atherogenic lipoprotein profile known to link IRS
and CVD will only significantly improve following treatment with fenofibrate and effects of
weight loss can effect both of these.

Inclusion Criteria:

Insulin Resistant Triglyceride 150 mg/dL or greater or triglyceride HDL-C ratio 3 or
greater BMI 25-35

Exclusion Criteria:

Diabetes Mellitus History of gall stones History of CHF History of CAD Severe
anemia,kidney, or liver disease