Comparing Tricor, Avandia, or Weight Loss to Lower Cardiovascular Risk Factors in People With High Triglycerides.
Condition: Insulin Resistance; Hypertriglyceridemia
MeSH terms: Insulin Resistance; Hypertriglyceridemia; Weight Loss
Study type: Interventional

Summary: 
      Approximately 1/4 of the US population has insulin resistance and the associated risk factors
      such as elevated lipid levels -triglycerides (type of fat from what we eat and what the liver
      produces and low HDL cholesterol which is the good cholesterol helping to protect against
      heart disease. Currently one known treatment for this a medication called fenofibrate,
      another medication that can improve insulin resistance is rosiglitazone, a third treatment
      known to improve insulin resistance an decrease triglycerides is weight loss. In this study
      insulin resistant individuals with elevated triglycerides and or a ratio of triglycerides to
      HDL cholesterol of 3:1 or greater will be randomized (selected by chance) to receive one of
      these treatments and results of insulin sensitivity and cardiac risk profiles will be
      compared at the end of the study.
    

Detailed description: 
      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.
    

Intervention name(s): Rosiglitazone; Fenofibrate; Weight Loss
Intervention type(s): Drug; Drug; Behavioral
Other intervention name(s): avandia; tricor
Intervention MeSH terms: Rosiglitazone; Fenofibrate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Insulin resistance; Insulin resistance syndrome; dyslipidemia; atherogenic dyslipidemia; triglyceride/HDL-C ratio