Fibrates and atherosclerosis

Outcome studies employing the statins have conclusively shown that reduction of LDL translates into reduced clinical cardiovascular events. However, in patients with normal LDL or after LDL levels have been normalized, TG and HDL levels assume an important role in the progression of atherosclerosis. The importance of HDL-cholesterol as an inverse risk factor for CAD is well known. Primary prevention trials such as the Helsinki Heart Study (15) using gemfibrozil therapy showed a 60% reduction in CAD events and a 34% reduction in cardiovascular deaths over a five year period in patients with low HDL levels.

Several secondary prevention trials using fibrates have evaluated the benefits of intervention in patients with normal to borderline total cholesterol and LDL levels with a low HDL level (<45 mg/dL) (32-35). The BECAIT trial using bezafibrate was the first major study to explore the effect of increasing HDL and/or decreasing TG on secondary prevention of CAD. This was a double-blinded placebo-controlled trial over 5 years in young males post myocardial infarction (MI). Effect on coronary atherosclerosis was studied by serial coronary angiograms. This trial showed that progression of coronary atherosclerosis was prevented, and coronary event rate was reduced primarily by lowering TG and increasing HDL without lowering serum LDL. The benefits were particularly marked on lesions of 20 to 50% stenosis at baseline.

The Veterans Affairs High-Density Lipoprotein Intervention Trial (VAHIT) study (36), was a double-blind randomized controlled trial in 2531 men with CAD whose major lipid abnormality was a low HDL-C of 40 mg/dL or less, treated with gemfibrozil during a period of 5.1 years. There was a 22% reduction in the primary end points, the risk of death from CAD or nonfatal MI, with an absolute risk reduction of 4%. The 22% reduction in major CAD was associated with a 6% increase in HDL-C, 33% decrease in TG, and no change in LDL-C levels.

These studies suggest the importance of TG-rich lipoprotein reduction and HDL raising for the retardation of atherosclerosis in mild to moderate lesions, and a role for fibric acid derivatives in secondary prevention. Analysis of data from Cholesterol Lowering Atherosclerosis Study (CLAS), the Program on the Surgical Control of Hyperlipidemias (POSCH), and MARS studies also provide evidence for the importance of TG rich lipoprotein in progression of CAD.

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