Fibrates: What Have We Learned in the Past 40 Years?

James M. Backes, Pharm.D.; Cheryl A. Gibson, Ph.D.; Janelle F. Ruisinger, Pharm.D.; Patrick M. Moriarty, M.D.

Disclosures

Pharmacotherapy. 2007;27(3):412-424. 

In This Article

Metabolic Effects

These mechanisms of action produce substantial reductions in plasma triglyceride concentrations (20-50%) and significant elevations in HDL concentrations (10-35%).[6] Fibrates have varying effects on LDL concentrations. Among patients with elevated LDL concentrations, modest reductions of 5-20% have been observed.[6] However, fibrates generally increase LDL concentrations if accompanied by hypertrigly-ceridemia, secondary to the increased intra-vascular lypolysis of VLDL by lipoprotein lipase.[5] Consequently, fibrates are primarily used for the treatment of hypertriglyceridemia and atherogenic dyslipidemia (i.e., elevated plasma triglyceride concentrations, small dense LDL particles, low HDL concentrations).

In addition to elevated plasma triglyceride concentrations, each of these lipid disorders is commonly associated with a myriad of other metabolic abnormalities such as low HDL levels, small dense LDL particles, increased LDL particle numbers and remnant lipoproteins, insulin resistance and elevated plasma glucose levels, elevated blood pressure, abdominal obesity, and increased concentrations of C-reactive protein (CRP) and fibrinogen.[6] Individuals with elevated plasma triglyceride concentrations will frequently meet the criteria for metabolic syndrome ( Table 1 ).[7] Fibrates have demonstrated benefit on these metabolic abnormalities by reducing concen-trations of CRP and fibrinogen, which appears to be secondary to cytokine inhibition.[4,8,9,10] In addition, a very recent publication suggests bezafibrate attenuates the progression of insulin resistance secondary to PPAR-α activity.[11] Finally, fibrates have demonstrated favorable effects on small dense LDL particles by reducing concentrations of this smaller LDL subtype.[12] Small dense LDL particles are considered to be more atherogenic than the larger and more buoyant LDL particles and increase the risk of cardiovascular events.[5,13] By markedly reducing plasma triglyceride concentrations, these agents produce a shift from small dense LDL to the larger and less atherogenic LDL subtype.[12,14,15]

The individual fibrates have similar metabolic effects, but unfortunately large, well-designed studies directly comparing these agents are extremely limited. Some reports indicate fenofibrate and bezafibrate may possess more marked changes than the other fibrates on major lipoproteins, including a greater reduction in LDL levels.[5,16,17,18] Further, fenofibrate has reduced concentrations of nontraditional cardiovascular risk factors such as lipoprotein(a) and uric acid.[19,20,21] However, this agent also appears to significantly increase concentrations of homocysteine and serum creatinine, whereas gemfibrozil has no effect.[22,23,24]

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