Atherosclerosis is an inflammatory process triggered by the presence of
lipids in the vascular wall and encompasses a complex interaction between inflammatory cells, vascular elements and
lipoproteins through the expression of several adhesion molecules and
cytokines. Activation of the
nuclear receptor peroxisome proliferator-activated receptor-alpha (
PPAR-alpha) has been demonstrated to modulate many aspects of
lipoprotein metabolism and
inflammation in vitro as well as in animal and human studies. The tissue distribution of
PPAR-alpha is extensive and it is abundantly present in the vascular wall where it may mediate many of anti-inflammatory and antiatherogenic effects. Major clinical trials, such as the Veterans Affairs
High-Density Lipoprotein Intervention Trial, the Helsinki Heart Study and the Diabetes
Atherosclerosis Intervention Study, have demonstrated the beneficial effects of synthetic agonists of
PPAR-alpha, specifically
fibric acid derivatives, on
cardiovascular disease outcome. Although
fibric acid trials have reported cardiovascular risk reduction in patients with
dyslipidemia, the favorable alterations in plasma
lipids can only partially explain the reduction in cardiovascular events in these studies. One common link among these trials was a cohort with a high prevalence of
insulin resistance or diabetes, conditions associated with heightened systemic
inflammation and increased risk for development and progression of
atherosclerosis. In this paper, we will review the many antiatherogenic effects of
PPAR-alpha ligands and evidence from
fibric acid trials that individuals with
insulin resistance or diabetes benefit the most from these drugs, consistent with their anti-inflammatory and antithrombotic properties.