Context: Fenofibrate is a peroxisome proliferator-activated receptor α agonist widely used in clinical practice, but its mechanism of action is incompletely understood.

Objective: The aim of the study was to assess whether improvement in subclinical inflammation or glucose metabolism contributes to its antiatherogenic effects in insulin-resistant subjects with the metabolic syndrome (MetS).

Design and Setting: We conducted a randomized, double-blind, placebo-controlled study in the research unit at an academic center.

Patients: We studied 25 nondiabetic insulin-resistant MetS subjects.

Intervention(s): We administered fenofibrate (200 mg/d) and placebo for 12 wk.

Main Outcome Measures: Before and after treatment, we measured plasma lipids/apolipoproteins, inflammatory markers (high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule/vascular cell adhesion molecule), adipocytokines (adiponectin, TNFα, leptin), and insulin secretion (oral glucose tolerance test). We also assessed adipose tissue, hepatic and peripheral (muscle) insulin resistance fasting and during a euglycemic insulin clamp with ³H glucose and ¹⁴C palmitate infusion combined with indirect calorimetry.

Results: Subjects displayed severe insulin resistance and systemic inflammation. Fenofibrate significantly reduced plasma triglyceride, apolipoprotein (apo) CII, apo CIII, and apo E (all P < 0.01), with a modest increase in high-density lipoprotein-cholesterol (+12%; P = 0.06). Fenofibrate markedly decreased plasma high-sensitivity C-reactive protein by 49.5 ± 8% (P = 0.005) and IL-6 by 29.8 ± 7% (P = 0.03) vs. placebo. However, neither insulin secretion nor adipose tissue, hepatic or muscle insulin sensitivity or glucose/lipid oxidation improved with treatment. Adiponectin and TNF-α levels were also unchanged. Improvement in plasma markers of vascular/systemic inflammation was dissociated from changes in triglyceride/high-density lipoprotein-cholesterol, apo CII/CIII, or free fatty acid concentrations or insulin secretion/insulin sensitivity.

Conclusions: In subjects with the MetS, fenofibrate reduces systemic inflammation independent of improvements in lipoprotein metabolism and without changing insulin sensitivity. This suggests a direct peroxisome proliferator-activated receptor α-mediated effect of fenofibrate on inflammatory pathways, which may be important for the prevention of CVD in high-risk patients.