Context. Apart from lowering lipid levels, peroxisome proliferator-activated receptor (PPAR) activators (fibrates) produce many other favorable effects that may contribute to their clinical effectiveness in dyslipidemic and diabetic patients.

Objective. To compare the impact of a short-term treatment with fenofibrate and the American Heart Association (AHA) step 1 diet on systemic inflammation, hemostasis and monocyte secretory function in relationship with their metabolic actions.

Design, Setting, Participants and Interventions. A prospective, randomized, placebo-controlled trial involving the group of 91 ambulatory patients with impaired glucose tolerance (IGT) (diagnosed on the basis of the American Diabetes Association criteria), randomly divided into three groups, simultaneously treated for 30 days with the AHA step 1 diet (n = 30), micronized fenofibrate (267 mg/d, n = 31), or placebo (n = 30). Control group included 34 age-, sex- and weight-matched subjects with normal glucose tolerance. Eighty-six (95%) patients and all control subjects completed the study.

Main outcome measures. Plasma markers of inflammation and hemostasis, and monocyte release of proinflammatory cytokines.

Results. Compared with subjects with normal glucose tolerance, IGT patients exhibited higher plasma levels/activities of fibrinogen, factor VII, PAI-1, high sensitivity C-reactive protein (hsCRP) and oxidized LDLs. Lipopolysaccharide-activated monocytes from IGT patients released significantly more tumor necrosis factor- (TNF-), interleukin-1, interleukin-6 and monocyte chemoattractant protein-1 (MCP-1) in comparison to monocytes from control subjects. Thirty-day treatment with fenofibrate but not with the AHA step 1 diet (1) improved lipid/lipoprotein profile and glucose metabolism and (2) reversed or alleviated all the above mentioned abnormalities. The favorable effects of fenofibrate on plasma hsCRP and on monocyte release of TNF-, interleukin-1, interleukin-6 and MCP-1 did not correlate with its action on plasma lipids but was related to the improvement in insulin sensitivity and weakly to free fatty acid-lowering action.

Conclusions. Our study is the first to show that relatively small disturbances in glucose metabolism are associated with marked and multidirectional abnormalities in plasma markers of inflammation and hemostasis and in monocyte secretory function. Moreover, fenofibrate may exhibit early pleiotropic effects in patients with IGT.