Peroxisome Proliferator-Activated Receptor-α Agonism With Fenofibrate Does Not Suppress Inflammatory Responses to Evoked Endotoxemia

Abstract

Background: Data conflict with regard to whether peroxisome proliferator-activated receptor-α agonism suppresses inflammation in humans. We hypothesized that in healthy adults peroxisome proliferator-activated receptor-α agonism with fenofibrate would blunt the induced immune responses to endotoxin (lipopolysaccharide [LPS]), an in vivo model for the study of cardiometabolic inflammation.

Methods and results: In the Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) trial, 36 healthy volunteers (mean age 26±7 years, mean body mass index 24±3 kg/m(2), 44% female, 72% white) were randomized to fenofibrate 145 mg or placebo daily. After 6 to 8 weeks of treatment, subjects underwent a low-dose LPS challenge. Clinical and blood measurements were collected at randomization, before LPS administration, and serially for 24 hours after LPS administration. We examined area under the curve for evoked responses by treatment group. Compared to placebo, but before LPS challenge, fenofibrate reduced total cholesterol and tended to decrease triglycerides, consistent with achieved therapeutic plasma levels of fenofibric acid. In the placebo group, LPS induced a modest inflammatory response with increased cytokines and chemokines (2- to 4-hour post-LPS 8-fold increase in tumor necrosis factor-α, 9-fold increase in interleukin-6, 9-fold increase in interleukin-10, and 10-fold increase in monocyte chemotactic protein-1; all P<0.001) and acute-phase reactants (24-hour post-LPS 15-fold increase in serum amyloid A and 9-fold increase in C-reactive protein; both P<0.001). Compared to placebo, however, fenofibrate did not significantly attenuate LPS-induced levels of plasma cytokines, chemokines, or acute-phase proteins.

Conclusions: These data suggest a lack of systemic antiinflammatory properties of fenofibrate at clinically relevant dosing in humans.

Clinical trial registration: URL: http://clinicaltrials.gov/ct2/show/NCT01048502. Unique identifier: NCT01048502. (J Am Heart Assoc. 2012;1:e002923 doi: 10.1161/JAHA.112.002923.).

Keywords: clinical trials; cytokines; endotoxemia; fenofibrate; inflammation.

Figure 1.

Design of the FFAME study.

Figure 2.

Flow diagram for the FFAME study. The fenofibrate and placebo arms of the trial were a portion of a larger, multi-arm trial.

Figure 3.

Fenofibrate has no effect on the clinical responses to endotoxemia. Temperature increased slightly (A) and heart rate increased modestly (B) in participants after LPS administration, whereas systolic and diastolic blood pressure did not change significantly (C). Mean values at each time point are presented by treatment group. Standard deviations are not presented because of marked overlap between groups. No significant differences in peak or ΔAUC values were seen by treatment group for any clinical parameter. LPS indicates lipopolysaccharide.

Figure 4.

Fenofibrate does not suppress the cytokine and chemokine response to endotoxemia. Changes in cytokine and chemokine parameters after endotoxin administration are presented as means with error bars indicating standard deviations. For clarity of presentation, 1-sided error bars are shown. Fenofibrate did not significantly modulate the cytokine or chemokine response to endotoxemia when analyzed as ΔAUC, total AUC, or peak response. LPS indicates lipopolysaccharide.

Figure 5.

Fenofibrate does not modulate hepatic acute-phase responses to endotoxemia. High-sensitivity CRP (A) and serum amyloid A (SAA) (B) increased after endotoxin. CRP responses did not differ significantly by treatment group. SAA trended lower in the fenofibrate group but did not reach statistical significance (ΔAUC, P=0.12), and the SAA:TG ratio (C) did not differ by treatment (ΔAUC, P=0.68). Values shown are mean±standard deviations. LPS indicates lipopolysaccharide.

Figure 6.

Lipid responses to endotoxemia did not differ by treatment group. Total cholesterol (A), LDL cholesterol (B), HDL cholesterol (C), and triglyceride (D) responses after endotoxin administration are presented as mean±standard deviation. No significant differences were observed by treatment group for any lipid variable as measured by ΔAUC. LPS indicates lipopolysaccharide; LDL, low-density lipoprotein; and HDL, high-density lipoprotein.