PPAR-α agonism with fibrates is proposed to reduce atherogenic inflammation. We used a low-dose endotoxemia protocol to assess the antiinflammatory effects of fenofibrate, at the maximum dose prescribed for lipid abnormalities, on an induced inflammatory state in healthy humans. Fenofibrate lowered lipoproteins as expected before LPS. Despite direct evidence (via measurement of fenofibric acid levels in plasma) that treated individuals were exposed to therapeutic drug levels before endotoxin administration,21
fenofibrate failed to significantly attenuate the clinical, innate immune, or acute-phase responses to endotoxemia in vivo. These findings suggest limited, if any, systemic antiinflammatory properties of fenofibrate in healthy humans at clinically relevant dosing.
Given the effects of PPAR-α on lipid homeostasis, fibrates have been used clinically for cardiovascular risk reduction, especially in high-risk patients with type 2 diabetes mellitus. Initial clinical trials with PPAR-α agonists, such as the Helsinki Heart Study25
and the Veterans Affairs HDL Intervention Trial,26
demonstrated a significant reduction in major cardiovascular events compared to placebo. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial in subjects with type 2 diabetes, fenofibrate did not have a significant effect on the primary composite endpoint of nonfatal myocardial infarction and coronary heart disease death but did seem to reduce the incidence of nonfatal myocardial infarction.27
In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, fenofibrate treatment in combination with simvastatin failed to produce a reduction in major cardiovascular events beyond that seen with simvastatin alone, although post hoc analyses suggest potential benefit in the subgroup of patients with the most elevated baseline TGs and lowest HDL.28
Thus, the FIELD trial, in which concomitant statin use was prevalent, and the ACCORD trial, in which all were treated with statins, have called into question the utility of fibrates in the current era of widespread statin use. Controversy exists about whether fibrates' cardiovascular benefits might be present only in specific at-risk populations, particularly those with insulin resistance and related lipid abnormalities. Furthermore, whether fibrates confer any antiinflammatory benefit and whether such benefit might be observed in chronic insulin-resistant inflammatory states remains unknown.
Previous studies suggest that PPAR-α agonism inhibits the expression of mediators that promote inflammation within atherosclerotic plaques. Mice lacking the Ppar-α
gene have a prolonged response to topical inflammatory stimuli compared to wild-type mice.5
Long-term treatment with fenofibrate blocked the IL-6–induced acute-phase response in wild-type but not in Ppar-α
–deficient mice, which suggests a role for PPAR-α as a modulator of the immune response at the hepatic level.6
Pharmacological PPAR-α agonism reduced TNF-α levels in murine in vivo LPS models of acute lung injury29
Fenofibrate also prevented the IL-1–induced secretion of IL-6 in a dose-dependent manner in human aortic smooth muscle cells4
and inhibited the TNF-α–mediated production of vascular cell adhesion molecule-1 in human endothelial cells.7
However, conflicting evidence suggests that PPAR-α actually may have proinflammatory in vivo effects. In a mouse model of endotoxemia, mice treated with PPAR-α agonists before in vivo LPS challenge had 5 times higher plasma TNF-α levels than vehicle-treated animals.31
The relevance of these mouse and cell data to fibrate actions in humans in vivo remains unclear.
In human clinical trials, there is limited evidence for the antiinflammatory properties of fibrates. Two small studies of patients mostly with established atherosclerosis found significant reductions in CRP and cytokines with 4 weeks of fenofibrate treatment, but these studies lacked a placebo control.8,10
A larger 3-month trial in subjects with mixed hyperlipidemia did report significant reductions in CRP with fenofibrate compared to placebo.11
In men with abdominal adiposity and the metabolic syndrome, 6 months of gemfibrozil treatment also decreased CRP but failed to reduce plasma IL-6 or TNF-α levels.12
Most trials of fibrates, however, did not address their antiinflammatory effects.
In this context, we sought to test the hypothesis that fenofibrate would blunt inflammatory responses during low-grade endotoxemia in healthy humans. This model is of proven relevance to cardiometabolic disease and provides a probe for the study of therapeutic and genomic influences on inflammatory effects in these disorders.17, 32–33
Abundant evidence links Toll-like receptor-4 signaling and subsequent activation of innate immunity with the pathogenesis of insulin resistance and atherosclerosis. We and others have shown that experimental endotoxemia induces adipose inflammation, insulin resistance, and HDL dysfunction in humans.14–18
Furthermore, endogenous ligands generated in obesity and atherosclerosis, such as fatty acids and modified lipids, can promote Toll-like receptor-4 signaling.34
In fact, deletion of Toll-like receptor-4 attenuated diet-induced obesity, insulin resistance,35
in rodent models. Importantly, endotoxemia protocols have been used safely in humans for decades to test the efficacy of numerous antiinflammatory compounds.37–40
To our knowledge, the present study is the first human study to evaluate the antiinflammatory effects of fenofibrate in healthy subjects submitted to evoked inflammation. Our study design has the advantage of interrogating induced inflammatory responses over time, which may provide greater insight into immune-modulatory interventions than that derived from single–time-point estimates in population studies or trials. Because our study was conducted in healthy volunteers without medical comorbidities, we minimized heterogeneity between subjects at baseline. The model permits direct assessment of interventions on the directional impact of induced inflammation, avoiding confounding and reverse causation, which are features of observational studies in which inflammatory changes may result from risk factors and disease rather than being causal.
Our study design has some limitations. As an acute model, experimental endotoxemia is not equivalent to the chronic inflammation of cardiometabolic disease. It remains possible that fenofibrate suppresses other proinflammatory mediators that were not measured in this study. However, we did examine multiple domains of inflammation and specifically selected biomarkers of known relevance to cardiometabolic disease risk. There was a 23% dropout rate before the inpatient endotoxin visit. This was anticipated, however, and the study was designed and powered on the basis of projected LPS visit completion, which reflected the rate that actually was observed. Of note, subjects who dropped out did not differ obviously from completers in demographics or clinical parameters.
Our results indicate that fenofibrate treatment, at dosages commonly used for lipid abnormalities and heart disease, does not suppress the clinical or inflammatory responses to low-dose endotoxin in healthy humans. These results suggest that the systemic antiinflammatory properties of fenofibrate are limited.