Fenofibrate Therapy Ameliorates Fasting and Postprandial Lipoproteinemia, Oxidative Stress, and the Inflammatory Response in Subjects With Hypertriglyceridemia and the Metabolic Syndrome

Abstract

OBJECTIVE -The aim of this study was to determine the effects of fenofibrate (160 mg/day) on fasting and postprandial lipoproteins, oxidized fatty acids, and inflammatory mediators in subjects with hypertriglyceridemia and the metabolic syndrome.RESEARCH DESIGN AND METHODS -Fifty-nine subjects with fasting hypertriglyceridemia (Ն1.7 and Ͻ6.9 mmol/l) and two or more of the Adult Treatment Panel III criteria for the metabolic syndrome were randomly assigned to fenofibrate (160 mg/day) or placebo in a double-blind, controlled clinical trial.RESULTS -Fenofibrate treatment lowered fasting triglycerides (Ϫ46.1%, P Ͻ 0.0001) and postprandial (area under the curve) triglycerides (Ϫ45.4%, P Ͻ 0.0001) due to significant reductions in postprandial levels of large (Ϫ40.8%, P Ͻ 0.0001) and medium (Ϫ49.5%, P Ͻ 0.0001) VLDL particles. The number of fasting total LDL particles was reduced in fenofibratetreated subjects (Ϫ19.0%, P ϭ 0.0033) primarily due to reductions in small LDL particles (Ϫ40.3%, P Ͻ 0.0001); these treatment differences persisted postprandially. Fasting and postprandial oxidized fatty acids were reduced in fenofibrate-treated subjects compared with placebo-administered subjects (Ϫ15.3%, P ϭ 0.0013, and 31.0%, P Ͻ 0.0001, respectively), and fenofibrate therapy lowered fasting and postprandial soluble vascular cell adhesion molecule-1 (VCAM-1) (Ϫ10.9%, P ϭ 0.0005, and Ϫ12.0%, P ϭ 0.0001, respectively) as well as fasting and postprandial soluble intercellular adhesion molecule-1 (ICAM-1) (Ϫ14.8%, P Ͻ 0.0001, and Ϫ15.3%, P Ͻ 0.0001, respectively). Reductions in VCAM-1 and ICAM-1 were correlated with reductions in fasting and postprandial large VLDL particles (P Ͻ 0.0001) as well as postprandial oxidized fatty acids (P Ͻ 0.0005).CONCLUSIONS -Triglyceride-lowering therapy with fenofibrate reduced fasting and postprandial free fatty acid oxidation and inflammatory responses, and these antiatherosclerotic effects were most highly correlated with reductions in large VLDL particles. Diabetes Care 30:1945-1951, 2007T he metabolic syndrome represents an agglomeration of interrelated risk factors that include abnormally high fasting triglyceride levels (1,2). In a recent analysis, hypertriglyceridemia (Ն1.7 mmol/l) represented the component of the metabolic syndrome most strongly associated with a history of myocardial infarction and stroke (3). Furthermore, elevated fasting triglyceride levels (Ն1.4 mmol/l) and an enlarged waist circumference (Ͼ89 cm) were the two characteristics of the metabolic syndrome that were associated with the greatest increased risk for all-cause mortality and cardiovascular deaths among postmenopausal women (4).Hypertriglyceridemia signifies the presence of increased plasma triglycerideremnant lipoproteins, and the concentrations of remnant-like lipoproteins are further enhanced postprandially among hypertriglyceridemic subjects (5). Remnant-like proteins have been shown to increase intracellular oxidant concentrations and lipid peroxide levels in culture media and to activate nuclear factor-B ...

Effects of Fenofibrate Treatment on Cardiovascular Disease Risk in 9,795 Individuals With Type 2 Diabetes and Various Components of the Metabolic Syndrome

“…In the setting of metabolic syndrome and hypertriglyceridemia, fenofibrate was shown to be more effective in reducing fasting triglyceride and increasing HDL cholesterol levels and in reducing postprandial triglyceride levels and oxidized fatty acid levels, which corresponded with a decrease in VLDL particle size and an increase in LDL particle size (21).…”

Association of Common C-Reactive Protein (CRP) Gene Polymorphisms With Baseline Plasma CRP Levels and Fenofibrate Response

“…However, analysis of two haplotypes that only differ for 3u2131CϾT showed marginally significant difference of plasma CRP levels (P ϭ 0.09), suggesting that the effect of this SNP may be subject to the haplotypic context. Studies have shown that fenofibrate along with other fibrates lowers inflammatory markers such as CRP in patients with dyslipidemia associated with insulin resistance, obesity, and the metabolic syndrome (17,18). The anti-inflammatory action is mediated by the activation of peroxisome proliferator-activated receptor ␣ (PPAR-␣), which functions as a negative regulator of genes involved in the inflammatory response by antagonizing the activity of transcription factors such as nuclear factor-B and activator protein-1 (19).…”

Fenofibrate Reduces Postprandial Hypertriglyceridemia in CD36 Knockout Mice

“…Fenofibrate, a PPAR-ligand, has been demonstrated to reduce TG levels in fasting and postprandial states in a cohort of hypertriglyceridemic subjects with MetS; this TG-lowering effect resulted primarily from reductions in fasting and postprandial concentrations of large and medium VLDL particles 17) . Moreover, fenofibrate has been shown to reduce non-fatal myocardial infarctions and coronary revascularizations in diabetic patients 18) .…”