ABSTRACT
OBJECTIVE: To examine the effects of fenofibrate (160mg/d) therapy on fasting and postprandial cytokine production in subjects with metabolic syndrome and hypertriglyceridemia. RESEARCH DESIGN AND METHODS: Randomized, double-blind, controlled trial that compared the effects of 3-month therapy with placebo and fenofibrate on fasting and postprandial cytokine production in 55 subjects with metabolic syndrome and elevated fasting triglycerides (>or=1.7 and <6.78mmol/L). RESULTS: Fenofibrate treatment reduced concentrations of monohydroxy fatty acids (OH-FA) by 15.5% (p=0.001), lipopolysaccharide activated monocyte chemotactic protein-1 (MCP-1/CCL2) production in fasting blood samples by 3.4% (p=0.01 vs. placebo), macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3) by 3.5% (p=0.01), and interleukin-1beta (IL-1beta) by 2.5% (p=0.04). After a standardized fat load (50kg/m(2)), OH-FA were reduced by 31.0% (p<0.0001), MCP-1/CCL2 was reduced by 5.2% (p=0.002), MIP-1alpha/CCL3 by 3.9% (p=0.007), and IL-1beta by 3.4% (p=0.02). Reductions in MCP-1/CCL2, MIP-1alpha/CCL3, and IL-1beta production correlated with changes in fasting and postprandial large very low-density lipoprotein (VLDL) (all p<0.005) and small low-density lipoprotein (LDL) particles (all p<0.05). In stepwise regression models that included age, gender, weight change, and drug assignment, large VLDL particles were associated with reductions in postprandial MCP-1/CCL2 (p=0.042), MIP-1alpha/CCL3 (p=0.003), and IL-1beta (p=0.02). CONCLUSIONS: This study reports that fenofibrate reduces whole blood production of inflammatory cytokines and hepatic-synthesized inflammatory proteins, and the anti-inflammatory effects of fenofibrate therapy involve VLDL- and LDL-mediated pathways.
Subject(s)
Cytokines/blood , Fenofibrate/therapeutic use , Hypertriglyceridemia/drug therapy , Hypolipidemic Agents/therapeutic use , Metabolic Syndrome/drug therapy , Aged , Double-Blind Method , Fasting , Female , Humans , Hypertriglyceridemia/blood , Hypertriglyceridemia/complications , Lipoproteins, LDL/blood , Lipoproteins, VLDL/blood , Male , Metabolic Syndrome/blood , Metabolic Syndrome/complications , Middle Aged , Postprandial Period , Treatment OutcomeABSTRACT
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 (> or = 1.7 and < 6.9 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 (-46.1%, P < 0.0001) and postprandial (area under the curve) triglycerides (-45.4%, P < 0.0001) due to significant reductions in postprandial levels of large (-40.8%, P < 0.0001) and medium (-49.5%, P < 0.0001) VLDL particles. The number of fasting total LDL particles was reduced in fenofibrate-treated subjects (-19.0%, P = 0.0033) primarily due to reductions in small LDL particles (-40.3%, P < 0.0001); these treatment differences persisted postprandially. Fasting and postprandial oxidized fatty acids were reduced in fenofibrate-treated subjects compared with placebo-administered subjects (-15.3%, P = 0.0013, and 31.0%, P < 0.0001, respectively), and fenofibrate therapy lowered fasting and postprandial soluble vascular cell adhesion molecule-1 (VCAM-1) (-10.9%, P = 0.0005, and -12.0%, P = 0.0001, respectively) as well as fasting and postprandial soluble intercellular adhesion molecule-1 (ICAM-1) (-14.8%, P < 0.0001, and -15.3%, P < 0.0001, respectively). Reductions in VCAM-1 and ICAM-1 were correlated with reductions in fasting and postprandial large VLDL particles (P < 0.0001) as well as postprandial oxidized fatty acids (P < 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.