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The effect of CYP7A1 polymorphisms on lipid responses to fenofibrate.
Shen, J, Arnett, DK, Parnell, LD, Lai, CQ, Straka, RJ, Hopkins, PN, An, P, Feitosa, MF, Ordovás, JM
Journal of cardiovascular pharmacology. 2012;(3):254-9
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Abstract
INTRODUCTION CYP7A1 encodes cholesterol 7α-hydroxylase, an enzyme crucial to cholesterol homeostasis. Its transcriptional activity is downregulated by fenofibrate. The goal of this study was to determine the effect of CYP7A1 polymorphisms on lipid changes in response to fenofibrate. METHODS We examined the associations of 3 tagging single nuclear polymorphisms (i6782C>T, m204T>G, 3U12536A>C) at CYP7A1 with triglyceride (TG) and high-density lipoprotein cholesterol (HDL)-C responses to a 3-week treatment with 160 mg/d of fenofibrate in 864 US white participants from the Genetics of Lipid Lowering Drugs and Diet Network study. RESULTS The m204T>G variant was significantly associated with TG and HDL-C responses with fenofibrate. Individuals homozygous for the common T allele of m204T>G single nuclear polymorphism displayed both the greater reduction of TG (-32% for TT, -28% for GT, -25% for GG, P = 0.004) and an increase of HDL-C response compared with noncarriers (4.1% for TT, 3.4% for GT, 1.2% for GG, P = 0.01). Conversely, individuals homozygous for the minor allele of i6782C>T showed a greater increase in the HDL-C response compared with noncarriers (2.8% CC, 4.5% for CT, 5.8% for TT, P = 0.02), albeit no significant effect on TG response. CONCLUSIONS Our data suggest that common variants at the CYP7A1 locus modulate the TG-lowering and HDL-C-raising effects of fenofibrate, and contribute to the interindividual variation of the drug responses.
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Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.
Scott, R, O'Brien, R, Fulcher, G, Pardy, C, D'Emden, M, Tse, D, Taskinen, MR, Ehnholm, C, Keech, A, ,
Diabetes care. 2009;(3):493-8
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Abstract
OBJECTIVE We explored whether cardiovascular disease (CVD) risk and the effects of fenofibrate differed in subjects with and without metabolic syndrome and according to various features of metabolic syndrome defined by the Adult Treatment Panel III (ATP III) in subjects with type 2 diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. RESEARCH DESIGN AND METHODS The prevalence of metabolic syndrome and its features was calculated. Cox proportional models adjusted for age, sex, CVD status, and baseline A1C levels were used to determine the independent contributions of metabolic syndrome features to total CVD event rates and the effects of fenofibrate. RESULTS More than 80% of FIELD participants met the ATP III criteria for metabolic syndrome. Each ATP III feature of metabolic syndrome, apart from increased waist circumference, increased the absolute risk of CVD events over 5 years by at least 3%. Those with marked dyslipidemia (elevated triglycerides >or=2.3 mmol/l and low HDL cholesterol) were at the highest risk of CVD (17.8% over 5 years). Fenofibrate significantly reduced CVD events in those with low HDL cholesterol or hypertension. The largest effect of fenofibrate to reduce CVD risk was observed in subjects with marked dyslipidemia in whom a 27% relative risk reduction (95% CI 9-42, P = 0.005; number needed to treat = 23) was observed. Subjects with no prior CVD had greater risk reductions than the entire group. CONCLUSIONS Metabolic syndrome components identify higher CVD risk in individuals with type 2 diabetes, so the absolute benefits of fenofibrate are likely to be greater when metabolic syndrome features are present. The highest risk and greatest benefits of fenofibrate are seen among those with marked hypertriglyceridemia.
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[The anti-inflammatory and antioxidants effects of micronized fenofibrate in patients with visceral obesity and dyslipidemia].
Broncel, M, Cieślak, D, Koter-Michalak, M, Duchnowicz, P, Mackiewicz, K, Chojnowska-Jezierska, J
Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 2006;(119):547-50
Abstract
UNLABELLED In recent studies it was observed the pleiotropic properties beyond hypolipemic effects of fenofibrate: anti-inflammatory, antioxidants effects, positive impact on glucose metabolism, thrombosis, fibrinolytic system endothelial dysfunction. THE AIM OF THE STUDY To estimate the effects of 4-weeks therapy of micronized fenofibrate in dose 267 mg/d on C-reactive protein (CRP), fibrinogen, thiobarbituric acid reaction substances (TBARS) concentrations in isolated erythrocyte membranes and the activities of antioxidants enzymes such: catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) in erythrocytes in patients with visceral obesity and atherogenic dyslipidemia. MATERIAL AND METHODS The study comprised 55 patients (pts), including 20 healthy volunteers and 35 pts with visceral obesity and dyslipidemia (TG>180 mg/dl, HDL-C < 40 mg/dl for men, <50 mg/dl for women) treated with micronized fenofibrate (267 mg/d). Before and after 4 weeks of active treatment the following parameters were determined: lipids (by enzymatic method using BioMerieux tests), CRP (by immunoturbidimetric method), fibrinogen (by Clauss'a method), TBARS concentrations (by method of Stock and Dormandy), CAT (method of Bartosz et al.), GSH-Px (method of Rice-Evansa), SOD (method of Misra) activities. RESULTS It was noticed significantly higher concentrations of CRP fibrinogen, TBARS and lower activities of CAT GSH-Px, SOD in patients with visceral obesity and atherogenic dyslipidemia than in the control group. The micronized fenofibrate caused a significant decrease in serum total cholesterol (by 15%), TG (by 38%), CRP (by 35%), fibrinogen (by 26%) and TBARS (by 33%) concentrations associated with a increase in CAT (by 35%), GSH-Px (by 63%), SOD (by 31%) activities. CONCLUSION We conclude that micronized fenofibrate beyond hipolipemic efficacy demonstrates the antioxidative and anti-inflammatory properties in patients with visceral obesity and atherogenic dyslipidemia.
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Effects of micronized fenofibrate and vitamin E on in vitro oxidation of lipoproteins in patients with type 1 diabetes mellitus.
Engelen, W, Manuel-y-Keenoy, B, Vertommen, J, De Leeuw, I, Van Gaal, L
Diabetes & metabolism. 2005;(2):197-204
Abstract
OBJECTIVE The primary objective was to compare the antioxidant activity of micronised fenofibrate 200 mg to 400 IU of vitamin E and placebo, on the LDL and VLDL particles of patients with type 1 diabetes. The secondary objective was to investigate the possible synergy between micronized fenofibrate and vitamin E and to compare the efficacy of these treatments on lipids. METHODS A double-blind, placebo-controlled trial in which patients were randomised into three treatment groups after a wash-out period of 8 weeks: the placebo group (Pla/Pla-group) in which patients received placebo during two consecutive periods of 8 weeks, the vitamin E group (Vit E/Vit E-group) in which patients received Vitamin E during two consecutive periods, and the fenofibrate/Vitamin E group (Fen/Fen + Vit E-group) in which patients received fenofibrate during the first period, followed by fenofibrate and vitamin E during the consecutive period. Blood samples taken at each visit, were analysed for routine biochemistry, blood lipids and copper mediated lipid peroxidation in vitro. RESULTS The lag time of the non-HDL lipoprotein oxidation increased in the group given fenofibrate. The lag-time increased further when fenofibrate and vitamin E were given in association. (This reached significance in the intention-to-treat population, P = 0.034). The AUC of TBARS formation in the Vit E/Vit E group decreased after the first period, but this effect was not enhanced by continuing vitamin E for another 8 weeks. The AUC of TBARS formation did not change significantly after the administration of fenofibrate. Only after the second period, when vit E was given in association, the AUC of TBARS formation decreased significantly (P = 0.004). Fenofibrate caused a significant decrease in total and LDL-cholesterol and triglycerides (P < 0.05). In contrast, vitamin E had no effect on lipids. CONCLUSIONS The combination of micronized fenofibrate 200 mg/day and vitamin E 400 IU/day tended to increase the resistance of non-HDL lipoproteins to copper-mediated oxidation, shown by a prolongation of the lag-time. Vitamin E administration only, decreased the oxidation of non-HDL lipoproteins shown by a reduction of TBARS formation. This protective effect of vitamin E tended to be amplified by micronized fenofibrate.
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Effect of fenofibrate on lipoprotein(a) in hypertriglyceridemic patients: impact of change in triglyceride level and liver function.
Ko, HS, Kim, CJ, Ryu, WS
Journal of cardiovascular pharmacology. 2005;(4):405-11
Abstract
We investigated the effect of fenofibrate on lipoprotein(a)levels in hypertriglyceridemic patients and the parameters relating to its effect. Patients with a triglyceride level ≥300 mg/dL or with a triglyceride level ≥200 mg/dL and a high density lipoprotein cholesterol level ≤40 mg/dL were treated either with 200 mg of fenofibrate(Fenofibrate group, n = 56) or with general measures (Control group,n = 56). Lipid and lipoprotein levels were measured at baseline and 2 months. Baseline lipoprotein(a) levels were negatively correlated with triglyceride (r = 20.30, P = 0.001) and alanine aminotransferase levels (r = 20.24, P = 0.012). Fenofibrate therapy increased lipoprotein(a) level from 9.4 6 10.6 to 15.6 6 17.5 mg/dL (P = 0.000). The more triglyceride levels decreased, the more lipoprotein(a) levels increased in all subjects (r = 20.46, P = 0.000) and in Control (r =20.35, P = 0.008) and Fenofibrate groups (r = 20.35, P = 0.008). Fenofibrate elevated lipoprotein(a) level greater in patients with a normal liver function. When Fenofibrate group was divided into two subgroups according to the degree of percentage change in lipoprotein(a) level, change in triglyceride level and alanine aminotransferase level were independent predictors by forward logistic regression analysis. In summary, fenofibrate therapy increases lipoprotein(a) level,and this elevation is associated with change in triglyceride level and liver function.
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The effect of fenofibrate on the levels of high sensitivity C-reactive protein in dyslipidemic obese patients.
Coban, E, Sari, R
Endocrine research. 2004;(3):343-9
Abstract
It is now well documented that obesity is associated with a chronic low-grade inflammatory state. Levels of high-sensitivity C-reactive protein, a marker of systemic inflammation and a mediator of atherothrombotic disease, have been shown to correlate with cardiovascular disease risk. Our objective was to evaluate the effect of fenofibrate on the levels of high-sensitivity C-reactive protein in dyslipidemic obese patients. We selected 30 dyslipidemic obese patients (body mass index > or = 30 kg/m2) and 20 normolipidemic, nonobese healthy subjects. Dyslipidemic obese patients were treated with fenofibrate 200 mg/day for 3 months. Serum high-sensitivity C-reactive protein and metabolic parameters were evaluated at baseline in both groups and after fenofibrate treatment in dyslipidemic obese patients. At baseline, significantly higher high-sensitivity C-reactive protein levels were found in dyslipidemic obese patients than normal subjects (0.58+/-0.3 vs 0.14+/-0.1 mg/dL, P < 0.01). Total cholesterol, low-density lipoprotein cholesterol, and triglyceride decreased significantly (P < 0.05, P < 0.05, and P < 0.01, respectively), and levels of high-density lipoprotein cholesterol significantly increased (P < 0.05) after treatment with fenofibrate in the dyslipidemic obese group. Levels of high-sensitivity C-reactive protein decreased significantly (approximately 74.1%) after fenofibrate treatment from a mean of 0.58+/-0.3 mg/dL to 0.15+/-0.2 mg/dL, P < 0.01. Our findings suggest that fenofibrate may be used as a first-line therapy for improving the plasma lipids profile, as well as the chronic low-grade inflammatory state in dyslipidemia and obesity.
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Preferential reduction of very low density lipoprotein-1 particle number by fenofibrate in type IIB hyperlipidemia: consequences for lipid accumulation in human monocyte-derived macrophages.
Milosavljevic, D, Griglio, S, Le Naour, G, Chapman, MJ
Atherosclerosis. 2001;(1):251-60
Abstract
The combined (mixed) type IIB phenotype is typically associated with premature atherosclerosis and characterised by concomitant elevation of plasma levels of atherogenic triglyceride-rich lipoproteins, consisting of very low density lipoprotein (VLDL)-1 (Sf 60-400), VLDL-2 (Sf 20-60), and intermediate density lipoprotein (IDL) (Sf 12-20), as well as small dense LDL. After dietary stabilisation, type IIB patients received micronised fenofibrate (267 mg/day) for up to 12 months. At baseline (T0), patients (n=11) displayed fasting triglyceride, cholesterol and apoB levels of 308+/-13, 350+/-17 and 187+/-9 mg/dl, respectively. Micronised fenofibrate (M-fenofibrate) induced marked reductions in plasma triglyceride (TG) (-61%, P<0.0001), total cholesterol (-32%, P=0.0005) and apolipoprotein (apo) B (-33%, P<0.001) at 12 months (T12); similar effects were seen after 3 months (T3) of treatment. These changes resulted from significant reductions in VLDL-1 (-75%, P=0.00001), VLDL-2 (-46%, P=0.002) and LDL (-33%, P<0.0003); IDL concentrations were unchanged. At baseline, VLDL-1 constituted the major TG-rich lipoprotein (TRL) fraction (50% of total mass), but only 25% at T12. These drug effects were accompanied by marked increase in HDL-C (+20%, P=0.018). Quantitative changes in triglyceride-rich lipoproteins were accompanied by significant qualitative modifications in particle size and chemical composition (VLDL-1: TG, -10.7%, P<0.001; FC, +59%, P=0.0002; PL, +19%, P=0.033; VLDL-2: FC, +11%, P=0.027; IDL: FC, +14%, P=0.0004; PL, +12%, P=0.002). Reduction in the TG content of VLDL-1 was reflected in a shift of particle size distribution to smaller diameters (mean 45.4 and 42.3 nm, respectively, at T0 and T12). We evaluated the relative atherogenicity of TRL subfractions by determining their capacity, when normalised to equal particle numbers (as apoB 100 content), to induce lipid accumulation in human monocyte-derived macrophages. Among TRL subfractions, VLDL-1 (100 microg apoB/ml) possessed the highest capacity to induce macrophage lipid loading (up to sevenfold increase in TG content, P<0.001; free cholesterol, up to 1.7-fold; P<0.05). At 100 microg apoB/ml, cellular TG loading from VLDL-1 was twofold greater than that for VLDL-2 (P<0.01), and fivefold greater than for IDL (P<0.01). Despite drug-induced changes in the qualitative properties of TRL subfractions, the activity of VLDL-1, VLDL-2 and IDL as ligands which lead to induction of macrophage lipid accumulation, at equivalent particle numbers, was not detectably altered. By contrast, the fibrate-mediated reduction in the number of circulating VLDL-1 and VLDL-2 particles (four and twofold, respectively) resulted in marked decrease in cellular lipid loading. Considered together, these findings suggest that fenofibrate may act at systemic and arterial levels to reduce the cardiovascular risk associated with VLDL subfractions in patients with a combined hyperlipidemic (type IIB) phenotype. Indeed, we speculate that reductions in circulating levels of VLDL-1 and VLDL-2 may diminish intimal penetration of these particles and thus their propensity to enhance arterial macrophage lipid accumulation and foam cell formation. Finally, fenofibrate further attenuated the atherogenic lipid profile in these patients by inducing marked reduction in LDL and elevation in cardioprotective HDL.
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Effects of fibrates on plasma prothrombotic activity in patients with type IIb dyslipidemia.
Okopien, B, Cwalina, L, Lebek, M, Kowalski, J, Zielinski, M, Wisniewska-Wanat, M, Kalina, Z, Herman, ZS
International journal of clinical pharmacology and therapeutics. 2001;(12):551-7
Abstract
OBJECTIVE Increased levels of fibrinogen and plasminogen activator inhibitor 1 (PAI-1) are associated with an increased risk of ischemic coronary disease and its complications. Since atherogenic dyslipidemias are well-known risk factors for coronary heart disease, this study aimed to determine whether Type IIb dyslipidemia, one of the most atherogenic dyslipidemias, is accompanied by increased PAI-1 and fibrinogen synthesis. The additional aim of this study was to evaluate the effect of micronized fibrates on the levels of PAI-1 and fibrinogen in patients with Type IIb dyslipidemia. SUBJECTS Thirty patients with Type IIb dyslipidemia and 12 age-matched control subjects were studied. Fourteen patients were treated with fenofibrate and 16 were treated with ciprofibrate for 1 month. METHODS Plasma PAI-1 levels were measured by the ELISA method with Diagnostica Stago kit. The level of fibrinogen was measured by the Clauss method. RESULTS PAI-1 levels in dyslipidemic patients before treatment differed significantly in both the fenofibrate and ciprofibrate treatment groups (101.18 +/- 36.47 ng/ml, 87.64 +/- 32.06 ng/ml, respectively) from those in the control group (32.32 +/- 7.39 ng/ml, p < 0.001). Compared with the control subjects (2.91 +/- 0.35 g/l), fibrinogen levels before treatment were higher in patients with dyslipidemia treated with ciprofibrate (3.42 +/- 0.59 g/l, NS) and fenofibrate (3.65 +/- 1.10 g/l, p < 0.05). One-month ciprofibrate treatment resulted in an insignificant decrease in PAI-1 levels (76.28 21.60 ng/ml, NS) and in a significant decrease in fibrinogen levels (2.73 +/- 0.40 g/l, p < 0.01). After one-month fenofibrate treatment PAI-1 levels (81.22 +/- 25.01 ng/ml, p < 0.01) and fibrinogen levels (2.95 0.72 g/l, p < 0.01) decreased significantly. CONCLUSION Type IIb dyslipidemic patients have increased levels of PAI-1 and fibrinogen. Micronized fibrates decreased not only lipid levels but also the levels of fibrinogen and PAI-1 in these patients.
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Impact of postprandial hypertriglyceridemia on vascular responses in patients with coronary artery disease: effects of ACE inhibitors and fibrates.
Bae, JH, Bassenge, E, Lee, HJ, Park, KR, Park, CG, Park, KY, Lee, MS, Schwemmer, M
Atherosclerosis. 2001;(1):165-71
Abstract
We analyzed vascular responses (endothelial function, oxidant stress) to postprandial hypertriglyceridemia (PHTG) in patients with coronary artery disease (CAD) to reveal potential therapeutical effects of angiotensin converting enzyme inhibition (ACE-I) and of lipid lowering (fibrate). The study population (n=39, mean age: 60 years) consisted of four groups, all of which had angiographically documented CAD. A high fat group (n=9) consumed a high fat meal, a low fat group (n=9) a low fat meal, and ACE-I (n=10) or fibrate (n=11) groups consumed a high fat meal plus lisinopril or fenofibrate. Serum triglycerides (TG) increased significantly 2 h after eating a test meal in all groups with the exception of the low fat group. In the high and low fat groups changes of serum TG were positively correlated (r=0.664, P<0.005) with changes of phorbol ester-activated leukocyte superoxide anion radical (O(2-.)) formation and were negatively correlated (r=-0.488, P<0.05) with flow-mediated brachial artery dilation (FMD). There was a negative correlation (r=-0.419, P=0.094) between FMD and changes of O(2-.) formation in the high and low fat groups. In the ACE-I and fibrate groups, O(2-.) formation decreased 2 h after eating a test meal (from 5.34+/-1.01 to 3.81+/-1.15 nmol/10(6)cells per min, P<0.01, and from 4.66+/-0.91 to 4.26+/-0.97 nmol/10(6)cells per min, P=0.374, respectively). However, endothelial function did not show any significant changes 2 h after eating a test meal in all groups. PHTG increases oxidant stress and further deteriorates endothelial function, even in patients with CAD. Both ACE-I and fibrates have an antioxidant effect but no acute beneficial effects in terms of endothelial function under conditions of PHTG in CAD patients.