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[What is the contribution of the review of the evidence on reducing macrovascular risk in patients with atherogenic dyslipidemia? Report on consensus of experts in the importance of the combined therapy by fenofibrate with statin].
Rosolová, H
Vnitrni lekarstvi. 2015;(11):971-5
Abstract
A meeting of European experts in cardiovascular (CV) disease and lipids was convened in Paris, November 2014, where an important problem of preventive cardiology--residual vascular risk done by atherogenic dyslipidemia (AD)--was discussed. On the basis of discussion have the experts summarised a consensus concerning AD, its CV risk and up to date evidence of combined therapy with statin and fenofibrate on CV risk. Atherogenic dyslipidemia should be the secondary aim of dyslipidemia treatment, because it is a reason of residual vascular risk. Non-HDL-cholesterol should be the secondary target of AD treatment, which is a most unexpensive and easiest marker of residual vascular risk. Combined therapy with statin and fenofibrate is safe, well tolerated and reduces plasma atherogenity and CV events in patients with AD and high CV risk, type 2 diabetes or metabolic syndrome.
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Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy?
Othman, A, Benghozi, R, Alecu, I, Wei, Y, Niesor, E, von Eckardstein, A, Hornemann, T
Journal of clinical lipidology. 2015;(4):568-75
Abstract
BACKGROUND The condensation of palmitoyl-CoA and L-Serine is the first step in the de novo formation of sphingolipids and catalyzed by the serine-palmitoyltransferase (SPT). Besides other acyl-CoAs the SPT can also metabolize L-alanine and glycine, which forms an atypical category of neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Several mutations in SPT are associated with pathologically increased 1-deoxySL levels, which cause the inherited sensory neuropathy HSAN1. 1-DeoxySL levels are also elevated in individuals with the metabolic syndrome and diabetes mellitus type II and seem to be involved in the pathology of the diabetic neuropathy. OBJECTIVE In previous studies, we observed a strong correlation between plasma 1-deoxySLs and triglycerides (TGs). We were therefore interested whether lowering plasma TG levels also affects plasma sphingolipid and in particular, 1-deoxySL levels. METHODS Sixty-six patients with dyslipidemia were treated for 6 wk with the TG-lowering drug fenofibrate (160 mg/d) or extended-release niacin (0.5 g/d for 3 wk, then 1 g/d) with 4 wk of washout between treatments. The sphingoid base profile was analyzed by liquid chromatography-mass spectrometry (LC-MS) before and after each treatment block. RESULTS Fenofibrate significantly lowered 1-deoxySLs and other atypical sphingoid bases (P < .001) but had no effect on the typical sphingolipids. In contrast, extended-release niacin had no effect on 1-deoxySL levels although both treatments lowered plasma TG levels. CONCLUSIONS The lowering of plasma 1-deoxySL levels by fenofibrate in dyslipidemic patients might be a novel therapeutic approach in the prevention and treatment of diabetic neuropathy.
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Fenofibrate and extended-release niacin improve the endothelial protective effects of HDL in patients with metabolic syndrome.
Gomaraschi, M, Ossoli, A, Adorni, MP, Damonte, E, Niesor, E, Veglia, F, Franceschini, G, Benghozi, R, Calabresi, L
Vascular pharmacology. 2015;:80-86
Abstract
BACKGROUND Fibrates and niacin are at present the most effective therapies to increase plasma levels of high density lipoprotein-cholesterol (HDL-C); to date, limited data are available on their effects on HDL protective functions. METHODS AND RESULTS Within a multicenter, randomized, open-label, cross-over study, 37 patients with metabolic syndrome received 6weeks' treatment with fenofibrate or extended-release niacin (ER niacin), with a 4weeks' wash-out period. HDL ability to preserve endothelial cell homeostasis was assessed by incubating cultured endothelial cells with HDL isolated from patients at baseline and after each treatment. HDL isolated from patients at baseline were as effective as control HDL in inhibiting vascular cell adhesion molecule-1 (VCAM-1) expression, but less efficient in promoting endothelial cell nitric oxide (NO) release. Both fenofibrate and ER niacin increased HDL ability to inhibit TNFα-induced VCAM-1 expression (+7% and +11%, respectively). Fenofibrate and ER niacin also improved the impaired HDL ability to induce the expression of endothelial nitric oxide synthase and NO production (+10% and +8%, respectively). Interestingly, HDL isolated after treatment showed an ability to promote endothelial NO release similar to HDL isolated from controls. No differences were observed between the two drugs. With both drugs, HDL function was improved irrespective of baseline HDL-C levels. CONCLUSION Treatment with fenofibrate or ER niacin in patients with metabolic syndrome not only increased HDL-C levels but also improved the endothelial protective effects of HDL.
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Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome.
Agouridis, AP, Kostapanos, MS, Tsimihodimos, V, Kostara, C, Mikhailidis, DP, Bairaktari, ET, Tselepis, AD, Elisaf, MS
International journal of clinical practice. 2012;(9):843-53
Abstract
BACKGROUND Raised triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL-C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). OBJECTIVE To compare the effect of high-dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω-3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. METHODS We previously randomised patients with low-density lipoprotein cholesterol (LDL-C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω-3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. RESULTS The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p < 0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL-C levels (by 7.7%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. CONCLUSIONS All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.
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Fenofibrate: a review of its use in dyslipidaemia.
McKeage, K, Keating, GM
Drugs. 2011;(14):1917-46
Abstract
Fenofibrate is a fibric acid derivative indicated for the treatment of severe hypertriglyceridaemia and mixed dyslipidaemia in patients who have not responded to nonpharmacological therapies. The lipid-modifying effects of fenofibrate are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. Fenofibrate improves the lipid profile (particularly triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with dyslipidaemia. Compared with statin monotherapy, fenofibrate monotherapy tends to improve TG and HDL-C levels to a significantly greater extent, whereas statins improve low-density lipoprotein-cholesterol (LDL-C) and total cholesterol levels to a significantly greater extent. Fenofibrate is also associated with promoting a shift from small, dense, atherogenic LDL particles to larger, less dense LDL particles. Combination therapy with a statin plus fenofibrate generally improves the lipid profile to a greater extent than monotherapy with either agent in patients with dyslipidaemia and/or type 2 diabetes mellitus or the metabolic syndrome. In the pivotal FIELD and ACCORD trials in patients with type 2 diabetes, fenofibrate did not significantly reduce the risk of coronary heart disease events to a greater extent than placebo, and simvastatin plus fenofibrate did not significantly reduce the risk of major cardiovascular (CV) events to a greater extent than simvastatin plus placebo. However, the risk of some nonfatal macrovascular events and the incidence of certain microvascular outcomes were reduced significantly more with fenofibrate than with placebo in the FIELD trial, and in the ACCORD trial, patients receiving simvastatin plus fenofibrate were less likely to experience progression of diabetic retinopathy than those receiving simvastatin plus placebo. Subgroup analyses in the FIELD and ACCORD Lipid trials indicate that fenofibrate is of the greatest benefit in decreasing CV events in patients with atherogenic dyslipidaemia. Fenofibrate is generally well tolerated when administered alone or in combination with a statin. Thus, in patients with dyslipidaemia, particularly atherogenic dyslipidaemia, fenofibrate is a useful treatment option either alone or in combination with a statin.
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Effects of coadministered ezetimibe plus fenofibrate in mixed dyslipidemic patients with metabolic syndrome.
Bays, HE, Shah, A, Macdonell, G, Taggart, WV, Gumbiner, B
Metabolic syndrome and related disorders. 2011;(2):135-42
Abstract
OBJECTIVE Patients with metabolic syndrome are at increased risk of atherosclerotic coronary heart disease, often have mixed dyslipidemia, and may thus require more aggressive treatment of multiple lipid parameters. The objective of this investigation was to compare the treatment response of ezetimibe co-administered with fenofibrate in mixed dyslipidemic patients with and without metabolic syndrome. METHODS This post hoc analysis evaluated 625 patients 18-75 years of age with mixed dyslipidemia, defined as elevated low-density lipoprotein cholesterol (LDL-C) levels (130-220 mg/dL) and elevated triglycerides (TG) levels (200-500 mg/dL). Patients were randomized in a 1:3:3:3 ratio to 1 of 4 treatments for 12 weeks: Placebo; ezetimibe 10 mg; fenofibrate 160 mg; or ezetimibe 10 mg plus fenofibrate 160 mg. Metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel III criteria and was identified at baseline in 450 patients. RESULTS Ezetimibe alone, fenofibrate alone, or their combination produced expected, and generally similar, lipid effects among those with or without metabolic syndrome with respect to LDL-C, apolipoprotein B (ApoB), and non-high-density lipoprotein cholesterol (HDL-C) levels. Ezetimibe alone may have resulted in greater LDL-C and ApoB lowering in the metabolic syndrome group than the non-metabolic syndrome group (P ≤ 0.05 for both). TG and high-sensitivity C-reactive protein had greater reductions in the fenofibrate and fenofibrate plus ezetimibe groups than the ezetimibe alone group (P ≤ 0.05 for both) CONCLUSIONS In this analysis of patients with mixed dyslipidemia, the lipid effects of ezetimibe plus fenofibrate were generally similar in metabolic syndrome patients versus those without metabolic syndrome.
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Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome.
Belfort, R, Berria, R, Cornell, J, Cusi, K
The Journal of clinical endocrinology and metabolism. 2010;(2):829-36
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Abstract
CONTEXT Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist widely used in clinical practice, but its mechanism of action is incompletely understood. OBJECTIVE The aim of the study was to assess whether improvement in subclinical inflammation or glucose metabolism contributes to its antiatherogenic effects in insulin-resistant subjects with the metabolic syndrome (MetS). DESIGN AND SETTING We conducted a randomized, double-blind, placebo-controlled study in the research unit at an academic center. PATIENTS We studied 25 nondiabetic insulin-resistant MetS subjects. INTERVENTION(S): We administered fenofibrate (200 mg/d) and placebo for 12 wk. MAIN OUTCOME MEASURES Before and after treatment, we measured plasma lipids/apolipoproteins, inflammatory markers (high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule/vascular cell adhesion molecule), adipocytokines (adiponectin, TNFalpha, leptin), and insulin secretion (oral glucose tolerance test). We also assessed adipose tissue, hepatic and peripheral (muscle) insulin resistance fasting and during a euglycemic insulin clamp with (3)H glucose and (14)C palmitate infusion combined with indirect calorimetry. RESULTS Subjects displayed severe insulin resistance and systemic inflammation. Fenofibrate significantly reduced plasma triglyceride, apolipoprotein (apo) CII, apo CIII, and apo E (all P < 0.01), with a modest increase in high-density lipoprotein-cholesterol (+12%; P = 0.06). Fenofibrate markedly decreased plasma high-sensitivity C-reactive protein by 49.5 +/- 8% (P = 0.005) and IL-6 by 29.8 +/- 7% (P = 0.03) vs. placebo. However, neither insulin secretion nor adipose tissue, hepatic or muscle insulin sensitivity or glucose/lipid oxidation improved with treatment. Adiponectin and TNF-alpha levels were also unchanged. Improvement in plasma markers of vascular/systemic inflammation was dissociated from changes in triglyceride/high-density lipoprotein-cholesterol, apo CII/CIII, or free fatty acid concentrations or insulin secretion/insulin sensitivity. CONCLUSIONS In subjects with the MetS, fenofibrate reduces systemic inflammation independent of improvements in lipoprotein metabolism and without changing insulin sensitivity. This suggests a direct peroxisome proliferator-activated receptor alpha-mediated effect of fenofibrate on inflammatory pathways, which may be important for the prevention of CVD in high-risk patients.
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"If it ain't broke, don't fix it": a commentary on the positive-negative results of the ACCORD Lipid study.
Tenenbaum, A, Fisman, EZ
Cardiovascular diabetology. 2010;:24
Abstract
Even using intensive statin monotherapy, many patients fail to achieve all the desired lipid goals and remain at high residual risk of cardiovascular events. In view of the still unproven decisively intensive "statin as monotherapy" strategy and "residual risk" concept, it is logical to ask whether other strategies, particularly fibrate/statin combination therapy, could be more beneficial and safer. A clear benefit of fibrate monotherapy did emerge previously among patients with atherogenic dyslipidemia (particularly high triglycerides and low high density lipoprotein cholesterol [HDL-C]) typically present in the metabolic syndrome and type 2 diabetes. In contrast, in patients without atherogenic dyslipidemia this favorable effect was not demonstrated. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus. However, relevant patients with atherogenic dyslipidemia represented less than 17 percent of the ACCORD Lipid population (941 out of 5518 patients). In this prespecified subgroup, the patients benefited from fenofibrate therapy in addition to simvastatin similar to the previous "fibrate's as monotherapy" trials: the primary outcome rate was 12.4% in the fenofibrate group, versus 17.3% in the placebo group (28% crude HR reduction, CI less than 1, e.g. statistically significant findings). Among all other 4548 patients without atherogenic dyslipidemia such rates were 10.1% in both fenofibrate and placebo study groups. Authors concluded that in the overall cohort of patients the combination of fenofibrate and simvastatin did not reduce the rate of the cardiovascular events as compared with simvastatin alone. Thus, their results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the general patients with type 2 diabetes. A recent large meta-analysis regarding effects of fibrates on cardiovascular outcomes noted greater effect sizes in trials that recorded a higher mean baseline triglyceride concentration (p = 0.030). As expected, in a so called "general population", reflecting a blend of effects in patients with and without atherogenic dyslipidemia, a mean "diluted" effect of fibrate therapy was reduced, but still producing a significant 10% relative risk (RR) decrease in major cardiovascular events (p = 0.048) and a 13% RR reduction for coronary events (p < 0.0001). It should be pinpointed that the epidemiological characteristics of the ACCORD Lipid study depart from those seen in real clinical practice: among people with type 2 diabetes, there is a high prevalence of atherogenic dyslipidemia and metabolic syndrome. For example, an analysis of NHANES III data in adults aged >or=50 years showed that approximately 86% of patients with type 2 diabetes also had the metabolic syndrome. Therefore, an important finding of ACCORD Lipid study was the observation that fibrates may lead to cardiovascular risk reduction in patients with atherogenic dyslipidemia not only as monotherapy but in combination with statins as well. In conclusion, in patients with atherogenic dyslipidemia (high triglycerides and low HDL-C, fibrates -- either as monotherapy or combined with statins - were associated with reduced risk of cardiovascular events. In patients without dyslipidemia this favorable effect - as expected - was absent.
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Fenofibrate and metabolic syndrome.
Kraja, AT, Province, MA, Straka, RJ, Ordovas, JM, Borecki, IB, Arnett, DK
Endocrine, metabolic & immune disorders drug targets. 2010;(2):138-48
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Abstract
The fibric acid derivative, fenofibrate (FF) has been used in the US since 1998 to manage patients with dyslipidemia. Typical changes in serum lipids as result a of FF treatment include clinically important mean reductions of serum triglycerides (TG) by a mean change of -93.7 mg/dL (-39.3%), increases of high density lipoprotein cholesterol (HDLC) by +5.5 mg/dL (+12.4%), and reductions in low density lipoprotein cholesterol (LDLC) by -17.9 mg/dL (-12.3%). The greatest reductions in serum TG are usually observed in subjects with elevated baseline TGs including those with the metabolic syndrome (MetS). Although statins remain the mainstay of therapy for most dyslipidemic patients, their combined use with FF would be expected to address residual risk resulting from less than optimal TG and HDLC levels in such patients. Clinical trials examining the cardiovascular benefits of FF alone or combined with statins have produced mixed results. These observations underscore our lack of understanding of which patients may benefit from FF therapy and which do not. Although FF's basic mechanism of action is known to involve PPAR-alpha agonist activity resulting in altered transcription of several genes, the actual genetic bases for variability in lipid response is poorly understood. Studies, such as our GOLDN study and others designed to better understand the genetic determinants of variability in the response to FF treatment and lipid levels. As a result several important genetic determinants of lipid levels have been identified. For example, in the GOLDN study SNPs from different genes were significantly associated with baseline lipid levels before treatment (APOA5- rs662799, rs3135506; APOC3- rs5128, rs2854117, rs4520); APOA4- rs5104; PPARA- rs9626730, rs135543, rs11703495; LPL- rs1801177), after treatment PPARA- rs11708495; LPL- rs1801177, and appeared to modulate overall response to FF treatment (NOS3- rs1799983). In this article, we will review the literature leading up to the contemporary use of FF as an agent to manage patients with dyslipidemia and focus on emerging understanding of the genetic variability in response to FF treatment. On the basis of the available evidence, we conclude that FF is of benefit in the treatment of dyslipidemia, especially among those with MetS. However, more work is needed to specifically identify which individuals derive a benefit from FF administration in terms of clinical outcomes and which do not - particularly in the context of type 2 diabetes.
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Heterogeneous postprandial lipoprotein responses in the metabolic syndrome, and response to fenofibrate therapy.
Rosenson, RS, Helenowski, IB, Tangney, CC
Cardiovascular drugs and therapy. 2010;(5-6):439-47
Abstract
BACKGROUND Hypertriglyceridemia subjects with metabolic syndrome exhibit variable postprandial triglyceride responses. We investigate the effects of fenofibrate therapy on postprandial triglyceride-containing lipoproteins in subjects with early (3.5 h) versus late (8 h) postprandial triglyceride responses. METHODS Fifty-five subjects with fasting hypertriglyceridemia (≥1.7 mmol/L (150 mg/ dL) and <5.8 mmol/L (500 mg/dL)) and ≥2 Adult Treatment Panel III criteria of the metabolic syndrome were randomized to daily fenofibrate (160 mg/d) or placebo for 12 weeks in a double-blind controlled clinical trial. A standardized fat load (50 g/m(2)) was given orally after a 12 h fast. Blood specimens were obtained at 0 h (fasting), 3.5 h, and 8 h after the test meal. Analysis is confined to the 53 subjects with clearly identifiable early or late triglyceride peaks prior to therapy. RESULTS Fenofibrate was more effective in late peakers (n = 8) when compared to early peakers (n = 15) with respect to reducing postprandial triglyceride concentrations (-67% vs. -34%, p = 0.0024) and large VLDL (-76% vs. -31%, p = 0.0016), and increasing total HDL particles (20% vs. 11%, p = 0.008) and large HDL particles (185% vs. 88%, p = 0.003). On fenofibrate therapy, 100% of those initially designated as late peakers were reclassified as early peakers; 47% of late peakers assigned to placebo were reclassified as early peakers. CONCLUSIONS Late postprandial triglyceride responders have attenuated clearance of large VLDL particles, but they were more responsive to fenofibrate.