High Density Lipoprotein Structural Changes and Drug Response in Lipidomic Profiles following the Long-Term Fenofibrate Therapy in the FIELD Substudy

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Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal

Long-term effects of fenofibrate on lipoproteins and surrogate markers of macrovascular and microvascular disease in people with type 2 diabetes

Background and aims. Diabetic dyslipidemia is a highly atherogenic triad of increased triglycerides, decreased HDL cholesterol, and small dense LDL. Fibrates have a beneficial effect on diabetic dyslipidemia, and they have reduced cardiovascular events in randomized trials. Fenofibrate has reduced albuminuria and markers of low-grade inflammation and endothelial dysfunction. The present studies were undertaken to characterize the alterations of VLDL and LDL subclasses and to investigate the binding of LDL to arterial wall in type 2 diabetes. Further purpose was to elucidate the effects of fenofibrate on several lipoprotein subclasses, augmentation index (AIx), carotid intima-media thickness (IMT), and renal function. Subjects. 239 type 2 diabetic subjects were recruited among participants of the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study at the Helsinki centre. The patients were randomized to fenofibrate (200mg/d) or placebo for 5 years. Additionally, a healthy control group (N = 93) was recruited. Results. VLDL1 triglycerides increased in similar proportion to total triglycerides in type 2 diabetic patients and control subjects. Despite the increase in total apoCIII levels, VLDL apoCIII was decreased in diabetic patients. Enrichment of LDL with apoCIII induced a small increase in binding of LDL to arterial wall proteoglycan. Intrinsic characteristics of diabetic LDL, rather than levels of apoCIII, were responsible for increased proteoglycan binding of diabetic LDL with high apoCIII. Fenofibrate reduced triglycerides, increased LDL size, and shifted HDL subclasses towards smaller particles with no change in levels of HDL cholesterol. High levels of homocysteine were associated with lower increase of HDL cholesterol and apoA-I during fenofibrate treatment. Long-term fenofibrate treatment did not improve IMT, AIx, inflammation, or endothelial function. Fenofibrate decreased creatinine clearance and estimated glomerular filtration rate. No effect on albuminuria was seen with fenofibrate. Instead, Cystatin C was increased during fenofibrate treatment. Conclusions. 1) Elevation of VLDL 1 triglycerides was the major determinant of plasma triglyceride concentration in control subjects and type 2 diabetic patients. 2) LDL with high apoCIII showed multiple atherogenic properties, that were only partially mediated by apoCIII per se in type 2 diabetes 3) Fenofibrate demonstrated no effect on surrogate markers of atherosclerosis. 4) Fenofibrate had no effect on albuminuria and the observed decrease in markers of renal function could complicate the clinical surveillance of the patients. 5) Fenofibrate can be used to treat severe hypertriglyceridemia or in combination therapy with statins, but not to increase HDL levels.Taustaa. Tyypin 2 diabetekseen liittyy yleensä korkea triglyseridiarvo, matala HDL-kolesteroli ja pienet, tiheät LDL-hiukkaset. Fibraattilääkityksellä voidaan vaikuttaa näihin jokaiseen, ja fibraattilääkitys onkin vähentänyt sydän- ja verisuonitapahtumia satunnaistetuissa tutkimuksissa. Fenofibraatilla on havaittu suotuisa vaikutus virtsan albumiinineritykseen sekä elimistön matala-asteisen tulehdustilan ja verisuonen seinämän toimintahäiriön merkkiaineisiin. Väitöskirjatyössä luonnehdittiin VLDL- ja LDL-hiukkasten diabetekseen liittyviä muutoksia sekä tutkittiin diabeetikoiden LDL-hiukkasten sitoutumista verisuonen seinämään. Lisäksi tutkittiin fenofibraattilääkityksen vaikutuksia useisiin lipidihiukkasten alaluokkiin, valtimoiden jäykkyyteen, kaulavaltimoiden seinämän paksuuteen ja munuaisten toiminnan mittareihin. Tutkittavat. Tutkimukseen osallistui 239 tyypin 2 diabetespotilasta FIELD-tutkimuksen (Fenofibrate Intervention and Event Lowering in Diabetes) Helsingin keskuksesta. Potilaat saivat FIELD-tutkimuksessa viiden vuoden ajan joko fenofibraattia (200mg/vrk) tai lumelääkettä. Vertailuryhmänä toimi 93 tervettä henkilöä. Johtopäätökset. 1) VLDL-hiukkasten aineenvaihdunta on häiriintynyt tyypin 2 diabeteksessa. 2) Diabeetikoiden runsaasti apoCIII-pintaproteiinia sisältävissä LDL-hiukkasissa on useita valtimonkovetustautiriskiä lisääviä ominaisuuksia, jotka kuitenkin vain osin selittyvät apoCIII-pitoisuudella. 3) Fenofibraatin käyttöä voidaan harkita vaikean hypertriglyseridemian hoidossa mutta HDL-pitoisuuksiin se ei vaikuta. 4) Fenofibraatilla ei ole vaikutusta kaulavaltimon seinämän paksuuteen, valtimoiden jäykkyyteen eikä elimistön matala-asteisen tulehdustilan ja verisuonen seinämän toimintahäiriön merkkiaineisiin. 5) Fenofibraatilla ei ole vaikutusta virtsan albumiinineritykseen. Havaitut alenemat munuaistoimintaa kuvaavissa muuttujissa voivat vaikeuttaa potilaiden seurantaa käytännön lääkärin työssä

Macrophage cholesterol efflux to plasma and HDL in subjects with low and high homocysteine levels: A FIELD substudy

Objectives: Increases of homocysteine (Hcy) by fenofibrate correlated inversely to changes in HDL-C and apoA-I in the FIELD study. This finding raised the question whether high Hcy may influence HDL function and counteract benefits of fenofibrate on cardiovascular outcomes. In a subset of the FIELD study we investigated whether fenofibrate therapy or high Hcy, separately or in concert, modulate: (1) ability of plasma or HDL to facilitate cholesterol efflux from THP-1 foam cells; (2) plasma potential to generate pre beta-HDL; (3) plasma phospholipid transfer protein (PLTP) activity, serum PON-1 mass and activity, HDL particle size and distribution. Methods: We selected 33 subjects in the FIELD fenofibrate arm according to quartiles of Hcy at 5th year: 17 subjects were in the lowest (Low Hcy group) and 16 subjects were in the highest quartile (High Hcy group). In addition, 14 subjects allocated to placebo were matched by close-out Hcy levels to Low Hcy group. This design allowed us to examine the effects of both fenofibrate (comparison between placebo vs Low Hcy groups) and Hcy (comparison between close-out Low and High Hcy groups) on plasma and HDL ability to facilitate cellular cholesterol removal in the efflux assay in vitro using THP-1 foam cells. Results: Hcy levels were 13.3 +/- 0.7 mu mol/L (placebo), 13.2 +/- 2 mu mol/L (Low Hcy) and 27.4 +/- 6.5 mu mol/L (High Hcy). Cholesterol efflux values to HDL and plasma, percentage of plasma pre beta-HDL, PLTP activity, serum PON-1 mass and HDL particle size and distribution were similar in both fenofibrate groups and comparable to those of the placebo group. Conclusions: In the present study cohort fenofibrate and high Hcy levels did not modulate HDL and plasma functions in the first step of reverse cholesterol transport, cholesterol efflux from foam cells. (C) 2011 Elsevier Ireland Ltd. All rights reserved

ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition and increased susceptibility for sphingomyelinase

Background/objectives: Apolipoprotein CIII (apoCIII) is an independent risk factor for cardiovascular disease, but the molecular mechanisms involved are poorly understood. Here, we investigated potential proatherogenic properties of apoCIII-containing LDL from patients with type 2 diabetes. Research design and methods: LDL was isolated from controls and subjects with type 2 diabetes, and from apoB transgenic mice. LDL-biglycan binding was analyzed with a solid-phase assay using immunoplates coated with biglycan. Lipid composition was analyzed with mass spectrometry. Hydrolysis of LDL by sphingomyelinase was analyzed after labeling plasma LDL with [3H]sphingomyelin. ApoCIII isoforms were quantified after isoelectric focusing. Human aortic endothelial cells were incubated with desialylated apoCIII after neuraminidase treatment. Results: We showed that enriching LDL with apoCIII only induced a small increase in LDL-proteoglycan binding, and this effect was dependent on a functional Site A in apoB100. Our findings indicated that intrinsic characteristics of diabetic LDL other than apoCIII per se are responsible for further increased proteoglycan binding of diabetic LDL with high endogenous apoCIII, and we showed alterations in the lipid composition of diabetic LDL with high apoCIII. We also demonstrated that high apoCIII increased susceptibility of LDL to hydrolysis and aggregation by SMase. In addition, we demonstrated that sialylation of apoCIII increased with increasing apoCIII content, and that sialylated apoCIII induced a more pronounced inflammatory response than desialylated apoCIII in HAEC. Conclusions: We have demonstrated a number of features of diabetic LDL with high apoCIII that could explain the proatherogenic role of apoCIII