Effects of fenofibrate and ezetimibe, both as monotherapy and in coadministration, on cholesterol mass within lipoprotein subfractions and low-density lipoprotein peak particle size in patients with mixed hyperlipidemia

Farnier, Michel; Macdonell, Geraldine; Perevozskaya, Inna; Davies, Michael J.; Gumbiner, Barry M.; Musliner, Thomas

doi:10.1016/j.metabol.2008.01.026

Cited by 40 publications

(35 citation statements)

References 30 publications

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“…Elevated plasma levels of LDL, particularly sdLDL, are the major risk factor and a likely causative agent of atherosclerosis (23)(24)(25). Conventional lipid-lowering therapies (including statins, fi brates, niacin, and their combinations) not only improve the overall plasma levels of lipoproteins but also decrease the proportion of sdLDL and thereby increase the median size of LDL ( 43,(53)(54)(55)(56)(57)(58)(59). The results in Fig.…”

Section: Effect Of the Particle Size On Ldl Fusion: Potential Metabolmentioning

confidence: 99%

Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

Gantz

Herscovitz

et al. 2012

Journal of Lipid Research

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of LDL cholesterol and, particularly, apoB are the strongest predictors of atherosclerosis and its causative agents ( 3 ). In atherosclerosis, LDL lipids are deposited in the arterial intima; according to the response-to-retention paradigm ( 4, 5 ), LDL retention by the arterial matrix proteoglycans triggers a cascade of pro-atherogenic events culminating in formation of atherosclerotic plaque ( 6-8 ). These events include biochemical modifi cations of LDL, such as oxidation and/or hydrolysis by the resident proteases and lipases, e.g., phospholipase A 2 and sphingomyelinase, which can reduce LDL affi nity for the LDL receptor, increase LDL affi nity for the proteoglycans, and promote LDL fusion (7)(8)(9)(10)(11)(12)(13)(14). In addition, ionic interactions with proteoglycans reduce LDL stability and promote their fusion and rupture (i.e., release of core lipids) ( 15 ). Fusion of lipoproteins prevents their exit from the arterial intima and thereby augments their further modifi cations, enhances LDL uptake by the arterial macrophages, and initiates the formation of atherosclerotic lesions ( 9, 16 ). Therefore, the pro-atherogenic potential of LDL is thought to be linked to their ability to fuse ( 9,10,17 ). Dissecting the pathogenic pathway of LDL fusion and identifying key factors that promote or inhibit this pathway can help obtain new therapeutic targets for atherosclerosis.Structural analysis of intact and modifi ed LDL has been limited to low resolution ( у 16 Å) by the large size and hydrophobicity of apoB and by LDL heterogeneity ( 1,(18)(19)(20)(21). Human plasma LDL consist of subclasses differing Abstract Fusion of modifi ed LDL in the arterial wall promotes atherogenesis. Earlier we showed that thermal denaturation mimics LDL remodeling and fusion, and revealed kinetic origin of LDL stability. Here we report the fi rst quantitative analysis of LDL thermal stability. Turbidity data show sigmoidal kinetics of LDL heat denaturation, which is unique among lipoproteins, suggesting that fusion is preceded by other structural changes. High activation energy of denaturation, E a = 100 ± 8 kcal/mol, indicates disruption of extensive packing interactions in LDL. Size-exclusion chromatography, nondenaturing gel electrophoresis, and negativestain electron microscopy suggest that LDL dimerization is an early step in thermally induced fusion. Monoclonal antibody binding suggests possible involvement of apoB N-terminal domain in early stages of LDL fusion. LDL fusion accelerates at pH < 7, which may contribute to LDL retention in acidic atherosclerotic lesions. Fusion also accelerates upon increasing LDL concentration in near-physiologic range, which likely contributes to atherogenesis. Thermal stability of LDL decreases with increasing particle size, indicating that the pro-atherogenic properties of small dense LDL do not result from their enhanced fusion. Our work provides the fi rst kinetic approach to measuring LDL stability and suggests that lipid-lowering therapies that reduce LDL concentration but increase t...

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Section: Effect Of the Particle Size On Ldl Fusion: Potential Metabolmentioning

confidence: 99%

Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

Gantz

Herscovitz

et al. 2012

Journal of Lipid Research

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“…Taking into consideration the association between sdLDL and coronary heart disease [46], the role of sdLDL could be underestimated in RTR with or without MS. It was reported that a decrease of non-HDL-C, in contrast to a decrease of LDL-C, is associated with a favorable effect on LDL size in a nontransplant hyperlipidemic population [47]. In agreement with the mechanism of sdLDL formation, no change in the proportion of sdLDL is observed in RTR despite signifi cant improvement of LDL-C levels after switching from CsA to tacrolimus or introduction of statins [48].…”

Section: Non-hdl-c Levelsmentioning

confidence: 84%

Dyslipidemia following kidney transplantation: Diagnosis and treatment

Badiou¹,

Cristol²,

Mourad

2009

Curr Diab Rep

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Lipid abnormalities are a common complication of kidney transplantation, occurring in up to 60% of patients. In fact, impairment of lipid metabolism is often present before renal transplantation due to the uremic state. After transplantation and recovery of renal function, lipid disturbances usually persist but show a different profile due to the various effects of immunosuppressive drugs on lipid metabolism. Actually, steroids, calcineurin inhibitors, and mammalian target of rapamycin inhibitors usually lead to quantitative and qualitative abnormalities of very low-density, low-density, and high-density lipoproteins. As cardiovascular diseases remain the leading cause of death in renal transplant recipients, management of dyslipidemia and other traditional risk factors, such as smoking, arterial hypertension, diabetes mellitus, and obesity, is of great importance to prevent cardiovascular complications and chronic allograft dysfunction. This review addresses the causes of dyslipidemia, the role of immunosuppressive drugs, and current recommendations to manage lipid disorders in renal transplant recipients.

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“…However, data on the effects of ezetimibe on LDL particle size is still conflicting. Other authors report no effect of ezetimibe alone on LDL particle size in patients with primary hypercholesterolemia or mixed dyslipidemia [73,74], while a recent study describes the same reduction in small dense LDL cholesterol particles during a 3 months treatment with the combination of simvastatin and ezetimibe compared to simvastatin alone. Unfortunately, this study did not include a group that was treated with ezetimibe alone [75].…”

Section: Lipid Lowering Agents Targeting Ldl Particle Distributionmentioning

confidence: 98%

Small dense low-density lipoprotein particles: priority as a treatment target in Type 2 diabetes?

Gerber¹,

Spinas²,

Berneis³

2012

Diabetes Management

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During the past two decades, the importance of the quality of low-density lipoprotein (LDL) particles -in addition to its quantity -has become of increasing interest. The risk of cardiovascular events was recognized to be closely linked to a predominance of small, dense LDL particles. In addition, in patients with Type 2 diabetes mellitus, the disease itself and its severity (in particular the degree of insulin resistance) is associated with this subclass of LDL particles. Lipid lowering as well as antihyperglycemic drugs have been evaluated in many studies concerning their effect on LDL particle size. It has increasingly been recognized that a reduction of LDL quantity is not necessarily associated with a beneficial effect on LDL quality. Advances in the understanding of alterations in LDL quality may therefore influence the choice of the therapeutic regimen in patients with diabetes in the future. SummaryDuring the last two decades, the importance of the quality of low-density lipoprotein (LDL) particles -in addition to its quantity -has become of increasing interest. The risk of cardiovascular events was recognized to be closely linked to a predominance of small, dense LDL particles. In addition, in patients with type 2 diabetes mellitus, the disease itself and its severity (in particular the degree of insulin resistance) is associated with this subclass of LDL particles. Lipid lowering as well as antihyperglycemic drugs have been evaluated in many studies concerning their effect on LDL particle size. It has increasingly been recognized that a reduction of LDL quantity is not necessarily associated with a beneficial effect on LDL quality. Advances in the understanding of alterations in LDL quality may therefore influence the choice of the therapeutic regimen in patients with diabetes in the future.

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Effects of fenofibrate and ezetimibe, both as monotherapy and in coadministration, on cholesterol mass within lipoprotein subfractions and low-density lipoprotein peak particle size in patients with mixed hyperlipidemia

Cited by 40 publications

References 30 publications

Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

Dyslipidemia following kidney transplantation: Diagnosis and treatment

Small dense low-density lipoprotein particles: priority as a treatment target in Type 2 diabetes?

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