Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia.

AIMS: To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia. METHODS AND RESULTS: This was a multicentre, randomized, double-blind, placebo-controlled, parallel arm trial in patients with mixed hyperlipidaemia [LDL-cholesterol (LDL-C), 3.4-5.7 mmol/L (2.6-4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3-5.7 mmol/L] and no history of coronary heart disease (CHD), CHD-equivalent disease (except for type 2 diabetes), or CHD risk score>20%. A total of 625 patients was randomized in a 1:3:3:3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO+EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO+EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P<0.001) reduced with FENO+EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO+EZE and FENO treatments when compared with placebo (P<0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline, >70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO+EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated. CONCLUSION: Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.     

Efficacy and safety of ezetimibe/simvastatin co- administered with fenofibrate in mixed hyperlipidemic patients with metabolic syndrome

Background: We compared the lipid-altering effects of ezetimibe/simvastatin (EZE/SIMVA) co-administered with fenofibrate (FENO) in mixed hyperlipidemic patients with (MetS) versus those without MetS. Methods: A total of 611 patients, 20 to 79 years old, with LDL-C 130-220 mg/dL (100-180 mg/dL for patients with type 2 diabetes [T2D]), triglycerides (TG) 150-500 mg/dL, and no history of CHD or other CHD risk equivalent disease (except for T2D), were randomized in a 1:3:3:3 ratio into one of the following four treatments for 12 weeks: placebo; EZE/SIMVA 10/20 mg; FENO 160 mg; or EZE/SIMVA+FENO. MetS status was determined in 607 patients using National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Percentage change from baseline in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), TG, apolipoproteins A-I and B, and C-reactive protein was assessed in these patients with or without MetS. The primary objective was to evaluate the lipid-altering efficacy of EZE/SIMVA+FENO versus FENO monotherapy in the MetS versus non-MetS subgroups. Results: At baseline, patients with MetS had a higher body mass index (BMI) and TG and lower HDL-C. At Week 12, treatment with EZE/SIMVA, FENO, and EZE/SIMVA + FENO led to similar improvements in lipid parameters in patients with MetS compared to those without MetS. Treatment with EZE/SIMVA + FENO and FENO also led to an increase in LDL particle-size pattern after 12 weeks in both subgroups of patients. Conclusions: This post-hoc analysis suggested that co-administration of EZE/SIMVA+FENO had consistent benefits on the lipid profile in mixed hyperlipidemic patients with or without MetS.     

Lipoprotein composition changes induced by fenofibrate in dysbetalipoproteinemia type III

Fenofibrate (300 mg daily) was given to 9 subjects (7 men, 2 women) with dysbetalipoproteinemia type III. The treatment brought about important plasma level reductions in cholesterol (-35%), triglycerides (-56%), VLDL-cholesterol (-63%) and VLDL-triglycerides (-59%). The VLDL-C/TG ratio, which was 0.40 before treatment, was 0.30 after 4 weeks of fenofibrate, still suggestive of type III. LDL-C, when measured by conventional methods, was unchanged but isolation of the IDL (1.006-1.019 g/ml) fraction from the 1.006 g/ml infranatant revealed that true LDL-C levels actually increased in 6 individuals while IDL-C decreased considerably. The total HDL-C increase was mostly due to a 33% HDL3-C change. Apolipoprotein levels were considerably modified, notably apo B, C-III and E which were decreased, as well as the lipoprotein particles containing combinations of these apolipoproteins, namely LpE:B and LpC-III:B. Apo A-I was slightly modified as LpA-I: A-II particle levels increased and LpA-I decreased. There were marked compositional modifications of apo B-containing lipoproteins which corresponded to changes of the whole lipoprotein profile. Some abnormal classes of lipoproteins (e.g., beta-VLDL, dense LDL), characteristic of this disease, tended to disappear and were in some cases replaced by material of different size and density.     

Effects of unopposed conjugated equine estrogen on lipoprotein composition and apolipoprotein-E distribution.

Administration of conjugated equine estrogen to 31 postmenopausal women for 3 months produced 14.6% and 9.4% decreases in low density lipoprotein cholesterol (LDL-C) and apolipoprotein-B (apoB), and 11.5%, 12.7%, and 9.6% increases in high density lipoprotein cholesterol (HDL-C), apoA-I and apoA-II, respectively. Phospholipids of HDL2 and HDL3 were increased 57.9% and 19.3%, respectively, while relatively small increases in cholesterol of the two subfractions were not significant. Compositions of LDL and HDL and its subfractions were altered substantially with estrogen treatment. The proportion of LDL triglyceride to LDL-C was increased. The phospholipid content in both the HDL2 and HDL3 subfractions (compared to cholesterol) was increased significantly (34.8% and 10.7%, respectively), while the triglyceride content was increased only in the HDL2 subfraction (43.6%). Estrogen use also caused a 9.1% reduction in total apoE levels and a redistribution of apoE to the very low density lipoprotein (VLDL) from the LDL plus HDL fraction, resulting in a significant 19.5% decrease in apoE in the LDL plus HDL fraction. Changes in apoE in the VLDL fraction were associated positively with changes in the cholesterol levels of the VLDL fraction and inversely with changes in LDL-C and apoB levels, while changes in apoE in the LDL plus HDL fraction were associated positively with changes in the levels of HDL-C. Thus, estrogen causes alterations in lipoproteins that could potentially affect their metabolism and/or function.     

The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia

We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs. +26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P>0.05). Cu(2+)-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.     

Effects of atorvastatin on oxidized low-density lipoprotein, low-density lipoprotein subfraction distribution, and remnant lipoprotein in patients with mixed hyperlipoproteinemia

Atorvastatin (10 to 20 mg/day) was administered for 3 months to 15 outpatients (average age 58 +/- 4 years) with hypercholesterolemia accompanied by hypertriglyceridemia without hypolipemic treatment. Changes in lipid profile, particularly oxidized low-density lipoprotein (LDL) (malondialdehyde LDL), subfractions of LDL, and remnant lipoprotein (RLP) cholesterol, were examined before and after administration. In addition, the influence of atorvastatin on lipoprotein(a) (known to be an independent risk factor for atherosclerosis), asymmetric dimethylarginine (known to be an endogenous inhibitor of nitric oxide synthase), and homocysteine (methionine metabolite) was also investigated. Administration of atorvastatin significantly decreased serum total cholesterol, LDL cholesterol, and triglycerides. Conversely, a significant increase in high-density lipoprotein cholesterol was shown. In LDL subfractions, large, buoyant LDL fractions were not influenced by treatment with atorvastatin (before administration, 99 +/- 14 mg/dl; after administration, 91 +/- 6 mg/dl, shown as a cholesterol content in each subfraction), but a marked decrease in small, dense LDL fractions (p <0.001) (before administration, 119 +/- 17 mg/dl; after administration, 43 +/- 10 mg/dl) was shown. Moreover, oxidized LDL was significantly decreased (p < 0.01) (before administration, 169 +/- 13 U/L; after administration, 119 +/- 10 U/L) and RLP cholesterol also was significantly decreased (p <0.01) (before administration, 11.9 +/- 2.0 mg/dl; after administration, 6.0 +/- 0.9 mg/dl) with atorvastatin treatment. No significant change was observed in fasting plasma glucose, hemoglobin A1c, lipoprotein(a), asymmetric dimethylarginine, homocysteine, and so on. These data suggest that administration of relatively low doses of atorvastatin to patients with hypercholesterolemia accompanied with hypertriglyceridemia results in a decrease not only in LDL cholesterol and triglycerides, but also in oxidized LDL and RLP cholesterol, with an increase in high-density lipoprotein cholesterol. Furthermore, small, dense LDL decreased with a shift in LDL subfractions to large, buoyant fractions, and these changes are considered to be involved in the inhibition of the onset and progression of atherosclerosis.     

The role of pioglitazone in modifying the atherogenic lipoprotein profile

Pioglitazone, a thiazolidinedione, has established efficacy in improving glycaemic control in patients with type 2 diabetes. Pioglitazone also improves components of the mixed dyslipidaemia profile common in these patients, as typified by raised levels of plasma triglycerides, low levels of HDL cholesterol (HDL-C) and a raised proportion of LDL cholesterol (LDL-C) occurring as the small dense subfraction. In head-to-head trials, pioglitazone has consistently shown superior benefits on LDL-C and HDL-C as well as triglycerides compared with rosiglitazone and sulphonylureas. Pioglitazone used as monotherapy or combination therapy reduces levels of small dense LDL₃ particles while raising levels of larger and less atherogenic LDL fractions. In addition, pioglitazone reduces cholesterol load and particle numbers of LDL₃. Importantly, the differential effects of pioglitazone on LDL subfractions are complimentary and additive to those of simvastatin. Pioglitazone increases total HDL-C levels by 10–20%, mainly because of an increase in the larger HDL₂ subfraction. Pioglitazone also significantly reduces plasma triglyceride levels by 10–25%. In recent studies, pioglitazone significantly reduced carotid and coronary atherosclerosis compared with the sulphonylurea glimepiride. The antidyslipidaemic effects of pioglitazone – in particular, improvements in HDL-C and reduction of small dense LDL₃– may have contributed to these effects.     

Effects of omega-3 fatty acid supplementation and exercise on low-density lipoprotein and high-density lipoprotein subfractions

The purpose of this study was to examine the effect of combining exercise with omega-3 fatty acids (n-3fa) supplementation on lipoprotein subfractions and associated enzymes. Subjects were 10 recreationally active males, aged 25 +/- 1.5 years (mean +/- SE), who supplemented n-3fa (60% eicosapentaenoic acid [EPA] and 40% docosahexaenoic [DHA]) at 4 g/d for 4 weeks. Before and after supplementation, subjects completed a 60-minute session of treadmill exercise at 60% Vo(2)max. Following a 24-hour diet and activity control period, blood was collected immediately before and after the exercise session to assess lipid variables: high-density lipoprotein cholesterol (HDL-C) and subfractions, low-density lipoprotein cholesterol (LDL-C) and subfractions and particle size, lecithin:cholesterol acyltransferase (LCAT) activity, and cholesterol ester transfer protein (CETP) activity. Supplementation with n-3fa alone increased total HDL-C and HDL(2)-C, while exercise alone increased total HDL-C, HDL(3)-C, and total LDL-C. LDL subfractions, particle size, and LCAT and CETP activities were not affected by supplementation. Combination treatment resulted in an additive effect for HDL(3)-C only and also increased LDL(1)-C versus baseline. LCAT and CETP activities were not affected by treatments. These results suggest that n-3fa supplementation or an exercise session each affect total HDL-C and subfractions but not LDL-C or subfractions. In addition, the combination of n-3fa and exercise may have additional effects on total HDL-C and LDL-C subfractions as compared to either treatment alone in active young men.     

Reduction of charge-modified LDL by statin therapy in patients with CHD or CHD risk factors and elevated LDL-C levels: the SPECIAL Study

Various forms of atherogenic modified low-density lipoprotein (LDL) including oxidized LDL and small, dense LDL have increased negative charge as compared to normal LDL. Charge-modified LDL (electronegative LDL) and normal LDL subfractions in plasma are analyzed by capillary isotachophoresis (cITP) as fast-migrating LDL (fLDL) and slow-migrating LDL (sLDL). We examined the effects of pravastatin and simvastatin on charge-based LDL subfractions as determined by cITP in patients with hypercholesterolemia. Patients (n=72) with CHD or CHD risk factors and elevated LDL cholesterol (LDL-C) levels were randomly assigned to receive pravastatin or simvastatin. After treatment with statins for 3 and 6 months, both cITP fLDL and sLDL were reduced (p<0.05) from the baseline, but the effects did not differ between treatment with pravastatin and simvastatin. At baseline and after treatment for 3 months, cITP sLDL was correlated with LDL-C, but fLDL was correlated with inflammatory markers, high-sensitive C-reactive protein and LDL-associated platelet-activating factor acetylhydrolase, and atherogenic lipoproteins, remnant-like particle cholesterol and small, dense LDL cholesterol. In conclusion, cITP fLDL was related to inflammatory markers and atherogenic lipoproteins and was reduced by treatment with statins. Charge-modified LDL subfraction could be a potential marker for atherosclerosis and a target for therapy.     

Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia

Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and often elevated low-density lipoprotein (LDL) cholesterol with predominance of small, dense LDL is a strong risk factor for atherosclerosis. It is unclear whether fibrate or statin therapy is more effective in these patients. We compared atorvastatin (10 mg/day) with fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men and 8 women; mean age 60.0+/-6.8 years; body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus (hemoglobin A1c 7.3+/-1.1%) and mixed hyperlipoproteinemia (LDL cholesterol 164.0+/-37.8 mg/dl, triglycerides 259.7+/-107 mg/dl, HDL cholesterol 48.7+/-11.0 mg/dl) using a randomized, crossover design. Lipid profiles, LDL subfraction distribution, fasting plasma viscosity, red cell aggregation, and fibrinogen concentrations were determined before and after each drug. Atorvastatin decreased all LDL subfractions (LDL cholesterol, -29%; p <0.01) including small, dense LDL. Fenofibrate predominantly decreased triglyceride concentrations (triglycerides, -39%; p <0.005) and induced a shift in LDL subtype distribution from small, dense LDL (-31%) to intermediate-dense LDL (+36%). The concentration of small, dense LDL was comparable during therapy to both drugs (atorvastatin 62.8+/-19.5 mg/dl, fenofibrate 63.0+/-18.1 mg/dl). Both drugs induced an increase in HDL cholesterol (atorvastatin +10%, p <0.05; fenofibrate +11%, p = 0.06). In addition, fenofibrate decreased fibrinogen concentration (-15%, p <0.01) associated with a decrease in plasma viscosity by 3% (p <0.01) and improved red cell aggregation by 15% (p <0.05), whereas atorvastatin did not affect any hemorheologic parameter. We conclude that atorvastatin and fenofibrate can improve lipoprotein metabolism in type 2 diabetes. However, the medications affect different aspects of lipoprotein metabolism.     

Influence of mild to moderately elevated triglycerides on low density lipoprotein subfraction concentration and composition in healthy men with low high density lipoprotein cholesterol levels

Epidemiologic studies have shown that a dyslipoproteinemia with low concentrations of high density lipoprotein (HDL) cholesterol and elevated serum triglycerides (TG) is associated with a particularly high incidence of coronary artery disease. This lipid profile is associated with increased concentrations of small, dense low density lipoprotein (LDL) particles. To evaluate the role of mild to moderately elevated TG on the LDL subfraction profile in patients with low HDL cholesterol, concentration and composition of six LDL subfractions was determined by density gradient ultracentrifugation in 41 healthy men (31+/-9 years, body mass index (BMI) 25.1+/-3.9 kg/m2) with equally low HDL cholesterol levels < 0.91 mmol/l but different TG levels: TG < 1.13 mmol/l, n = 16; TG = 1.13-2.26 mmol/l, n = 13: TG = 2.26-3.39 mmol/l, n = 12. Those men with moderately elevated TG levels between 2.26 and 3.39 mmol/l had significantly higher concentrations of very low density lipoprotein (VLDL), intermediate low density lipoprotein (IDL), and small, dense LDL apoB and cholesterol than men with TG < 1.13 mmol/l. With increasing serum TG, the TG content per particle also increased in VLDL, IDL as well as total LDL particles while the cholesterol and phospholipid (PL) content decreased in VLDL and IDL, but not in LDL particles. LDL subfraction analysis revealed that only large, more buoyant LDL particles (d < 1.044 g/ml) but not the smaller, more dense LDL, were enriched in TG. Small, dense LDL particles were depleted of free cholesterol (FC) and PL. This study has shown that in men with low HDL cholesterol levels mild to moderately elevated serum TG strongly suggest the presence of other metabolic cardiovascular risk factors and in particular of a more atherogenic LDL subfraction profile of increased concentration of small, dense LDL particles that are depleted in surface lipids.     

Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia.

OBJECTIVES: This study sought to determine the long-term safety and efficacy of co-administered fenofibrate (FENO) and ezetimibe (EZE) in patients with mixed hyperlipidemia. BACKGROUND: Both EZE and FENO offer complementary benefits to the lipid profile of patients with mixed hyperlipidemia. METHODS: After completing the 12-week randomized, double-blind base study that compared EZE 10 mg, FENO 160 mg, FENO 160 mg plus EZE 10 mg, and placebo in patients with mixed hyperlipidemia, patients continued into a double-blind, 48-week extension phase. Those patients in the FENO plus EZE and FENO groups continued on their respective base study treatment, and patients in the EZE and placebo groups were switched to FENO plus EZE and FENO, respectively. RESULTS: Of the 587 patients who completed the base study, 576 continued into the extension study (n = 340 in FENO plus EZE and n = 236 in FENO). The FENO plus EZE produced significantly greater reductions in low-density lipoprotein-cholesterol compared with FENO (-22% vs. -9%, respectively; p < 0.001). There were also significantly greater improvements in triglycerides, high-density lipoprotein cholesterol (HDL-C), total cholesterol, non-HDL-C, and apolipoprotein B with FENO plus EZE compared with FENO. Changes in apolipoprotein A-I and high-sensitivity C-reactive protein were similar between groups. Overall, FENO plus EZE was well tolerated during the extension study. The proportion of patients with consecutive elevations of alanine aminotransferase/aspartate aminotransferase > or =3 times upper limit of normal were similar between the FENO plus EZE (1.2%) and FENO (1.7%) groups. No cases of creatine phosphokinase elevations > or =10 times upper limit of normal or myopathy were observed in either group. CONCLUSIONS: Long-term, 48-week co-administration of FENO plus EZE was well tolerated and more efficacious than FENO in patients with mixed hyperlipidemia.     

Alcohol dose and low density lipoprotein heterogeneity in squirrel monkeys (Saimiri sciureus).

The present study was designed to determine whether normolipidemic male squirrel monkeys (Saimiri sciureus) exhibit low density lipoprotein (LDL) heterogeneity similar to that observed in humans and if present, whether LDL subfractions are altered by consumption of low vs. high dose ethanol (EtOH). Primates were divided into three groups designated control, low, and high EtOH and fed isocaloric liquid diets containing 0%, 12% and 24% of calories as EtOH, respectively, for 6 months. The 12% EtOH caloric level resulted in a modest, non-significant increase in high density lipoprotein (HDL) cholesterol and no change in LDL cholesterol or plasma apolipoprotein B (apo B), while the 24% dose produced significant elevations in plasma, LDL and HDL cholesterol and apo B. Using a single-spin density gradient ultracentrifugation procedure developed for humans, three distinct LDL subclasses designated LDL1a (d = 1.031 g/ml), LDL1b (d = 1.038 g/ml) and LDL 2 (d = 1.046 g/ml) were isolated from all three treatment groups. Monkey LDL subfractions were nearly identical to very light, light and heavy LDL subspecies isolated from human plasma in terms of their: (1) isopycnic densities following ultracentrifugation; (2) co-migration as single bands with beta-electrophoretic mobility in cellulose acetate and agarose electrophoretic gels; (3) size-dependent migration pattern in polyacrylamide gradient electrophoretic gels; (4) co-migration as a single band corresponding to apo B-100, following SDS polyacrylamide gel electrophoresis; and (5) decrease in total cholesterol/protein ratios with increasing LDL subclass density. Although there were no treatment differences in LDL particle size, within each treatment group, mean particle size for each LDL subfraction was significantly different from every other subfraction. Low (12%) dose alcohol had no effect on LDL subfraction mass relative to controls while high alcohol consumption resulted in marked increases in all lipid (except triglyceride) and protein of the larger, buoyant LDL subspecies (LDL1a and LDL1b). Moreover, the best correlation between plasma apo B and LDL subfraction total mass was demonstrated with LDL1b (r = 0.735). Since neither the lipid nor the protein concentration of the small, dense, purportedly more atherogenic, LDL2 changed with the 24% EtOH dose, we propose that the LDL subfraction alterations associated with high alcohol intake in squirrel monkeys (increased LDL1a, increased LDL1b, LDL2 no effect) may represent a compensatory response to modulate the overall atherogenic lipoprotein profile associated with elevations in total LDL cholesterol and plasma apolipoprotein B.     

Low-density lipoprotein cholesterol: association with mortality and hospitalization in hemodialysis patients

BACKGROUND/AIMS: Hypocholesterolemia is a common finding in hospitalized elderly people, critically ill surgical patients, septic patients and end-stage renal disease patients. The different effect of lipid subfractions on patients with end-stage renal disease has never been demonstrated. We aim to study the effect of lipid subfractions on hospitalization and mortality in maintenance hemodialysis (MHD) patients. METHODS: Lipid subfractions, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured in 210 patients with MHD in a single dialysis center. Patients were stratified into three groups based on the tertiles of lipid levels, and differences in patient characteristics and survival were evaluated. RESULTS: Of a total of 22 deceased patients in our MHD cohort, infection-related mortality (50%) was higher than cardiovascular-related mortality (18.2%). Significant differences (p < 0.05) in the duration and frequency of hospitalization and in mortality events were observed when patients were divided into different subgroups according to the tertiles of baseline TC and LDL-C levels. Patients with lower LDL had significantly lower levels of albumin, TC and TG. The LDL-C tertiles were similar in terms of age, hypertension, diabetes, biochemical results, hematocrit, adequacy of hemodialysis and normalized protein catabolism rate. Both TC and LDL-C predicted survival (p < 0.001), but not TG and HDL-C in the Kaplan-Meier model. The Cox proportional hazard model demonstrated that baseline serum LDL-C was the best lipid subfraction in predicting all-cause death with an adjusted hazard ratio (95% confidence interval) for each 10 mg/dl of 0.752 (0.631-0.898; p = 0.002). CONCLUSIONS: We firstly demonstrated that lipid subfractions, including TC and LDL-C, predict poor outcomes in a MHD cohort with high infection-related mortality.     

Effect of levothyroxine on total lipid profiles as assessed by analytical capillary isotachophoresis in a patient with hypothyroidism

The patient was a 51-year-old Japanese female who had been diagnosed with hyperlipidemia. At the first medical examination, her serum levels of total cholesterol (TC) and triglyceride (TG) were 482 and 205 mg/dl, respectively. Since hyperlipidemia was not improved by pravastatin, atorvastatin or niceritrol, and since the levels of thyroid-stimulating hormone (TSH) and free T4 were 730 IU/ml and 0.3 ng/dl, respectively, the patient was diagnosed as secondary hyperlipidemia with hypothyroidism. A method for the charge isolation of lipoproteins using capillary isotachophoresis (cITP) is proposed as a clinical application because it allows us to quantitatively measure electronegative low-density lipoprotein cholesterol (LDL-C), a potent marker of coronary heart disease. After 5 months of treatment with levothyroxine, Serum TC and LDL-C levels drastically decreased without statin treatment and high-density lipoprotein cholesterol (HDL-C) increased. In the lipoprotein profiles as assessed by cITP after treatment with levothyroxin, all HDL-C subfractions were increased and fast-migrating LDL/electronegative LDL appeared to be greatly reduced after treatment, while the area under the non-modified LDL peak was increased. The cITP analysis was able to obtain more information about coronary risk factors and may be clinically useful for evaluating the effect of treatment with levothyroxine in patients with hypothyroidism and secondary hyperlipidemia.     

Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size.

Oxidative modification of low density lipoproteins (LDL) has been implicated in the sequence of events leading to fatty streak formation in the arterial intima. Increased oxidative modifications of dense versus buoyant LDL particles could contribute to increased atherosclerosis associated with lipoprotein profiles enriched in small, dense LDL. In the present studies, we compared rates of copper-induced oxidative changes for six LDL subfractions ranging in density from 1.023 to 1.053 g/ml and mean particle diameter from 282 +/- 10 to 245 +/- 3. Rates of formation of thiobarbituric acid-reactive substances (TBARS), as indicated by the time required for half-maximal TBARS formation (T1/2max), decreased with increasing density and decreasing particle diameter to a minimum in fraction 5 (d = 1.046 g/ml, diameter = 250 +/- 5) (P = 0.007). In parallel studies using unfractionated LDL (d = 1.019-1.063 g/ml), T1/2max values were inversely correlated with the predominant LDL species diameter as determined by 2-16% gradient gel electrophoresis (P less than 0.05), consistent with the involvement of subclass composition in determining oxidative behavior. In separate experiments, subfraction differences in oxidation rates as assessed by TBARS formation were verified by the finding of similarly dispartate changes in fluorescence intensity and anionic electrophoretic mobility. T1/2max values were not related to LDL contents of alpha-tocopherol, beta-carotene, protein, triglycerides or phospholipids, but were significantly correlated with unesterified cholesterol content (r = 0.46; P less than 0.001) and were inversely associated with cholesteryl ester content (r = 0.28; P less than 0.05). The positive association of T1/2max with unesterified cholesterol suggests that this constituent may impart resistance to oxidative modification, possibly by altering properties of the surface monolayer where it resides.     

Effect of fluvastatin slow-release on low density lipoprotein (LDL) subfractions in patients with type 2 diabetes mellitus: baseline LDL profile determines specific mode of action

The objective of this study was to determine the effect of slow-release (XL) fluvastatin on low density lipoprotein (LDL) subfractions in type 2 diabetes. A multicenter, double-blind, randomized, parallel-group comparison of fluvastatin XL 80 mg (n = 42) and placebo (n = 47), each given once-daily for 8 wk, in 89 patients with type 2 diabetes (HbA1c: 7.2 +/- 1.0%, LDL cholesterol (LDL-C): 3.4 +/- 0.7 mmol/liter, high density lipoprotein cholesterol: 1.1 +/- 0.3 mmol/liter, and triglycerides (TG): 2.4 +/- 1.4 mmol/liter). At baseline and on treatment, plasma lipoproteins were isolated and quantified. Eight weeks of fluvastatin treatment decreased total cholesterol (-23.0%, P < 0.001), LDL-C (-29%, P < 0.001) and TG (-18%, P < 0.001), compared with placebo. At baseline, there was a preponderance of dense LDL (dLDL) (apolipoprotein B in LDL-5 plus LDL-6 > 25 mg/dl) in 79% of patients, among whom fluvastatin decreased all LDL subfractions, reductions in dLDL being greatest (-28%, P = 0.001; cholesterol in dLDL -29%). In patients with low baseline dLDL (apolipoprotein B in LDL-5 plus LDL-6 相似文献   

Utility of non-high-density lipoprotein cholesterol in hemodialyzed patients

Non-high-density lipoprotein-cholesterol (HDL-C) is proposed as a strong predictor of cardiovascular disease (CVD). Measuring non-HDL-C, as total cholesterol minus HDL-C, is convenient for routine practice because, among other advantages, fasting is not required. There are limited data of non-HDL-C in end-stage renal disease patients. We applied non-HDL-C calculation to 50 chronic renal patients receiving maintenance hemodialysis (HD) and 20 healthy subjects, apart from measurement of low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) HDL, intermediate-density lipoprotein-cholesterol (IDL-C), apoprotein (apo) B, and triglycerides. HD patients presented higher plasma triglycerides and IDL-C and lower HDL-C than the control group, even after adjustment for age (P < .05). VLDL-C increased in HD patients (P < .001) while differences in non-HDL-C did not reach significance (P = .08). To detect which parameter constitutes a better marker of CVD risk among HD patients, a receiver-operating characteristic (ROC) analysis was performed considering HD patients in the highest risk group for CVD. In the ROC graphic, the plots of VLDL and IDL-C exhibited the greater observed accuracy and the best performance, while non-HDL-C showed a curve close to the 45 degrees line indicating that this parameter is a poor discriminator for evaluating CVD risk among HD patients. Non-HDL-C calculation, expressing all apo B-containing lipoproteins, may miss the significant contribution of each atherogenic lipoprotein, such as increase in IDL. This observation would not be in agreement with the currently proposed application of non-HDL-C a useful tool for risk assessment among HD patients.     

Regional adiposity patterns in relation to lipids, lipoprotein cholesterol, and lipoprotein subfraction mass in men

Anatomical adipose tissue distribution patterns are reported to relate to plasma lipids and risk of cardiovascular disease. Waist to hip girth ratios (WHR) and subscapular 10 triceps skinfold thickness ratios (STR) were compared with percent body fat and body mass index values as correlates of plasma lipids and lipoprotein cholesterol and serum lipoprotein subfraction mass by analytic ultracentrifugation in 81 sedentary middle-aged men in a typical range of adiposity. WHR was significantly and positively correlated with plasma concentrations of triglycerides, cholesterol, and low and very low density lipoprotein (LDL and VLDL) cholesterol and inversely correlated with high density lipoprotein (HDL) cholesterol. STR followed these trends, though less strongly, in relation to plasma triglycerides, VLDL cholesterol, and HDL cholesterol. Pronounced differences were found between regional adiposity patterns in their relationships to lipoprotein subfractions, as determined by analytic ultracentrifugation. WHR was negatively correlated with HDL2 (flotation rate F(1.2) 3.5-9), positively with small LDL (S.f 0-7), intermediate density lipoprotein (S.f 12-20), and VLDL (S.f 20-400), while STR correlated with larger LDL (S.f 7-12) and larger VLDL (S.f 60-400). Overall adiposity was not significantly associated with plasma lipoprotein levels after adjusting for regional adiposity patterns. Plasma sex hormone-binding globulin and percent free testosterone were associated with regional adiposity, but did not account for the correlations between WHR and lipoproteins. WHR and STR are measures of fat distribution that correlate with plasma lipoprotein profiles consistent with cardiovascular disease risk and have different relationships to lipoprotein mass subfractions.     

Association of hypertension with small, dense low-density lipoprotein in patients without metabolic syndrome

A higher proportion of small, dense low-density lipoprotein (sdLDL) is known to be associated with a high prevalence of cardiovascular disease in association with metabolic syndrome (MS). Hypertension (HTN) is one of the known risk factors for MS. However, whether HTN is associated with sdLDL in patients without MS is not yet clear. The lipid profiles, including low-density-lipoprotein (LDL) subfractions, of 383 consecutive subjects were evaluated. The patients without MS consisted of 198 hypertensive patients (non-MS/HTN group) and 108 normotensive subjects (non-MS/non-HTN group). The peak and mean particle diameter of LDL were measured by gradient gel electrophoresis. Plasma total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride (TG), HDL cholesterol/Apo A1, LDL-C/ApoB and Apo(A1, B, CII and E) levels did not differ between the non-MS/non-HTN and non-MS/HTN groups. When analyzing LDL subfraction, the absolute amount of patterns A and B was not different between the non-MS/non-HTN and non-MS/HTN groups. Compared with the non-MS/non-HTN groups, the proportion of sdLDL was higher in the non-MS/HTN group (37.7% versus 39.9%, P=0.046), but not significant after adjustment of waist circumference, serum TG, age and statin usage. The proportion of sdLDL to total LDL was higher in hypertensive subjects, even those without MS, than in normotensive subjects. However, this difference of LDL subfraction in hypertensive patients is associated with higher waist circumference, higher serum TG, older age and more statin usage. This result suggests that HTN may contribute to atherosclerosis and endothelial dysfunction with associated risk factors that influence LDL size.