doi: 10.1161/hq1201.100259
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Effect of Statin Therapy on Remnant Lipoprotein Cholesterol Levels in Patients With Combined Hyperlipidemia
From the Albert Einstein College of Medicine (D.T.S.), Bronx, NY, and the University of Texas Southwestern Medical Center (S.D., D.B., B.A.-H., I.J.), Dallas, Tex.
Correspondence to Ishwarlal Jialal, MD, PhD, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, CS3.114, Dallas, TX 75390-9073. E-mail jialal.i{at}pathology.swmed.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Clinical trials with statins have demonstrated significant reductions in cardiovascular events. Remnant lipoproteins are independent predictors of cardiovascular events. Because of the paucity of data on the effect of statins on remnant lipoproteins, we tested the effect of pravastatin, simvastatin, and atorvastatin on remnant lipoprotein cholesterol (RLP-C) levels in a randomized crossover study in patients with combined hyperlipidemia. After a 6-week diet phase, patients (n=22) were randomized to pravastatin (40 mg/d), simvastatin (20 mg/d), or atorvastatin (10 mg/d) for 6 weeks, with a 3-week washout between each drug. All 3 drugs significantly decreased total and low density lipoprotein (LDL) cholesterol (P<0.001). Mean reduction in LDL cholesterol with pravastatin, simvastatin, and atorvastatin was 21%, 29%, and 32%, respectively. None of the drugs affected high density lipoprotein cholesterol levels. Median levels of triglycerides were significantly reduced with simvastatin (26%, P=0.001) and atorvastatin (24%, P=0.0001) but not with pravastatin (9%, P=0.18). Non–high density lipoprotein cholesterol decreased significantly with all 3 statins (20%, 29%, and 32% with pravastatin, simvastatin, and atorvastatin, respectively; P<0.001). Median RLP-C levels were significantly reduced with simvastatin (6%, P<0.05) and atorvastatin (25.9%, P<0.001) but not with pravastatin (2.9%, P=0.58). Thus, atorvastatin and simvastatin, in addition to reducing LDL cholesterol and triglyceride levels, significantly reduced RLP-C levels. This could be another potential mechanism to explain their cardiovascular benefits.
Key Words: statins • non-HDL cholesterol • remnants
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Classic concepts of the pathogenesis of coronary artery disease (CAD) have implicated elevated cholesterol, particularly LDL cholesterol (LDL-C), as the central atherogenic lipoprotein. Recently reported large cholesterol-lowering trials using the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have unequivocally established their benefit in reducing cardiovascular events and coronary and total mortality in certain studies.1–6 Although the benefit of statin therapy has generally been ascribed to reduction in LDL-C, other atherogenic classes of lipoproteins may be beneficially affected by statin therapy. This is particularly pertinent because the majority of patients with CAD have only mildly elevated cholesterol levels and frequently have other lipoprotein abnormalities, including hypertriglyceridemia and decreased levels of HDL cholesterol (HDL-C).
Accumulating data suggest that apoB-containing lipoproteins other than LDL, particularly in the setting of mild to moderate hypertriglyceridemia, confer additional atherogenic risk beyond that due to LDL-C levels alone.7 Triglyceride-rich remnant lipoproteins (RLPs) are formed in the circulation when apoB-48, containing chylomicrons of intestinal origin, or apoB-100, containing VLDL of hepatic origin, are converted by lipoprotein lipase (and to a lesser extent by hepatic lipase) into smaller and more dense particles. Compared with their nascent precursors, the remnants are depleted of triglycerides, phospholipids, and apoCs and are enriched in cholesteryl esters and apoE and are believed to be more atherogenic than the larger triglyceride-rich lipoproteins (TRLs).8–12
Several lines of evidence have implicated RLPs as playing an etiologic role in atherosclerosis.13 Increased IDL levels have been associated with an increased incidence or recurrence of CAD.14 Increased IDL levels are also found in diseases associated with premature or accelerated atherosclerosis, such as type III hyperlipidemia, type 2 diabetes mellitus, chronic renal failure, and familial combined hyperlipidemia.15 In fact, the recent ATP III panel identifies non–HDL-C as a secondary target of therapy in persons with high triglycerides (>200 mg/dL), because this is a readily available measure of atherogenic RLPs.16 Accurate quantification of plasma remnants is difficult because (1) they are difficult to differentiate from their triglyceride-rich precursors, (2) as a result of rapid catabolism, they are present in plasma at low concentrations, and (3) being at various stages of catabolism, they are heterogeneous in size, density, and composition.8
Measurement of remnant particles, particularly IDL, is not routinely performed because of the necessity for specialized testing, such as ultracentrifugation or capillary isotachophoresis. Recently, an immunoaffinity chromatography method was introduced for assaying levels of RLPs according to their apolipoprotein content and immunospecificity.8,17 In this assay, RLPs are separated from plasma by immunoaffinity chromatography with a gel containing an anti–apoA-1 and a specific apoB-100 monoclonal antibody (JI-H). The former antibody recognizes all HDL and any newly synthesized chylomicrons containing apoA-1, whereas the latter antibody recognizes all apoB-100–containing lipoproteins, except for certain particles enriched in apoE. HDLs, LDLs, large chylomicrons, and most VLDLs are thus retained by the gel. The unbound RLPs are made up of remnant-like VLDLs containing apoB-100 and TRLs containing apoB-48. By use of this assay, plasma concentrations of RLP cholesterol (RLP-C) have been shown to be higher in patients with CAD, in diabetic patients, in fed patients versus fasted patients, in hemodialysis patients, in patients with coronary artery restenosis after angioplasty, and in patients experiencing sudden cardiac death. Increased RLP-Cs are a significant predictor of myocardial infarction in patients with vasospastic angina and have recently been shown to be strongly associated with angiographically verified progression of focal coronary atherosclerosis.18–25 The atherogenicity of RLP is supported by the observations that RLP can promote lipid accumulation by mouse peritoneal macrophages, stimulate whole-blood platelet aggregation, and impair endothelium-dependent vasorelaxation.8 Thus, this assay is a valid measure of RLPs that are proatherogenic.
Current concepts of lipoprotein metabolism suggest that remnant particles are taken up by a receptor-mediated process in the liver.26 Furthermore, the LDL receptor is upregulated by inhibition of HMG-CoA reductase and leads to the potent LDL-lowering effect associated with statins. However, there is a paucity of data comparing the effect of statins on RLP. Thus, we tested the effect of 3 widely used statins (pravastatin, simvastatin, and atorvastatin) on RLP-C levels at doses resulting in similar reductions in LDL-C.27
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients
Patients were recruited from the Lipid Clinics at the University of Texas Southwestern Medical Center, Dallas, without restriction to sex or socioeconomic status. The protocol was approved by the Institutional Review Board, and all patients gave informed consent. Inclusion criteria included the following: age 18 to 70 years, plasma triglyceride level between 160 and 600 mg/dL, and LDL-C level
130 mg/dL. Exclusion criteria were as follows: use of lipid-lowering drugs or drugs known to affect lipid metabolism within 6 weeks of the study start, antioxidant supplements, warfarin/heparin for the past 4 weeks, liver or renal dysfunction, diabetes, hypothyroidism, infection, cancer, and recent major surgery or illness.
Study Design
This was a randomized double-blind triple-crossover study. A total of 22 patients were enrolled. There was a 6-week lead-in dietary phase when the patients were instructed by the dietitian to follow an American Heart Association step-1 diet for the study duration, followed by a 6-week drug-therapy phase with a 3-week washout period between drugs. The statins used included pravastatin (40 mg/d), simvastatin (20 mg/d), and atorvastatin (10 mg/d).26
Laboratory Methods
Three fasting blood samples were obtained at baseline 5 days apart, and 2 fasting blood samples were obtained during each drug phase (weeks 5.5 and 6) and at the end of each washout phase (weeks 8.5 and 9). Levels of total cholesterol, total triglycerides, LDL-C, and HDL-C were assayed by routine laboratory techniques with the use of methodology of the Lipid Research Clinics, as reported previously.28 If plasma triglycerides were 400 mg/dL, LDL-C was assessed by a direct method.29 Only 3 of the 22 patients studied had baseline triglyceride levels 400 mg/dL. ApoB was quantified by using immunonephelometry. The assay is standardized to the World Health Organization reference material.
RLP-C Assay
In this assay, RLPs are separated from plasma by immunoaffinity chromatography with a gel containing an anti–apoA-1 and a specific apoB-100 monoclonal antibody (JI-H). The former antibody recognizes all HDLs and any newly synthesized chylomicrons containing apoA-1, whereas the latter antibody recognizes all apoB-100–containing lipoproteins, except for certain particles enriched in apoE. HDLs, LDLs, large chylomicrons, and most VLDLs are thus retained by the gel. The unbound RLPs are made up of remnant-like VLDLs containing apoB-100 and TRLs containing apoB-48. These RLPs are quantified by measuring cholesterol enzymatically in the unbound fraction.8,17
For the RLP-C assay, 300 µL of the immunoaffinity gel containing antibodies to apoA-1 and apoB-100 was pipetted into separation cups containing steel balls and placed in a magnetic mixer manufactured by Otsuka Electronics. After the gel was allowed to settle for 5 minutes, 5 µL of blank (buffer), control, or plasma was pipetted onto the surface of the gel and incubated with continuous mixing for 2 hours at room temperature. After incubation, the gel was allowed to settle for 15 minutes, and 200 µL of the supernatant was placed into sample cups. Cholesterol levels were then measured by using a peroxidase-based assay on the Cobas Mira S autoanalyzer (Roche Diagnostic Systems). The intra-assay and interassay coefficients of variation (<5%) have been previously reported.18 This laboratory also participated in the quality control and assay standardization program in the United States and was 1 of the 6 laboratories that reported RLP-C levels.
Statistical Analysis
All statistical analyses were performed by using SAS version 8.0. Treatment order for this crossover study was assessed by repeated-measures ANOVA models with the use of logarithmic transformations for skewed data. Because some variables were skewed (eg, triglycerides and RLP-C), nonparametric tests were used for these analyses. The 3 statin drugs were further compared with the Friedman test and the Wilcoxon signed rank test for pairwise comparisons: the means of the 3 baselines were compared with the mean of the 2 measurements obtained on therapy or during washout. Spearman correlation coefficients were computed to assess associations between variables of interest. The level of significance was set at P<0.05 (2-sided test).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The salient characteristics of the participants in the present study were as follows: age 47.2±9.7 years, male/female ratio 10/12, and body mass index 24.5±4.9 kg/m2.
As is evident in the Table, there was a significant reduction in total cholesterol and LDL-C with all 3 drugs (pravastatin, simvastatin, and atorvastatin). The mean reduction in total cholesterol with pravastatin, simvastatin, and atorvastatin was 16%, 24%, and 27%, respectively (P<0.001 compared with baseline). The mean reduction in LDL-C with pravastatin, simvastatin, and atorvastatin was 21%, 29%, and 32%, respectively (P<0.001 compared with baseline). Exclusion of the patients with triglyceride levels 400 mg/dL (n=3) did not change this finding (pravastatin 22%, simvastatin 32%, and atorvastatin 34%, respectively). The percent reduction in total cholesterol and LDL-C with simvastatin and atorvastatin was significantly greater than that with pravastatin (P<0.005). There was a significant reduction in median triglyceride levels with simvastatin (26.3%, P<0.001) and atorvastatin (24.2%, P<0.0001), Pravastatin resulted in a nonsignificant (9.3%) reduction in triglyceride levels (P=0.18). The percent reduction in triglycerides with atorvastatin and pravastatin was significantly different (P<0.01). There were no significant differences in percent reduction in cholesterol, LDL-C, and triglycerides between atorvastatin and simvastatin. None of the drugs had a significant effect on HDL-C levels in these patients, with mean baseline levels of 45±13 mg/dL. According to the new National Cholesterol Education Program (NCEP) guidelines,16 the secondary goal in patients with triglyceride levels 200 mg/dL is non–HDL-C. This was also calculated, and the data are shown in Figure 1. Non–HDL-C changes closely mirrored changes in total cholesterol and LDL-C, decreasing significantly by 20.2%, 29.3%, and 31.6% in the pravastatin, simvastatin, and atorvastatin groups (P<0.0001). The reductions in non–HDL-C were not significantly different with the 3 drugs. During the washout periods, lipid and lipoprotein values predictably returned to baseline. Washout periods were not significantly different from each other and, thus, were combined for all parameters. Combined washout data reflected values very similar to the baseline lipid concentrations (Table). Also, in a subset of patients (n=13) in whom there was remaining plasma, apoB levels were measured. There was a significant reduction in apoB levels with all 3 drugs (28%, 37%, and 37%, respectively, with pravastatin, simvastatin, and atorvastatin; P<0.001). No significant differences were seen between the 3 drugs in percent apoB reduction.
|
|
Baseline RLP cholesterol values were 13.1±6.8 mg/dL, which was greater than the 90th percentile for men and women in the 5th decade according to recently published population data from the Framingham cohort30; the assay was the same assay used in the present study. Statin treatment resulted in variable decreases in RLP-C. Pravastatin therapy did not result in any significant reduction in RLP-C (2.9% reduction, P=0.58 compared with baseline). However, simvastatin and atorvastatin resulted in a significant reduction in median RLP-C levels (for simvastatin, 6.0%, P=0.03; for atorvastatin, 25.9%, P<0.0001) compared with baseline. The reduction of RLP-C with atorvastatin was significantly greater than that with pravastatin (P<0.004) and approached significance (P=0.055) compared with that with simvastatin (Figure 2).
|
Changes in RLP-C were significantly correlated with decreases in several plasma lipid fractions, including triglycerides (r=0.67, P=0.0006), non–HDL-C (r=0.54, P=0.01), and total cholesterol (r=0.49, P=0.02). There was no significant correlation with LDL-C (r=0.20, P=0.37) or HDL-C (r=0.07, P=0.76). The correlation with calculated VLDL cholesterol was not significant (r=0.35, P=0.12). Because we have previously shown in these patients that all 3 statins reduce C-reactive protein levels significantly,31 we also correlated the change in RLP-C with the change in CRP levels. The correlation was not significant (r=0.12, P=0.6).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The efficacy of statin therapy on LDL-C lowering and reduction of cardiovascular events is well established.1–6 However, the effect on other atherogenic lipoprotein classes has not been well studied. Increasing evidence points to a significant role for TRLs in atherogenesis.8–14 RLPs are products of lipolytic degradation of TRL produced by the liver (VLDL) and intestine (chylomicrons). TRLs are heterogeneous and, therefore, difficult to isolate by use of a single biochemical technique.8 Recently, a novel method to measure RLPs based on the immunochemical properties of these lipoproteins has become available. This assay has been shown to be a valid measure of atherogenic TRLs.18–25 It appears that this RLP-C assay quantifies cholesterol contents of mainly chylomicron remnants as well as a subpopulation of apoE-enriched TRLs.8,17 There have been limited studies to date examining the effect of lipid-lowering therapy on RLP-C. The present study is the first study to compare the effects of HMG-CoA reductase inhibitors at equipotent LDL-lowering doses on RLP-C concentrations in patients with combined hyperlipidemia by use of a crossover design. With 22 subjects, the present study has the power of 0.76 at the 0.05 significance level to detect a 15% difference in remnant particle levels between treatments, conservatively assuming a standard deviation of the differences of 25%.
In the present study, all 3 drugs (pravastatin, simvastatin, and atorvastatin) significantly decreased LDL-C. However, only atorvastatin and simvastatin reduced the levels of RLP-C significantly. Pravastatin, although used at a maximum dose (40 mg/d), failed to reduce RLP-C significantly. According to the comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study),27 in patients with primary hypercholesterolemia, the chosen doses of pravastatin, simvastatin, and atorvastatin decreased LDL by an expected 34%, 35%, and 38%, respectively, and there were no significant differences in LDL-lowering with the 3 drugs at these doses. In the present study, in patients with combined hyperlipidemia, the 3 statins decreased LDL-C slightly less than in the CURVES study (24%, 30%, and 32% for pravastatin, simvastatin, and atorvastatin, respectively). With regard to triglyceride levels, there was a significant reduction in triglycerides with simvastatin and atorvastatin but not with pravastatin therapy. Furthermore, the percent reduction in triglycerides with atorvastatin and pravastatin was significantly different (P<0.01). In the CURVES study, they also reported significant differences in percent reductions in triglyceride levels between atorvastatin (10 mg) therapy versus pravastatin (40 mg) therapy, as seen in the present study. However, most previous trials have been performed with subjects with isolated hypercholesterolemia. One previous study has reported the effect of pravastatin (40 mg/d) in subjects with mixed hyperlipidemia (n=13 middle-aged men), as was performed in the present trial, and they also observed only a 20% reduction in LDL and a nonsignificant (4%) reduction in triglycerides.32 In the large clinical trials with pravastatin,1,3,4 a significant reduction in triglycerides ranging from 11% to 14% compared with placebo was seen; thus, it is possible that the present study did not have a sufficient sample size to confirm this effect. However, it should be pointed out that patients in the present study had higher triglyceride levels than did patients in the large clinical trials1,3,4 and that simvastatin and atorvastatin at lower doses resulted in a significant hypotriglyceridemic effect. Thus, the greater potency of atorvastatin and simvastatin with respect to triglyceride reduction may be more pronounced with a larger sample size. Also, the failure to see a significant effect on HDL-C could be due to the small sample size and the relatively high baseline HDL-C (45±13 mg/dL) compared with the larger trials (mean levels ranging from 36 to 44 mg/dL). This was also seen in the CURVES study, in which baseline HDL-C levels in patients receiving these doses of statins ranged from 49 to 51 mg/dL and in which no significant effect was seen on HDL-C levels.27
With regard to RLP-C levels, our population of patients with combined hyperlipidemia had elevated RLP-C, which exceeded the 90th percentile in North Americans from the Framingham Study cohort.30 Statin therapy has previously been shown to lower TRL in patients with hypercholesterolemia. Fluvastatin (20 mg/d for 6 weeks) has been shown to significantly decrease levels of IDL (43%, P<0.01) and apoE (22%, P<0.01) in patients with heterozygous familial hypercholesterolemia.33 Two other studies with pravastatin34,35 in subjects with moderate hypercholesterolemia have shown similar decreases in IDL (
45%). With regard to the effect of statin therapy on RLPs, by use of the RLP-C assay, it has recently been shown that high-dose simvastatin (80 mg/d for 3 months) in 7 patients with familial hypercholesterolemia significantly reduced fasting and postprandial remnant levels, as assessed by the new immunoassay.36 Although levels in the subjects were very high (42±19 mg/dL), there was a significant reduction (13±3 mg/dL) in RLP-C levels with high-dose simvastatin therapy. In the present study, statin therapy (simvastatin and atorvastatin but not pravastatin) produced a significant reduction in RLP-C. This could be explained by 2 factors: (1) baseline RLP-C levels being only double those seen in the normal population, and (2) the dose of statin used. It is possible that greater reductions will be observed with higher doses of statin therapy, and this remains to be established, inasmuch as higher doses result in greater reduction in LDL-C and triglycerides.37,38 Recently, Karpe et al39 have shown in the Lipid Coronary Angiography Trial (LOCAT) that gemfibrozil reduced median RLP-C by 33%. In that trial, there was a very strong correlation between the reduction in RLP-C with reduction in VLDL lipids and plasma triglycerides. Interestingly, our results also suggest a strong correlation between reductions in plasma triglycerides with reductions in RLP-C levels compared with reductions in LDL-C. However, the reduction in triglycerides can only account for 44% of the reduction in RLP-C (Pearson correlation on logarithmically transformed data, r=0.66). Furthermore, although the median reduction in triglycerides with simvastatin and atorvastatin was 26.3% and 24.2%, respectively, the median reduction in RLP was 6% and 25.9%, respectively. If the effects were due solely to an increased clearance of remnants along with LDL via an increased activity of the remnant/LDL receptor, then the percent decreases of LDL-C and RLP-C should be similar. The stronger association with changes in plasma triglycerides with RLP-C suggests that either remnants containing both triglycerides as well as cholesterol were being preferentially cleared compared with LDL or that production rates of VLDL were decreased in addition to enhanced clearance of remnant and LDL particles. Because this study is unique in its crossover design, the differences in statins noted are likely to be due to true differences in drug action compared with differing metabolic environments. Given the relatively small sample size, these conclusions should be treated with caution and confirmed in a larger study using kinetic methodology. Also, in the present study, there was a significant correlation between RLP-C and non–HDL-C in these patients with combined hyperlipidemia. This supports the notion of the ATP III panel, who have suggested the use of non–HDL-C levels in the assessment of atherosclerotic risk in patients with hypertriglyceridemia as a surrogate for RLPs. Two other prospective angiographic trials also suggest that non-LDL apoB-containing lipoproteins or RLPs are more predictive of atherosclerotic progression than are LDL levels.40,41
The effects of statins to reduce circulating RLPs may be due to their effects on lipoprotein kinetics. Also, statins may decrease input rates for VLDL apoB and VLDL triglycerides.7 Studies of the effects of statins on VLDL, IDL, and LDL kinetics in subjects with combined hyperlipidemia have yielded variable results.42–46 However, the exact effect of statins on the uptake of remnants is, as yet, unclear. Although a potential explanation for the disparate results of statin actions in states of hypertriglyceridemia remains elusive, they may simply reflect the heterogeneous nature of metabolic defects leading to combined hyperlipidemia. Inasmuch as cholesterol depletion in the liver with statins could alter VLDL assembly and secretion, it is possible that the reduction in RLP-C seen in the present report is due to decreased production and increased clearance.47 Because atorvastatin appears to be more potent, it is quite possible that in another group of patients, eg, patients with type IV hyperlipidemia, the differences among the statins will be more accentuated.
In summary, in a randomized double-blind crossover trial in subjects with combined hyperlipidemia, we demonstrate for the first time that atorvastatin and simvastatin reduce RLP-C levels significantly, whereas pravastatin does not, and this differential effect is likely mediated by differences in TRL remnant kinetics. Given that RLPs are atherogenic, it is not unreasonable to ascribe part of the benefit of statins in reducing cardiovascular events to the reduction in RLP levels.
|
Acknowledgments |
|---|
This study was supported by grants from the National Institutes of Health (K24 AT-00596), Merck, and Pfizer. We thank Scott Grundy, MD, PhD, for his valuable suggestions.
Received September 7, 2001; accepted September 26, 2001.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;1995: 333: 1301–1307.
2. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with CAD: Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.[Medline] [Order article via Infotrieve]
3.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996; 335: 1001–1009.
4.
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339: 1349–1357.
5.
Downs JR. Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AMJr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998; 279: 1615–1622.
6.
Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000; 101: 207–213.
7. Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol. 1999; 83: 25F–29F.[Medline] [Order article via Infotrieve]
8.
Cohn JS. Marcoux C, Davignon J. Detection, quantification, and characterization of potentially atherogenic triglyceride-rich remnant lipoproteins. Arterioscler Thromb Vasc Biol. 1999; 19: 2474–2486.
9.
Havel R. TG-rich lipoproteins and atherosclerosis: new perspectives. Am J Clin Nutr. 1994; 59: 795–799.
10. Krauss RM. Atherogenicity of TG-rich lipoproteins. Am J Cardiol. 1998; 81: 13B–17B.[Medline] [Order article via Infotrieve]
11. Karpe F, Steiner G, Uffelman K, Olivvectona T, Hamsten A. Postprandial lipoproteins and progression of CAD. Atherosclerosis. 1994; 106: 83–97.[Medline] [Order article via Infotrieve]
12.
Hodis HN. Triglyceride-rich lipoprotein remnant particles and risk of atherosclerosis. Circulation. 1999; 99: 2852–2854.
13. Karpe F. Postprandial lipoprotein metabolism and atherosclerosis. J Intern Med. 1999; 246: 341–355.[Medline] [Order article via Infotrieve]
14.
Hodis HN, Mack WJ, Dunn M, Liu C, Selzer RH, Krauss RM. IDL and progression of carotid atherosclerosis. Circulation. 1997; 95: 2022–2026.
15.
Steiner G, Schwartz L, Shumak S, Poapst M. The association of increased levels of intermediate-density lipoproteins with smoking and with coronary artery disease. Circulation. 1987; 75: 124–130.
16.
Cleeman JI, Grundy SM, Becker D, Clark LT, Cooper RS, Denke MA, Howard WJ, Hunninghake DB, Illingworth DR, Luepker RV, et al. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001; 285: 2486–2497.
17. Nakajima K, Saito T, Tamura A, Suzuki M, Nakano T, Adachi M, Tanaka A Tada N, Nakamura H, Campos E, et al. Cholesterol in remnant-like lipoproteins in human serum using monoclonal anti apo B-100 and anti apo A-I immunoaffinity mixed gels. Clin Chim Acta. 1993; 223: 53–71.[Medline] [Order article via Infotrieve]
18. Devaraj S, Vega G, Lange R, Grundy SM, Jialal I. RLP-cholesterol levels in patients with dysbetalipoproteinemia and CAD. Am J Med. 1998; 04: 445–450.
19.
Hirany S, O’Byrne D, Devaraj S, Jialal I. Remnant-like particle-cholesterol concentrations in patients with type 2 diabetes mellitus and end-stage renal disease. Clin Chem. 2000; 46: 667–672.
20. Tanaka A, Ejiri N, Fujinuma Y, Yui K, Tamura M, Nakajima K, Morohoshi M, Fujisawa K, Uchimura I, Numano F. Remnant-like particles and restenosis of coronary arteries after PTCA. Ann NY Acad Sci. 1995; 748: 595–598.[Medline] [Order article via Infotrieve]
21. Takeichi S, Yukawa N, Nakajima Y, Osawa M, Saito T, Seto Y, Nakano T, Saniabadi AR, Adachi M, Wang T, et al. Association of plasma triglyceride-rich lipoprotein remnants with coronary atherosclerosis in cases of sudden cardiac death. Atherosclerosis. 1999; 142: 309–315.[Medline] [Order article via Infotrieve]
22. Masuoka H, Kamei S, Wagayama H, Ozaki M, Kawasaki A, Tanaka T, Kitamura M, Katoh S, Shintani U, Misaki M, et al. Association of remnant-like particle cholesterol with coronary artery disease in patients with normal total cholesterol levels. Am Heart J. 2000; 139: 305–310.[Medline] [Order article via Infotrieve]
23. Sekihara T, Nakano T, Nakajima K. High postprandial plasma remnant-like particles-cholesterol in patients with coronary artery diseases on chronic maintenance hemodialysis. Jpn J Nephrol. 1996; 38: 220–228.
24. Oda H, Yorioka N, Okushin S, Nishida Y, Kushihata S, Ito T, Yamakido M. Remnant-like particle cholesterol may indicate atherogenic risk in patients on chronic hemodialysis. Nephron. 1997; 76: 7–14.[Medline] [Order article via Infotrieve]
25. Shimizu H, Mori M, Saito T. An increase of serum remnant-like particles in non-insulin-dependent diabetic patients with microalbuminuria. Clin Chim Acta. 1993; 221: 191–196.[Medline] [Order article via Infotrieve]
26.
Mahley RW, Ji ZS. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res. 1999; 40: 1–16.
27. Jones P, Kafonek S, Lauroroa I, Hunninghake D, for CURVES investigators. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin and fluvastatin in patients with hypercholesterolemia (the CURVES Study). Am J Cardiol. 1998; 81: 582–587.[Medline] [Order article via Infotrieve]
28. Jialal I, Hirany SV, Devaraj S, Sherwood TA. Comparison of an immunoprecipitation method for direct measurement of LDL-cholesterol with beta-quantification (ultracentrifugation). Am J Clin Pathol. 1995; 104: 76–81.[Medline] [Order article via Infotrieve]
29. Maitra A, Hirany SV. Jialal I. Comparison of two assays for measuring LDL cholesterol. Clin Chem. 1997; 43(pt 1): 1040–1047.
30. McNamara JR, Shah PK, Nakajima K, Cupples LA, Wilson PW, Ordovas JM, Schaefer EJ. Remnant lipoprotein cholesterol and triglyceride reference ranges from the Framingham Heart Study. Clin Chem. 1998; 44(pt 1): 1224–1232.
31.
Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001; 103: 1933–1935.
32. Vega GL, Grundy SM. Effect of statins on metabolism of apo-B-containing lipoproteins in hypertriglyceridemic men. Am J Cardiol. 1998; 81 (suppl I): B36–B42.[Medline] [Order article via Infotrieve]
33. Broyles FE, Walden CE, Hunninghake DB, Hill-Williams D, Knopp RH. Effect of fluvastatin on IDL (remnants) and other lipoprotein levels in hypercholesterolemia. Am J Cardiol. 1995; 76: 129A–135A.[Medline] [Order article via Infotrieve]
34. Vega GL, Krauss RM, Grundy SM. Pravastatin therapy in primary moderate hypercholesterolemia. J Intern Med. 1990; 227: 81–94.[Medline] [Order article via Infotrieve]
35. Mabuchi H, Kamon N, Fujita H, Michishita I, Takeda M, Kajinami K, Itoh H, Wakasugi T, Takeda R. Effects of CS-514 on serum lipoprotein lipid and apolipoprotein levels in patients with familial hypercholesterolemia. Metabolism. 1987; 36: 475–479.[Medline] [Order article via Infotrieve]
36.
Twickler TB, Dallinga-Thie GM, de Valk HW, Schreuder PCNJ, Jansen H, Cabezas MC, Erkelens DW. High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2000; 20: 2422–2427.
37. Miller M, Dolinar C, Cromwell W, Otvos JD. Effectiveness of high doses of simvastatin as monotherapy in mixed hyperlipidemia. Am J Cardiol. 2001; 87: 232–234.[Medline] [Order article via Infotrieve]
38. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol. 1998; 81: 66B–69B.[Medline] [Order article via Infotrieve]
39. Karpe F, Taskinen M, Nieminen MS, Frick MH, Kesaniemi YA, Pasternack A, Hamsten A, Syvanne M. RLP cholesterol concentration and progression of coronary and vein graft atherosclerosis in response to gemfibrozil treatment. Atherosclerosis. 2001; 157: 181–187.[Medline] [Order article via Infotrieve]
40.
Hodis HN, Mack WJ, Azen SP, Alaupovic P, Pogoda JM, LaBree L, Hemphill LC, Kramsch DM, Blankenhorn DH. Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin. Circulation. 1994; 90: 42–49.
41.
Phillips NR, Waters D, Havel RJ. Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation. 1993; 88: 2762–2770.
42. Gaw A, Packard CJ, Lindsay GM, Griffin BA, Caslake MJ, Lorimer AR, Shepherd J. Overproduction of small very low density lipoproteins (Sf 20–60) in moderate hypercholesterolemia: relationships between apolipoprotein B kinetics and plasma lipoproteins. J Lipid Res. 1995; 36: 158–171.[Abstract]
43. Aguilar-Salinas CA, Barrett PH, Kelber J, Delmez J, Schonfeld G. Physiologic mechanisms of action of lovastatin in nephrotic syndrome. J Lipid Res. 1995; 36: 188–199.[Abstract]
44.
Parhofer KG, Barrett PH, Schwandt P. Atorvastatin improves postprandial lipoprotein metabolism in normolipidemic subjects. J Clin Endocrinol Metab. 2000; 85: 4224–4230.
45. Le NA, Innis-Whitehouse W, Li X, Bakker-Arkema R, Black D, Brown WV. Lipid and apolipoprotein levels and distribution in patients with hypertriglyceridemia: effect of triglyceride reductions with atorvastatin. Metabolism. 2000; 49: 167–177.[Medline] [Order article via Infotrieve]
46. McKenney JM, McCormick LS, Weiss S, Koren M, Kafonek S, Black DM. A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia: Collaborative Atorvastatin Study Group. Am J Med. 1998; 104: 137–143.[Medline] [Order article via Infotrieve]
47. Huff MW, Burnett JR. HMG-CoA reductase inhibitors and hepatic apo B secretion. Curr Opin Lipidol. 1997; 8: 138–145.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  G Ferns, V Keti, and B Griffin Investigation and management of hypertriglyceridaemia J. Clin. Pathol., November 1, 2008; 61(11): 1174 - 1183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hansel, C. Nicolle, F. Lalanne, F. Tondu, T. Lassel, Y. Donazzolo, J. Ferrieres, M. Krempf, J.-L. Schlienger, B. Verges, et al. Effect of low-fat, fermented milk enriched with plant sterols on serum lipid profile and oxidative stress in moderate hypercholesterolemia Am. J. Clinical Nutrition, September 1, 2007; 86(3): 790 - 796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Robinson, B. Smith, N. Maheshwari, and H. Schrott Pleiotropic Effects of Statins: Benefit Beyond Cholesterol Reduction?: A Meta-Regression Analysis J. Am. Coll. Cardiol., November 15, 2005; 46(10): 1855 - 1862. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Wanner, U. Bahner, R. Mattern, D. Lang, and J. Passlick-Deetjen Effect of dialysis flux and membrane material on dyslipidaemia and inflammation in haemodialysis patients Nephrol. Dial. Transplant., October 1, 2004; 19(10): 2570 - 2575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P.J. Halcox and J. E. Deanfield Beyond the Laboratory: Clinical Implications for Statin Pleiotropy Circulation, June 1, 2004; 109(21_suppl_1): II-42 - II-48. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.B. Twickler, G.M. Dallinga-Thie, J.S. Cohn, and M.J. Chapman Elevated Remnant-Like Particle Cholesterol Concentration: A Characteristic Feature of the Atherogenic Lipoprotein Phenotype Circulation, April 27, 2004; 109(16): 1918 - 1925. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Trovati and F. Cavalot Optimization of Hypolipidemic and Antiplatelet Treatment in the Diabetic Patient with Renal Disease J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S12 - 20. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. H. Hsia Non-HDL Cholesterol: Into the Spotlight Diabetes Care, January 1, 2003; 26(1): 240 - 242. [Full Text] [PDF]
|
|
|
|
|
|
P. R. W. de Sauvage Nolting, M. B. Twickler, G. M. Dallinga-Thie, R. J.A. Buirma, B. A. Hutten, J. J.P. Kastelein, and for the Examination of Probands and Relatives in S Elevated Remnant-Like Particles in Heterozygous Familial Hypercholesterolemia and Response to Statin Therapy Circulation, August 13, 2002; 106(7): 788 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Jialal and S. Devaraj Remnant Lipoproteins: Measurement and Clinical Significance Clin. Chem., February 1, 2002; 48(2): 217 - 219. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||