(Circulation. 2001;103:1942.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Fluvastatin Lowers Atherogenic Dense Low-Density Lipoproteins in Postmenopausal Women With the Atherogenic Lipoprotein Phenotype
From the Division of Clinical Chemistry (W.M., H.S., M.M.H., H.W.) and the Division of Sports Medicine, Department of Medicine (A.B., J.K., M.W.B.), Albert Ludwigs-University, Freiburg, Germany; and Novartis Pharma AG, Nürnberg, Germany (C.A.).
Correspondence to Winfried März, MD, Department of Medicine, Hugstetter Straße 55, D-79106 Freiburg, Germany. E-mail maerz{at}med1.ukl.uni-freiburg.de
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Abstract |
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Background—Although HMG-CoA reductase inhibitors (HMGRIs) are effective lipid-lowering agents, it remains controversial whether these agents also lower dense LDL (dLDL), a predominance of which is considered to contribute to the atherogenicity of the metabolic syndrome.
Methods and Results—In a multicenter, double-blind, randomized, placebo-controlled study, we determined the effect of the HMGRI fluvastatin on lipids, apolipoproteins, and LDL subfractions (by equilibrium density gradient ultracentrifugation). A total of 52 postmenopausal women with combined hyperlipidemia and increased dLDL were treated with either fluvastatin 40 mg/d (n=35) or placebo (n=17). After 12 weeks’ treatment, significant reductions (P<0.001) in total cholesterol (-19%), IDL cholesterol (-35%), LDL cholesterol (-23%), apolipoprotein B (-21%), and apolipoprotein B in dLDL (-42%) were apparent among fluvastatin recipients. No significant changes in triglycerides or HDL cholesterol were observed. The effect of fluvastatin on dLDL was correlated with baseline values. There was no consistent relationship, however, between the effect of fluvastatin on triglycerides and the decrease in dLDL.
Conclusions—Fluvastatin lowers total and LDL cholesterol and the concentration of dLDL. This profile may contribute to an antiatherogenic effect for fluvastatin that is greater than expected on the basis of changes in lipids and apolipoproteins.
Key Words: fluvastatin • coronary disease • lipoproteins
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Low-density lipoprotein (LDL) comprises a heterogeneous group of particles, of which the dense subfraction (dLDL) is considered most atherogenic.1 2 3
A link between dLDL and increased risk of coronary heart disease (CHD) was first proposed by Austin and coworkers.4 Subsequent case-control and prospective studies have shown that a predominance of dLDL increases the risk of CHD by up to 7-fold.5 6 7 8 9 10 11 12 Evidence for a role of dLDL in CHD also comes from angiographic trials. In the St Thomas’ Atherosclerosis Regression Study, patients showing regression of coronary atherosclerosis had low concentrations of dLDL during treatment.13 Dense LDLs are associated with other components of the metabolic syndrome, particularly elevated triglycerides and low HDL cholesterol (HDL-C). The independent contribution of dLDL to the risk of CHD has therefore been difficult to determine. Thus, LDL subclass profile remained predictive of CHD after adjustment for triglycerides or HDL in some9 11 but not all studies.6 7 8 10 12 Very recently,14 dLDLs were shown to cause endothelial dysfunction independent of LDL cholesterol (LDL-C), triglycerides, and HDL-C. Clearly, any therapeutic principle that lowers LDL-C and triglycerides and raises HDL-C might therefore be enhanced by a reduction in dLDL.
The effects of HMG-CoA reductase inhibitors (HMGRIs) on LDL subfractions have been studied by gradient gel electrophoresis (GGE) and ultracentrifugation.15 16 17 18 19 20 21 22 23 24 Providing a coarse estimate of the size distribution of LDL rather than the concentration of dLDL, GGE did not reveal increases of the average LDL diameter during HMGRI treatment.16 19 20 25 Some of the ultracentrifugation-based studies showed a decrease of the concentration of dLDL15 19 on HMGRI; others did not.18 19 22 23 24 It is thus controversial whether these agents lower dLDL. The HMGRI fluvastatin offers a wide spectrum of clinical benefits in various patient subgroups, including the elderly.26 We therefore examined the effect of short-term therapy with fluvastatin on dLDL levels in patients at increased risk of CHD, namely, postmenopausal women with an atherogenic lipoprotein profile.
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Methods |
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Study Design
This was a double-blind, randomized, placebo-controlled, 20-week study comprising an 8-week run-in phase followed by an active treatment period of 12 weeks, conducted at 10 sites in Germany. The study protocol was approved by the Ethics Committee of the University of Freiburg and the institutional review boards at each study site. All patients gave informed, written consent.
Patients
A total of 52 postmenopausal women (
12 months
since last menstrual period, levels of follicle-stimulating hormone
>28 IU/L), 44 to 75 years old, with LDL-C >150 mg/dL, triglycerides
>120 mg/dL, and apolipoprotein (apo) B in dLDL (LDL-5+LDL-6) >25
mg/dL, participated. Major exclusion criteria were LDL-C 300 mg/dL;
triglycerides 500 mg/dL; acute myocardial infarction within 3 months
of study commencement; insulin-dependent diabetes mellitus or poorly
controlled non–insulin-dependent diabetes mellitus (glucose >150
mg/dL or HbA1c >8%); severe obesity; overt
liver disease; chronic renal failure; myopathy; alcohol or drug abuse;
several other significant diseases; known hypersensitivity to HMGRIs;
or use of other lipid-lowering therapy, immunosuppressants,
erythromycin and/or neomycin, ketoconazole, and hormone-replacement
therapy.
Patients commenced an 8-week run-in period, during which previous lipid-lowering therapy was discontinued. Dietary advice was provided according to the American Heart Association Step I diet, and patients were requested to maintain smoking habits, physical activity, and alcohol consumption. After the run-in phase, patients were randomized to receive either fluvastatin 40 mg every evening (n=35) or placebo (n=17) for 12 weeks. A randomization ratio of 2:1 was selected to reduce the number of patients receiving the potentially inferior treatment. At week 6, concomitant diseases, adverse events, and compliance (capsule counting) were recorded, and at week 12, laboratory assessments and physical examinations were repeated.
Laboratory Assessments
Two weeks before randomization (baseline) and after
12 weeks’ active treatment, fasting venous blood samples were drawn.
Serum samples were stored up to 1 week at 4°C before lipoprotein
subfractionation. Previous experiments indicated that the lipid and
lipoprotein measurements were not affected by storage at 4°C for 1
week. All laboratory assessments were performed centrally at the
Department of Medicine, University of Freiburg,
Germany.
Lipids and Apolipoproteins
Cholesterol, triglycerides, and phospholipids were
measured with enzymatic methods, calibrated with secondary standards
from Roche Diagnostics. ApoB was determined by kinetic nephelometry
(Beh-ring), standardized by reference to the Centers for Disease
Control standard.27 Lipid
and apoB measurements had coefficients of variation of
<5%.
Lipoproteins and Lipoprotein
Subfractions
Quantitative lipoprotein
electrophoresis28 was used
to estimate LDL-C before subfractionation at week -2. VLDL
(d<1.0063 kg/L), IDL
(1.0063<d<1.019 kg/L), LDL
(1.019<d<1.065 kg/L), and HDL
(1.065<d<1.21 kg/L) were
isolated by
ultracentrifugation.29 LDL
was subsequently fractionated into 6 density classes by equilibrium
density gradient
centrifugation.27 LDL
subfractions were quantified by measurement of lipids and apoB. The
coefficients of variation for the analysis of cholesterol, free
cholesterol, phospholipids, and apoB in LDL subfractions were <7%
(and <10% in the case of triglycerides). Radii of LDL subfractions
were calculated as
described.27
Statistical Methods
Contingency tables were analyzed by Fisher’s exact
test. Intraindividual changes between baseline and week 12 were
calculated and compared between treatment groups by Student’s
t test. Bivariate correlations
were analyzed by Pearson’s correlation coefficients. A value of
P<0.05 was considered
significant.
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Results |
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A total of 162 women were included in the dietary run-in period, of whom 52 (32%) met the inclusion criterion regarding apoB in dLDL (>25 mg/dL) and were randomized. All randomized patients completed the study according to protocol. Overall, the 2 treatment groups were comparable in terms of clinical characteristics and baseline lipid and lipoprotein concentrations (Table 1
). There was no significant difference in the
changes of body mass index between groups
(P=0.382).
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Patients were recruited from 10 centers, 1 of which was overrepresented (providing 11 and 6 patients in the fluvastatin and placebo groups, respectively). Exclusion of patients at this center from the statistical analyses did not affect the study findings.
Changes in Lipids, Lipoproteins, and
Apolipoproteins
After 12 weeks’ treatment, significant reductions in
total cholesterol, LDL-C, and total apoB were observed among
fluvastatin recipients compared with placebo
(Table 2). Tri-glycerides and HDL-C did not change
significantly.
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Major ApoB-Containing Lipoproteins
No significant changes in VLDL constituents were
observed
(Table 3). More marked changes were apparent for IDL. With
the exception of triglycerides (decrease by 9%), all constituents of
IDL decreased by 
35%, with apoB in IDL decreasing by almost 30%
(Table 3). With regard to LDL, total cholesterol decreased
by 23%, and apoB in LDL decreased by 24%; similar changes were
observed for esterified and nonesterified cholesterol and phospholipid
content
(Table 3). Relative to placebo, the effect of fluvastatin on
LDL triglycerides (-14%) was not statistically significant. No
significant changes in particle radius were apparent for VLDL, IDL, or
LDL during fluvastatin therapy
(Table 3).
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LDL Subfractions
Among LDL subfractions, the most marked changes were
observed in LDL-5 and LDL-6
(Figure 1). Fluvastatin lowered lipids and apoB in LDL-5 by
40% to 45%
(Table 4). In LDL-6, the respective reductions ranged from
36% to 42%, with the exception of triglycerides, which decreased by
25%
(Table 4). For dLDL (LDL-5+LDL-6), relative changes were
39% to 44% for apoB, cholesterol, and phospholipids and 33% for
triglycerides
(Table 4). Less marked (but statistically significant)
changes in the concentration of LDL-4 were also observed, whereas the
lightest subfractions (LDL-1 and LDL-2) remained unaffected
(Figure 1).
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Correlation Analysis
The decrease in LDL-6 apoB was most closely related to
the levels of LDL-6 apoB before treatment
(r=-0.878,
P<0.001), ie, the higher the
baseline LDL-6 apoB level, the greater the reduction evoked by
fluvastatin
(Figure 2). Total triglycerides
(r=-0.403,
P=0.016) and VLDL apoB
(r=-0.589,
P<0.001) were weaker, albeit
significant, predictors of the change in LDL-6 apoB. Interestingly,
positive correlations were obtained between apoB in LDL-2 to LDL-4 and
the change in LDL-6 apoB, ie, the higher the apoB level in these
fractions, the smaller the change in LDL-6 apoB during fluvastatin
therapy
(Figure 2).
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Changes in Triglycerides and LDL
Subfractions
An inverse correlation between triglycerides and dLDL
was described
previously.5 6 30
We therefore examined whether the decrease in dLDL was associated with
changes in triglycerides. The overall correlation between change in
triglycerides and change in LDL-6 apoB was weak
(r=-0.101). Only in those
patients showing triglyceride reductions during fluvastatin therapy
(n=23; mean reduction 27%) did changes in LDL-6 apoB correlate
significantly with changes in tri-glycerides
(r=0.655,
P=0.001). The remaining
patients (n=12) showed a mean increase in triglycerides of 50%, but
experienced a substantial decrease in LDL-6 apoB as well (average of
-19.6 mg/dL, compared with -5.7 mg/dL in those patients showing a
decrease in triglycerides).
Safety and Tolerability
Fluvastatin was well tolerated, and there were no
safety concerns. Mean serum levels of total bilirubin, transaminases,
alkaline phosphatase, 
-glutamyl transferase, and creatine
phosphokinase did not change.
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Discussion |
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Of available lipid-lowering agents, it is generally believed that only fibrates1 21 23 31 32 33 and niacin34 have the potential to alter the distribution of LDL subclasses. Indeed, most reports using GGE or ultracentrifugation to study the effects of HMGRIs on the distribution of LDL subfractions have been negative.16 18 19 20 22 25 Two ultracentrifugation-based reports indicated that HMGRIs lowered dLDL.18 22 For fluvastatin, 2 negative studies have been published.24 25 Given the inconsistency of these investigations, we examined the effect of fluvastatin on dLDL in patients at increased risk of CHD with an atherogenic lipoprotein profile. Because we were aware that an atherogenic lipoprotein profile appears to have a greater impact on cardiovascular risk in women than in men,35 the study was performed in postmenopausal women.
Our major finding was that fluvastatin decreased dLDL by
40%, an effect that was almost twice the change in total LDL-C
(-23%). Buoyant LDL subfractions did not change, whereas IDL (which
includes atherogenic remnants of triglyceride-rich lipoproteins)
decreased by 30%. In designing the study, we expected that
substantial reductions in dLDL would be seen in individuals exhibiting
high concentrations of dLDL at baseline. Hence, we selectively
recruited women with apoB in dLDL >25 mg/dL, which approximately
corresponds to the median in postmenopausal women (unpublished
observations). This assumption was confirmed in the present
study.
Our findings contrast with the general literature pertaining
to the effect of HMGRI on LDL subfractions. There are subtle
differences, however, between the present and previous studies. For
example, most studies derived LDL subfraction distribution from
measurements of LDL peak particle size by
GGE.16 17 19 20 24 25
Similarly, we were unable to detect a significant increase in the mean
size of whole LDL when particle radius was calculated according to a
previously published
algorithm.27 This is
surprising, given the substantial reduction in dLDL, but consistent
with theoretical considerations. Using the concentrations and particle
radii of all LDL subfractions, we calculated the expected radii for
whole LDL at baseline and at week 12 as weighted means of the
individual LDL subfractions. This yielded particle radii of 9.8 and 9.9
nm, respectively, at these time points, values close to those
determined empirically (9.7 and 9.9 nm, respectively;
Table 3
). Provided that there are no substantial changes in
the sizes of individual subfractions, it cannot therefore be expected
that the changes of LDL-5 and LDL-6 in the present study would
translate into more than a small change of the average size of the
whole LDL fraction. Other studies that used ultracentrifugation for LDL
subfractionation did not specifically select patients on the basis of
an atherogenic lipoprotein
profile.18 22 In
this context, it is noteworthy that 3 GGE-based studies that included
such patients were small (
12 patients) and may therefore have been
underpowered.16 19 25
The difference in findings between the present investigation and other
ultracentrifugation-based
studies15 18 21 22 23 36
may have methodical reasons. If ultracentrifugation is not performed
until complete equilibrium is reached (as in the present study),
separation may be driven not only by density but also by particle size.
Other explanations may relate to the study design. For example, most
studies that used ultracentrifugation failed to specifically select for
individuals with elevated dLDL at
baseline,15 18 21 22 23 36
and some lacked placebo
groups.15 18 22 23 36
The mechanisms by which fluvastatin selectively decreased the most atherogenic lipoprotein fractions, IDL and dLDL, remain elusive. One potential mechanism relates to the effect of HMGRIs on the release of triglyceride-rich particles in the liver, because an inverse correlation exists between dLDL and triglycerides.5 6 30 Surprisingly, however, there was no consistent relationship between changes in triglycerides and dLDL for the overall patient population, ruling out the possibility that alterations in VLDL metabolism (eg, reduced secretion of VLDL or high lipoprotein lipase activity) fully accounted for the changes in dLDL. The latter finding contrasts with those of Tilly-Kiesi,15 who reported decreases in dLDL on lovastatin only in those individuals who responded with decreases in triglycerides.
Treatment with fluvastatin stimulates the expression of hepatic LDL receptors,37 which also catabolize IDL.38 The most obvious explanation for the decrease in IDL in the present study is therefore that these lipoproteins are taken up by LDL receptors at an enhanced rate during fluvastatin therapy. The change in dLDL is less easily explained, because these particles are poor ligands of LDL receptors,2 and other, less evident, mechanisms might be active. One possible mechanism, an altered rate of transfer of cholesteryl esters from HDL to apoB-containing lipoproteins,39 was ruled out by the finding that activity of cholesteryl ester transfer protein was unchanged during fluvastatin therapy (not shown). Another potential mechanism focuses on hepatic lipase, which has been implicated in the generation of dLDL.40 41 42 In individuals showing high concentrations of triglyceride-rich lipoproteins, transfer of triglycerides (in exchange with cholesteryl esters) into LDL and HDL may occur; these triglycerides may then be hydrolyzed by hepatic lipase, leading to the formation of smaller, lipid-depleted particles.39 In the present study, significant correlations were found between the decreases in LDL-5 and LDL-6 and an increase of HDL-2b, the most buoyant HDL subfraction (not shown). Because buoyant HDL particles are the preferred substrate of hepatic lipase, this would accord with the suggestion of decreased hepatic lipase during fluvastatin therapy. This is also supported by Hoogerbrugge and Jansen,43 who found that atorvastatin lowers hepatic lipase.
The possibility that our results were confounded by
lifestyle changes and/or concomitant cardiovascular therapy (eg,
antihypertensive drugs) warrants discussion. For example, other authors
have shown that ß-adrenergic receptor antagonists raise both
IDL44 and
dLDL.8 In total, 7 patients
(fluvastatin, n=5; placebo, n=2) received ß-adrenergic receptor
antagonists, and no patient received 
-adrenergic receptor–blocking
agents. Thus, the proportion of patients receiving ß-adrenergic
receptor antagonists was small and comparable for each treatment group,
and no dosage adjustments were made during the study. Exclusion of
these patients from the statistical analyses had no effect on the
statistical significance of the findings, indicating that concomitant
ß-blocker therapy did not affect our results to a relevant extent.
Exclusion of diabetic individuals also did not affect the statistical
significance of our results
(P<0.001 for the change in
dLDL for all patients, P<0.001
for the nondiabetic patients). A similar conclusion can be drawn with
regard to the potential confounding effect of lifestyle changes. Thus,
although patients were not requested to formally record their dietary
habits and degree of exercise during the study (rather, patients were
advised to adhere to a lipid-modified diet and not change usual
exercise habits), there is no reason to assume that minor changes
occurred more frequently in the fluvastatin group than in those treated
with placebo. Moreover, there was no significant difference between the
changes in body mass index for either treatment group. ANOVA using the
change of dLDL as the dependent variable, treatment as the independent
variable, and the variation of body mass index as a covariable says
that changes in LDL subfractions remain significant after adjustment
for body mass index (data not shown).
In conclusion, fluvastatin produces a shift in LDL subfractions toward more buoyant, less atherogenic LDL particles in patients at increased risk of CHD. This profile may contribute to an antiatherogenic effect for fluvastatin that is greater than expected on the basis of changes in lipids and apolipoproteins.
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Acknowledgments |
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The authors thank Novartis Pharma AG, Nürnberg, Germany, for financial support and Sabiene Jotterand, Dagmar Reduth, Gisela Zöllner, and Rita Glaeser for technical assistance.
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Footnotes |
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Dr Abletshauser is an employee of Novartis Pharma AG, Nürnberg, Germany, and Dr März serves as one of its consultants. Novartis Pharma AG provided financial support for this study.
Received September 6, 2000; revision received January 16, 2001; accepted January 22, 2001.
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References |
|---|
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. de Graaf J, Hendriks JC, Demacker PN, et al. Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects: normalization after clofibrate treatment. Arterioscler Thromb. 1993;13:712–719.
2. Nigon F, Lesnik P, Rouis M, et al. Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor. J Lipid Res. 1991;32:1741–1753.[Abstract]
3.
Galeano NF,
Al-Haideri M, Keyserman F, et al. Small dense low density lipoprotein
has increased affinity for LDL-receptor-independent cell surface
binding sites: a potential mechanism for increased atherogenicity.
J Lipid Res. 1998;39:1263–1273.
4.
Austin MA, Breslow
JL, Hennekens CH, et al. Low density lipoprotein subclass patterns and
risk of myocardial infarction.
JAMA. 1988;260:1917–1921.
5.
Austin MA, King
M-C, Vranizan KM, et al. Atherogenic lipoprotein phenotype: a proposed
genetic marker for coronary heart disease.
Circulation. 1990;82:495–506.
6.
Campos H, Genest
JJ, Blijlevens E, et al. Low density lipoprotein particle size and
coronary artery disease. Arterioscler
Thromb. 1992;12:187–195.
7. Coresh J, Kwiterovich PO Jr, Smith HH, et al. Association of plasma triglyceride concentration and LDL particle diameter, density, and chemical composition with premature coronary artery disease in men and women. J Lipid Res. 1993;34:1687–1697.[Abstract]
8. Griffin BA, Freeman DJ, Tait GW, et al. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis. 1994;106:241–253.[Medline] [Order article via Infotrieve]
9.
Gardner CD,
Fortmann SP, Krauss RM. Association of small low-density lipoprotein
particles with the incidence of coronary artery disease in men and
women. JAMA. 1996;276:875–881.
10.
Stampfer MJ,
Krauss RM, Ma J, et al. A prospective study of triglyceride level,
low-density lipoprotein particle diameter, and risk of myocardial
infarction. JAMA. 1996;276:882–888.
11.
Lamarche B,
Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein
particles as a predictor of the risk of ischemic heart disease in men:
prospective results from the Quebec Cardiovascular Study.
Circulation. 1997;95:69–75.
12.
Gray RS, Robbins
DC, Wang W, et al. Relation of LDL size to the insulin resistance
syndrome and coronary heart disease in American Indians: the Strong
Heart Study. Arterioscler Thromb Vasc
Biol. 1997;17:2713–2720.
13. Watts GF, Mandalia S, Brunt JN, et al. Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas’ Atherosclerosis Regression Study (STARS). Metabolism. 1993;42:1461–1467.[Medline] [Order article via Infotrieve]
14.
Vakkilainen J,
Mäkimattila S, Seppälä-Lindroos A, et al. Endothelial dysfunction
in men with small LDL particles.
Circulation. 2000;102:716–721.
15. Tilly-Kiesi M. The effect of lovastatin on low-density lipoprotein hydrated density distribution and composition in patients with intermittent claudication and primary hypercholesterolemia. Metabolism. 1991;40:623–628.[Medline] [Order article via Infotrieve]
16. Cheung MC, Austin MA, Moulin P, et al. Effects of pravastatin on apolipoprotein-specific high density lipoprotein subpopulations and low density lipoprotein subclass phenotypes in patients with primary hypercholesterolemia. Atherosclerosis. 1993;102:107–119.[Medline] [Order article via Infotrieve]
17.
Contacos C,
Barter PJ, Sullivan DR. Effect of pravastatin and omega-3 fatty acids
on plasma lipids and lipoproteins in patients with combined
hyperlipidemia. Arterioscler
Thromb. 1993;13:1755–1762.
18. de Graaf J, Demacker PN, Stalenhoef AF. The effect of simvastatin treatment on the low-density lipoprotein subfraction profile and composition in familial hypercholesterolaemia. Neth J Med. 1993;43:254–261.[Medline] [Order article via Infotrieve]
19.
Franceschini G,
Cassinotti M, Vecchio G, et al. Pravastatin effectively lowers LDL
cholesterol in familial combined hyperlipidemia without changing LDL
subclass pattern. Arterioscler
Thromb. 1994;14:1569–1575.
20. Zambon S, Cortella A, Sartore G, et al. Pravastatin treatment in combined hyperlipidaemia: effect on plasma lipoprotein levels and size. Eur J Clin Pharmacol. 1994;46:221–224.[Medline] [Order article via Infotrieve]
21. Bredie SJ, de Bruin TW, Demacker PN, et al. Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile, and low-density lipoprotein oxidizability. Am J Cardiol. 1995;75:348–353.[Medline] [Order article via Infotrieve]
22.
Guerin M, Dolphin
PJ, Talussot C, et al. Pravastatin modulates cholesteryl ester transfer
from HDL to apoB-containing lipoproteins and lipoprotein subspecies
profile in familial hypercholesterolemia.
Arterioscler Thromb Vasc Biol. 1995;15:1359–1368.
23. Kontopoulos AG, Athyros VG, Papageorgiou AA, et al. Effects of simvastatin and ciprofibrate alone and in combination on lipid profile, plasma fibrinogen and low density lipoprotein particle structure and distribution in patients with familial combined hyperlipidaemia and coronary artery disease. Coron Artery Dis. 1996;7:843–850.[Medline] [Order article via Infotrieve]
24. Yuan J, Tsai MY, Hegland J, et al. Effects of fluvastatin (XU 62-320), an HMG-CoA reductase inhibitor, on the distribution and composition of low density lipoprotein subspecies in humans. Atherosclerosis. 1991;87:147–157.[Medline] [Order article via Infotrieve]
25. Superko HR, Krauss RM, Di Ricco C. Effect of fluvastatin on low-density lipoprotein peak particle diameter. Am J Cardiol. 1997;80:78–81.[Medline] [Order article via Infotrieve]
26. Langtry HD, Markham A. Fluvastatin: a review of its use in lipid disorders. Drugs. 1999;57:583–606.[Medline] [Order article via Infotrieve]
27. Baumstark MW, Kreutz W, Berg A, et al. Structure of human low-density lipoprotein subfractions, determined by x-ray small-angle scattering. Biochim Biophys Acta. 1990;1037:48–57.[Medline] [Order article via Infotrieve]
28.
Wieland H, Seidel
D. Improved assessment of plasma lipoprotein patterns, IV: simple
preparation of a lyophilized control serum containing intact human
plasma lipoproteins. Clin Chem. 1982;28:1335–1337.
29. Lindgren FT. Preparative ultracentrifuge laboratory procedures and suggestions for lipoprotein analysis. In: Perkins EG, ed. Analysis of Lipids and Lipoproteins. Champaign, Ill: American Oil Chemical Society; 1975:204–224.
30.
McNamara JR,
Jenner JL, Ji Z, et al. Change in LDL particle size is associated with
change in plasma triglyceride concentration.
Arterioscler Thromb. 1992;12:1284–1290.
31. Tsai MY, Yuan J, Hunninghake DB. Effect of gemfibrozil on composition of lipoproteins and distribution of LDL subspecies. Atherosclerosis. 1992;95:35–42.[Medline] [Order article via Infotrieve]
32. Bruckert E, Dejager S, Chapman MJ. Ciprofibrate therapy normalises the atherogenic low-density lipoprotein subspecies profile in combined hyperlipidemia. Atherosclerosis. 1993;100:91–102.[Medline] [Order article via Infotrieve]
33.
Guerin M,
Bruckert E, Dolphin PJ, et al. Fenofibrate reduces plasma cholesteryl
ester transfer from HDL to VLDL and normalizes the atherogenic, dense
LDL profile in combined hyperlipidemia.
Arterioscler Thromb Vasc Biol. 1996;16:763–772.
34. Superko HR, Krauss RM. Differential effects of nicotinic acid in subjects with different LDL subclass patterns. Atherosclerosis. 1992;95:69–76.[Medline] [Order article via Infotrieve]
35. Castelli WP, Anderson K, Wilson PW, et al. Lipids and risk of coronary heart disease: the Framingham Study. Ann Epidemiol. 1992;2:23–28.[Medline] [Order article via Infotrieve]
36.
Gaw A, Packard
CJ, Murray EF, et al. Effects of simvastatin on apoB metabolism and LDL
subfraction distribution. Arterioscler
Thromb. 1993;13:170–189.
37. Hayashi K, Kurokawa J, Nomura S, et al. Effect of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase, on the induction of low-density lipoprotein receptor in HepG2 cells. Biochim Biophys Acta. 1993;1167:223–225.[Medline] [Order article via Infotrieve]
38. Soutar AK, Myant NB, Thompson GR. The metabolism of very-low-density and intermediate-density lipoproteins in patients with familial hypercholesterolemia. Atherosclerosis. 1982;43:217–231.[Medline] [Order article via Infotrieve]
39.
Packard CJ,
Shepherd J. Lipoprotein heterogeneity and apolipoprotein B metabolism.
Arterioscler Thromb Vasc Biol. 1997;17:3542–3556.
40.
Zambon A, Austin
MA, Brown BG, et al. Effect of hepatic lipase on LDL in normal men and
those with coronary artery disease.
Arterioscler Thromb. 1993;13:147–153.
41. Watson TDG, Caslake MJ, Freeman DJ, et al. Determinants of low-density lipoprotein subfraction distribution and concentrations in young normolipidemic subjects. Atherosclerosis. 1994;107:45–54.[Medline] [Order article via Infotrieve]
42.
Tan CE, Forster
L, Caslake MJ, et al. Relations between plasma lipids and postheparin
plasma lipases and VLDL subfractions in normolipidemic men and women.
Arterioscler Thromb Vasc Biol. 1995;15:1839–1848.
43. Hoogerbrugge N, Jansen H. Atorvastatin increases low-density lipoprotein size and enhances high-density lipoprotein cholesterol concentration in male, but not in female patients with familial hypercholesterolemia. Atherosclerosis. 1999;146:167–174.[Medline] [Order article via Infotrieve]
44. Superko HR, Wood PD, Krauss RM. Effect of alpha- and selective beta-blockade for hypertension control on plasma lipoproteins, apoproteins, lipoprotein subclass, and postprandial lipemia. Am J Med. 1989;86(suppl 1B):26–31.
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  R. H. Samson The Role of Statin Drugs in the Management of the Peripheral Vascular Patient Vascular and Endovascular Surgery, August 1, 2008; 42(4): 352 - 366. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Rizzo and K. Berneis Low-density lipoprotein size and cardiovascular risk assessment QJM, January 1, 2006; 99(1): 1 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M Backes and C. A Gibson Effect of Lipid-Lowering Drug Therapy on Small-Dense Low-Density Lipoprotein Ann. Pharmacother., March 1, 2005; 39(3): 523 - 526. [Abstract] [Full Text] [PDF]
|
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 |
|
 F. M. Sacks and H. Campos Low-Density Lipoprotein Size and Cardiovascular Disease: A Reappraisal J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4525 - 4532. [Full Text] [PDF]
|
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|
 |
|
 K. Winkler, T. Konrad, S. Fullert, I. Friedrich, R. Destani, M. W. Baumstark, K. Krebs, H. Wieland, and W. Marz Pioglitazone Reduces Atherogenic Dense LDL Particles in Nondiabetic Patients With Arterial Hypertension: A double-blind, placebo-controlled study Diabetes Care, September 1, 2003; 26(9): 2588 - 2594. [Abstract] [Full Text] [PDF]
|
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|
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R. A. Kreisberg and A. Oberman Medical Management of Hyperlipidemia/Dyslipidemia J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2445 - 2461. [Full Text] [PDF]
|
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|
|
|
K. Winkler, C. Abletshauser, M. M. Hoffmann, I. Friedrich, M. W. Baumstark, H. Wieland, and W. Marz 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 J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5485 - 5490. [Abstract] [Full Text] [PDF]
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 R. M. Krauss, H. Campos, and F. M. Sacks Is the Size of Low-Density Lipoprotein Particles Related to the Risk of Coronary Heart Disease? JAMA, February 13, 2002; 287(6): 712 - 713. [Full Text] [PDF]
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