European Heart Journal Supplements (2004) 6 (Supplement C), C58–C63
Are the effects of statins on HDL-cholesterol
clinically relevant?
M.J. Chapman
^pital de la Pitie
, Paris Cedex 13, France
National Institute for Health and Medical Research (INSERM), Unit 551, Ho
KEYWORDS
It has been established that the level of plasma high-density lipoprotein (HDL)-cholesterol is inversely proportional to the risk of coronary heart disease (CHD). HDL
particles are highly heterogeneous, particularly in terms of their biological activities,
many of which are atheroprotective. For example, in addition to carrying out reverse
cholesterol transport, HDL protects the vascular endothelium by inhibiting monocyte
adhesion and the oxidative modification of low-density lipoprotein (LDL), eliminates
some of the atherogenic products of LDL oxidation, and possesses antithrombotic
activity, due to the inhibition of platelet activation and aggregation. Statin therapy
has been shown to increase the level of plasma HDL-cholesterol. However, the clinical
benefit of statin-induced elevation of HDL-cholesterol is unclear from trial data,
perhaps as a result of the concomitant overwhelming risk benefit of statin-induced
reduction of LDL-cholesterol.
c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights
reserved.
Atheroprotection;
High-density lipoprotein;
Low-density lipoprotein;
Statin therapy
Introduction
The relationship between plasma high-density lipoprotein
(HDL)-cholesterol levels and the development of atherosclerosis is complex. However, it has been established
that an independent, inverse relationship exists between
the level of plasma HDL-cholesterol concentration and
the risk of coronary heart disease (CHD).1 Subnormal HDLcholesterol levels (<44 mg dl1 ) constitute the most
common form of familial dyslipidaemia occurring in kindreds with CHD.2 Moreover, a meta-analysis of four prospective studies (the Framingham Heart Study, the
Multiple Risk Factor Intervention Trial (MRFIT), the Lipid
Research Clinics Prevalence Mortality Follow-up Study
and the Coronary Primary Prevention Trial) revealed that
CHD risk is elevated by 3% in women and 2% in men for
each 1 mg dl1 (0.026 mmol l1 ) decrement in HDL-cholesterol.3 However, the question of whether each 1
mg dl1 increment in HDL-cholesterol may confer a 2–3%
decrease in CHD risk awaits confirmation in prospective
trials in which the clinical benefit of raising HDL-cholesterol can be readily identified, independently of reduction
Correspondence: National Institute for Health and Medical Research,
^pital de la Pitie
, 83, boulevard de l’ho
^pital, 75651 Paris Cedex 13,
Ho
France. Tel./fax: þ33-1-45-82-81-98.
E-mail address: [email protected] (M.J. Chapman).
in levels of atherogenic apolipoprotein B-containing
lipoproteins. Nevertheless, high levels of HDL-cholesterol
(>65 mg dl1 (1.7 mmol l1 ) were shown to afford protection against CHD events in the Framingham Study,
even when low-density lipoprotein (LDL)-cholesterol
concentrations were elevated above 160 mg dl1
(4.1 mmol l1 ) (Fig. 1).4 At low levels of HDL-cholesterol,
however, the level of LDL-cholesterol is the more robust
predictor of risk and, indeed, CHD risk is elevated at all
concentrations of LDL-cholesterol (Fig. 1).4
Despite such observations at the population level, the
precise impact and value of raising HDL-cholesterol in a
given individual remains uncertain, particularly as clinical benefit may be conditioned by the global risk profile
of that individual, thereby reflecting risk factor interaction.5 The guidelines of the Third Adult Treatment
Panel (ATP III) of the National Cholesterol Education
Program (NCEP) recognize low levels of HDL-cholesterol
as a major cardiovascular risk factor, although specific
targets for HCL-C are not recommended.6
The structure and function of HDL
In order to understand the mechanistic basis of the antiatherogenic activity of circulating HDL particles, it is
1520-765X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ehjsup.2004.04.002
Are the effects of statins on HDL-cholesterol clinically relevant?
C59
FC,PL
ABCA1
ApoAI
Apo AI
FC+PL
Pre-β-HDL
LCAT
Liver
Intestine
LCAT
Discs
(PL+FC+apoAI)
Plasma
HDL
Pool
Surface
fragments
Lipolysis
PL+FC
+ Apo’s
Chylomicrons
VLDL
Fig. 1 HDL-cholesterol versus LDL-cholesterol as a predictor of cardiovascular risk: Framingham data. This information was originally published
in [4].
necessary to consider their structure and function. The
HDL fraction is defined as that isolated over the density
range from 1.063 to 1.21 g/ml; these particles equally
exhibit small size (Stokes diameter 5–17 nm).7 HDL
particles are highly heterogeneous, due to qualitative
and quantitative differences in lipid, protein and enzyme
content, and vary in their hydrated density, surface and
core fluidity, surface charge and antigenicity.8 Typically,
ultracentrifugation separates two major HDL fractions:
HDL2 (1:063 < d < 1:125 g/ml) and HDL3 (1:125 < d <
1:250 g/ml). HDL contains two major apolipoproteins –
ApoA-I and ApoA-II, and minor amounts of the low molecular weight apolipoproteins ApoE, C-I, C-II and C-III.
The surface of an HDL particle is covered by apoproteins,
phospholipid and free cholesterol. The core of HDL
particles, which may constitute up to 20% of the total
particle mass, contains both cholesteryl ester (CE) and
triglycerides (TG). Most HDL particles are quasi-globular
in shape and migrate on agarose gel electrophoresis in a
fraction with a-electrophoretic mobility. However,
newly synthesized HDL molecules lack a central nonpolar core, have a disc-like bilayer structure, and exhibit
pre-a- or pre-b-electrophoretic mobility. Structurally,
there are two major families of HDL particles: those
that contain ApoA-I alone, and those that contain
both ApoA-I and ApoA-II. The former contains two major particle subpopulations on the basis of size,
whereas the latter contains three. These particle
species are spread throughout the density range
1.063–1.21 g/ml.
In addition to their physicochemical heterogeneity,
HDL particles are highly heterogeneous in their origin,
formation, intra-vascular metabolism and tissue catabolism. Furthermore, it is becoming increasingly clear
that HDL particles are even more heterogeneous in terms
of their biological activities.
HDL formation
The liver and intestine are able to produce the major
apoproteins of HDL and there are three major pathways
of HDL formation (Fig. 2).
LDL
Fig. 2 Pathways of HDL formation.
1. ApoA-I can be secreted in lipid-poor form and,
through the ATP binding cassette transporter protein
AI (ABCA1), it can pick up free cholesterol on
phospholipid from peripheral cells, to form pre-bHDL particles, which are avid acceptors of cellular
cholesterol. Under the influence of the lecithin:cholesterol acyltransferase (LCAT) enzyme, free cholesterol is esterified to CE and these particles are
transformed into spherical, mature HDL, which contains a CE-rich hydrophobic core.
2. Nascent discoid particles containing ApoA-I, phospholipid and free cholesterol are secreted and transformed, by the action of the LCAT enzyme, into
mature HDL.
3. TG-rich lipoproteins, chylomicrons and very low-density lipoprotein (VLDL) are lipolyzed by lipoprotein lipase and, as a consequence, surface fragments
containing phospholipid, free cholesterol and small
apoproteins are released from these particles. These
surface fragments sequester to the HDL pool. Since
this pathway is deficient in individuals with hypertriglyceridaemia, we can reasonably predict that HDL
levels will be subnormal in these individuals.
Biological properties of HDL particles
Since the original seminal hypothesis of Gordon et al.
was proposed in 1977,9 the atheroprotective role associated with HDL has become widely recognized. Whether HDL is implicated directly or indirectly in
atherogenesis has still to be determined, but a plethora
of potential mechanisms that may account for the cardioprotective effects of HDL have been documented,
several of which may be mutually interactive and,
indeed, synergistic.
The inverse correlation between HDL levels and CHD
risk might be explained by the ability of HDL to remove
cholesterol from the peripheral circulation and deliver it
to the liver for excretion in the bile, in the process known
as reverse cholesterol transport.10 ApoB100-containing
particles deliver cholesterol to peripheral tissues and to
C60
the developing plaque, whereas HDL, primarily through
the scavenger receptor class B type I (SR-BI/Cla-1) and
LIMPII analogous 1 (CD-36) receptor on human macrophages, is able to pick up cholesterol from atherosclerotic plaque and return it to the liver for excretion in the
form of bile acids. Although reverse cholesterol transport
is one of the major functions of HDL particles, HDL exerts
several other potentially anti-atherogenic actions.
An early cellular event in atherogenesis is the adhesion of mononuclear leukocytes to the endothelium.
This occurs via the expression of cell adhesion molecules on the endothelial surface, principally vascular
cell adhesion molecule-1 (VCAM-1), but also intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Cytokine-induced expression of VCAM-1, ICAM-1 and
E-selectin is inhibited by HDL, the most pronounced
inhibition of these molecules occurring at physiological
concentrations of HDL.11–13 HDL, in particular HDL2 , has
also been shown to abrogate the adhesion of monocytes
to endothelial cells that is induced as a result of the upregulation of monocyte chemotactic protein-1 by oxidized LDL.14
The oxidation of LDL is an integral part of the atherosclerotic process. Oxidized LDL acts as a chemoattractant for monocytes, transforms macrophages into
foam cells, exerts cytotoxic effects on the endothelium,
stimulates the migration and proliferation of vascular
smooth muscle cells (VSMC), and exacerbates the vasodilative effect of nitric oxide.15;16 HDL has been shown to
inhibit the oxidative modification of LDL.17;18 This antioxidant activity is due in part to the fact that HDL particles contain the enzyme paraoxonase, which hydrolyzes
lipid peroxides.10;19 HDL can also eliminate some of the
products of LDL oxidation, such as cytotoxic lipoperoxides and lysophosphatidylcholine.20–22
The formation of atherosclerotic plaques is generally
preceded by functional changes in the vessel wall, which
include reduced local availability of nitric oxide, enhanced surface expression of cell adhesion molecules,
changes in inflammatory markers, production of cytokines, and the oxidative modification of lipoproteins.23–25
Vessel function is controlled predominantly by the endothelium, and endothelial dysfunction may promote
intra-vascular coagulation and macrophage infiltration
into the vessel wall, decrease fibrinolysis and impair
vasorelaxation.26 By inhibiting the oxidation of LDL, HDL
protects the endothelium from acetylcholine-mediated
vasodilatation, and antagonizes the inhibition of vasodilatation caused by lysophosphatidylcholine.27;28 HDL has
also been shown to inhibit the infiltration of oxidized LDL
into the vessel wall.28
HDL can protect endothelial cells from complementmediated lysis29;30 and has been shown to be a carrier of
the glycoprotein protectin, which inhibits complement
cytolysis.31 In addition, HDL can stimulate endothelial
synthesis of prostacyclin and prolong its plasma half-life,
which enhances vasorelaxation.32;33 Similarly, HDL can
stimulate the production of endothelin-1 by endothelial
cells,34 and modulate the production of naturietic peptide C.35 HDL also possesses antithrombotic activity, due
to the inhibition of platelet activation.36;37 Platelet ag-
M.J. Chapman
gregation is antagonized due to the presence of HDL
receptors on their surface.38;39
Statins and HDL
In the atherogenic dyslipidaemias, statins act to decrease levels of atherogenic lipoproteins and to re-establish equilibrium between cardioprotective HDL and
atherogenic ApoB-containing lipoproteins.40 As a consequence, cholesterol efflux from the plaque is enhanced,
whereas cholesterol influx from atherogenic lipoproteins
is considerably diminished. A decrease in plaque cholesterol and macrophage content decreases inflammation and enhances plaque stability, resulting in a
decrease in cardiovascular events (Fig. 3).40
Such features of statin action have been demonstrated in a recent study, in which the effect of atorvastatin on the progression of atherosclerosis was
quantified using postmortem Raman spectroscopic plaque imaging in APOE*3 Leiden transgenic mice, who were
fed a high-fat/high-cholesterol diet for 28 weeks.41 In
the control group, Raman spectroscopy revealed large
areas of cholesterol-loaded foam cells and a minimal
area of VSMC. By contrast, in the group treated with
atorvastatin, there was a greatly reduced surface area of
macrophage foam cells and a dramatic increase in the
area of extra-cellular matrix and VSMC.41
At their most frequently used doses, treatment with
atorvastatin, fluvastatin, pravastatin and simvastatin
results in an elevation in HDL-cholesterol that varies
between 3% and 12% in type IIA and type IIB hyperlipidaemia. However, there are indications from recent
literature that these effects may be, to some degree,
phenotype-specific.42
The Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study was a randomized, doubleblind trial that compared the effects of 2 years of
treatment with either high-dose atorvastatin (80 mg/
day) or moderate-dose simvastatin (40 mg/day) in 325
patients with familial hypercholesterolaemia.42 The
Fig. 3
Statins, HDL and plaque stability. From Sposito and Chapman.40
Are the effects of statins on HDL-cholesterol clinically relevant?
C61
study showed that both statins induced a significant
(P < 0:0001) increase in HDL-cholesterol levels of approximately 13%.42
The mechanistic basis of statin-mediated
HDL-cholesterol elevation
Animal studies have demonstrated that the CLA-1/SR-B1
receptor pathway accounts for approximately 50% of the
cholesterol that is returned to the liver by HDL
particles.42 The remaining 50% of reverse cholesterol
transport is carried out via the cholesterol-ester-transfer-protein-mediated mechanism. The CE formed in HDL
by LCAT is transferred to both VLDL and LDL, and so this
mechanism is potentially atherogenic, since the cholesterol content and mass of these particles is increased
(Fig. 4).
Statins induce an increase in ApoA-I production of
approximately 15%, primarily in the liver.43 In addition,
as a result of an increase in the expression of LDL receptors, there is a dramatic reduction (up to approximately 50%) in the numbers of potentially atherogenic
acceptors of CE via the CE transfer protein (CETP)
mechanism from HDL. Guerin et al.44;45 have shown that
low-dose atorvastatin induces a 30% reduction in the
ability of CETP to transfer CE from HDL to these particles, as a result of a marked reduction in the numbers of
ApoB-100-containing particle acceptors. Moreover, treatment with atorvastatin significantly increased plasma
ApoA-I levels (þ24%; P < 0:05), suggesting that this statin enhances ApoA-I production and the formation of
nascent pre-b HDL particles.43
Statin-induced HDL-cholesterol elevation and
HDL particle function
Guerin et al.44 recently investigated the ability of plasma
from patients with type IIB dyslipidaemia to enhance free
cholesterol efflux from cultured Fu5AH hepatoma cells.
These cells release cholesterol via the SR-B1 mechanism.
The study showed that plasma from patients treated with
10 mg/day atorvastatin increased cholesterol efflux by
15% (P ¼ 0:0003), and plasma from patients treated with
Fig. 4
The mechanism of statin action on HDL-cholesterol.
Fig. 5 Prospective Pravastatin Pooling Project: baseline HDL and CHD
events. From Sacks et al.46
40 mg/day increased cholesterol efflux by a further 35%
(P < 0:0001), compared with baseline levels.
Clinical relevance of statin-induced elevation in
HDL-cholesterol
In the Prospective Pravastatin Pooling Project, data
from three large randomized trials with pravastatin
40 mg/day (the West Of Scotland COronary Prevention
Study (WOSCOPS), the Cholesterol And Recurrent Events
study (CARE), and the Long-term Intervention with
Pravastatin in Ischemic Disease study (LIPID)) were analyzed using a prospectively defined protocol.46 When
CHD event rates were plotted against HDL quintile
ranges, it was shown that, in patients treated with
placebo, an increasing level of HDL-cholesterol was
associated with a reduction in event rate (Fig. 5). In
patients treated with pravastatin, there was no apparent additional effect due to HDL-cholesterol in terms of
reduction of events, and cardiovascular risk remained
very high in patients with low levels of HDL-cholesterol
(Fig. 5).46
A meta-analysis of four prospective studies (the Framingham Heart Study, the Multiple Risk Factor Intervention Trial [MRFIT], the Lipid Research Clinics
Prevalence Mortality Follow-up Study and the Coronary
Primary Prevention Trial) showed that every 1 mg dl 1
(0.026 mmol l1 ) increase in HDL-cholesterol is associated with a significant CHD risk reduction of 2% in men
and 3% in women.3 However, in both primary and
secondary prevention trials with statins, only small,
insignificant increases in HDL-cholesterol were achieved:
in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), treatment with lovastatin
resulted in a 6% mean increase in HDL-cholesterol;47 in
the West Of Scotland COronary Prevention Study
(WOSCOPS), treatment with pravastatin resulted in a 5%
increase;48 in the Cholesterol And Recurrent Events trial
(CARE), pravastatin also increased HDL-cholesterol by
5%;49 and in the Scandinavian Simvastatin Survival Study
(4S), simvastatin increased HDL-cholesterol by 8% (nonsignificant when corrected for the placebo group).50
Therefore, at the present time, there is no clear
indication that HDL-cholesterol elevation by statins
translates into clinical benefit.
C62
Conclusion
The anti-atherogenic actions of HDL particles are now
well established, and epidemiological data from several
cohort studies suggest that HDL-cholesterol elevation is
associated with a reduction in CHD risk.
At commonly used doses, treatment with statins is
associated with minor elevations in HDL-cholesterol.
Recent data suggest that statin therapy may be associated with enhanced cholesterol efflux and enhanced reverse cholesterol transport. However, definitive proof
for the clinical relevance of statin-mediated elevation of
HDL-cholesterol is presently lacking. This may be a
consequence of the difficulty in disassociating this effect
from the overwhelming risk benefit associated with the
major reduction in LDL-cholesterol achieved with statin
therapy.
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