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Pleiotropic Effects of Statins
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Acta Cardiol Sin 2005;21:190-8
Pleiotropic Effects of Statins
Daniel Pella, Rafael Rybar and Viola Mechirova
In the last decades, substantial progress has been made in understanding the relationship between lipid disorders and
the prevention of cardiac ischemic disease. The identification of new therapeutic targets and new lipid-modifying
agents expands treatment options. Statins have been described as the principal and most effective class of drugs to
reduce serum cholesterol levels and cardiovascular events in patients with or without coronary artery disease.
Since the discovery of the first statin nearly 30 years ago, this class of drugs has advanced to become the mainstay of
cholesterol-lowering therapy. It was found during recent years that many of statins, positive effects could not be
explained simply by lowering of atherogenic lipids. There were shown also to exist non-lipid-modifiable effects of
statins called pleiotropic ones, which could be responsible for this additional benefit. The most important positive
pleiotropic effects of statins are antiinflammatory, antiproliferative, and antithrombotic ones, improving endothelial
dysfunction and others.
Key Words:
Statins · Pleiotropic effects · Atherosclerosis
INTRODUCTION
able to inhibit activity of one of the enzymes in the
cascade of cholesterol synthesis, 3-hydroxy-3 methylglutaryl coenzyme A reductase (HMG CoA reductase).3
This substance was used for further name statins (vastatins). Two decades of research after discovery were
sufficient for conclusion that statins were considered a
very important group of drugs (professor Roberts stated
that statins were for atherosclerosis the same as was penicillin for infectious diseases).4 Statins have become one
of the basic pillars in the secondary and primary prevention of atherosclerosis.5-9 Their role is documented in
preventing progression of atherosclerosis, and they are
even able to cause regression of the disease. Decrease of
cardiovascular endpoints, but also total mortality found
in clinical studies could not be explained only by the decrease of atherogenic lipids – it was greater than benefit
from lipid lowering. Speculation about so called pleiotropic effects (non-lipid-modifiable) appeared and was
confirmed by further research activity.
Cardiovascular disease, which includes coronary
heart disease, stroke, and peripheral arterial disease, is
the leading cause of death worldwide. In 2001, cardiovascular diseases contributed to nearly one third of all
global deaths.1 According to World Health Organization
statistics, more than 16 million people die of cardiovascular disease each year, and 7.2 million deaths in 2001
were caused by heart disease. 2 By the year 2020, approximately 25 million deaths annually worlwide are expected from cardiovascular disease, and almost half of
those deaths (11.1 million) will be from coronary heart
disease.2
Statins were discovered in 1976 when Endo et al.
found that a product of mould Penicillium citricum was
Received: December 29, 2004 Accepted: July 7, 2005
1st Internal Clinic, Faculty of Medicine PJ Safarik University Kosice,
Slovakia
Address correspondence and reprint requests to: Prof. Daniel Pella,
MD, PhD, 1st Internal Clinic, Faculty of Medicine PJ Safarik
University, Trieda SNP 1, 040 66 Kosice, Slovakia. Tel: 421 55 640
3409; Fax: 421 51 7725 118; E-mail: [email protected]
Acta Cardiol Sin 2005;21:190-8
CHARACTERISTICS OF STATINS
Statins are a chemically and pharmacologically di190
Pleiotropic Effects of Statins
questions about additional beneficial effects of statins,
because mevalonate, the product of the enzyme reaction,
is the precursor not only of cholesterol but also of many
nonsteroidal isoprenoid compounds, and inhibition of
HMG-CoA reductase may produce pleiotropic effects
(see Figure 1).
Indeed, the mevalonate pathway yields a series of
isoprenoids that are vital for diverse cellular functions.11
These isoprenoids include: isopentanyl adenosine, present in some types of transfer RNA; dolichols, required
for glycoprotein synthesis; and polyisoprenoid side
chains of ubiquinone and heme A, involved in electron
transport. Several proteins have also been identified that
are post-translationally modified by the covalent attachment of mevalonate-derived isoprenoid groups-either
farnesyl or geranylgeranyl pyrophosphate. These proteins must be prenylated as a prerequisite for membrane
association, which is required for their function. Members of this family are involved in a number of cellular
processes, including cell signaling, cell differentiation
and proliferation, myelination, cytoskeleton dynamics,
verse group of drugs that share the ability to inhibit
hydroxymethylglutaryl coenzyme A reductase (HMGCoA reductase), the enzyme that controls the ratelimiting step of cholesterol synthesis, but this inhibition
is followed by other subsequences associated with the
mevalonate pathway (Figure 1).
The clinically beneficial effects of statins were usually assumed to result from their ability to reduce cholesterol synthesis. In 1994, the landmark Scandinavian
Simvastatin Survival Study (4S) established the benefits
of a HMG-CoA reductase inhibitor on mortality in patients with atherosclerosis.5 In accord with traditional
acceptance of atherosclerosis as a consequence of lipid
disorders, post-hoc analysis of the 4S trial suggested that
the benefit provided by simvastatin in individual patients
indeed related to the magnitude of change in low-density
lipoprotein cholesterol.10 Subsequent studies, however,
differed with this conclusion even as they affirmed the
clinical benefits of statins as a class on cardiovascular
morbidity and mortality in patients with or without established atherosclerotic disease.6-9 These studies raised
Acetyl CoA
HMG-CoA
HMG CoA reductase
mevalonate
isopentanyl – PP*
geranyl-PP ® dekaprenyl-PP ® dekaprenyl 4OH benzoate ® CoQ10
squalene ¬ ¾ farnesyl-PP ¾ ® farnesylated proteins
cholesterol
geranylated proteins activation NFkB** ® inflammation
proliferation of SMC***
*PP – pyrophosphate
**NFkB – nuclear factor kappa B
***SMC – smooth muscle cells
Figure 1. Cholesterol (mevalonate) synthesis pathway.
191
Acta Cardiol Sin 2005;21:190-8
Daniel Pella et al.
terol particles, and secondly, they have protective effect
on myocyte membrane in ubiquinone deficiency which
may appear during long-term statin therapy.16,18
The main action of statins is to specifically and reversibly inhibit HMG-CoA reductase, which controls the
rate-limiting step in cholesterol synthesis. Several studies have compared lipid-lowering effects of different
statins head to head. In one of the latest, STELLAR
study, rosuvastatin in the dosage of 40 mg was more
effective than all currently available statins in all recommended doses. LDL cholesterol was lowered by 55%
with rosuvastatin 40 mg daily.19
These differences in efficacy were confirmed in a
meta-analysis of 164 studies published in 2003. Here
also, the different statins showed a two- to three-fold difference in the extent of LDL cholesterol lowering across
the dosage range.20
The effect on HDL cholesterol was compared as
well in the STELLAR study. It was shown that rosuvastatin had the greatest potency to increase HDL cholesterol, followed by simvastatin and atorvastatin (maximal
increase 9.6% vs 6.8% vs 5.7%).21 The recent study of
Bevilacqua showed different results.22 Compared were
fluvastatin extended release form 80 mg daily, which
was superior to atorvastatin 20 mg daily. However, in
general, statins have much lower potency to increase
HDL in comparison with fibrates or nicotinic acid.
Surprisingly, it was shown in the MIRACL trial that
high-density lipoprotein, but not low-density lipoprotein
cholesterol levels, influenced short-term prognosis after
acute coronary syndrome, and this finding suggested that
the clinical benefit of atorvastatin after acute coronary
syndrome was mediated by qualitative changes in the
and endocytotic/exocytotic transport.
Hence, through the inhibition of HMG-CoA reductase, statins may affect a variety of processes; this may
help to explain their non-lipid-related pharmacologic
properties. Indeed, several recent in vitro and in vivo experiments have demonstrated that HMG-CoA reductase
inhibitors have antiatherosclerotic effects that are not related to lipid lowering. Because of their broad effects
and their extremely low incidence of side effects, statins
might even be seen as the new aspirin.12
The currently available statins are lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin and rosuvastatin. Cerivastatin was withdrawn from the market
in 2001 due to increased number of fatal rhabdomyolyses.13
It seems that the process of metabolization of statins
is important from the safety point of view. Several of
them are metabolized via cytochrome P450 (see Table
1).14-16 However, only a small proportion of rosuvastatin
and fluvastatin are metabolized via cytochrome P450
2C9, so there is no high risk of dangerous drug interactions associated with the use of these statins as well.
Patients taking several drugs metabolized by the same
cytochrome P450 are at higher risk of side effects of
statins. Only two of the currently available statins are
hydrophilic – pravastatin and rosuvastatin – this could
also be important in prevention of “increased fluidity” of
muscle cell membrane and then increased risk of myopathy or even rhabdomyolysis.16 Antioxidant activities
of statins differ (the greatest is observed in atorvastatin,
with surprisingly much lower activity observed in rosuvastatin) and might be cardioprotective in two different
ways. Firstly, statins decrease oxidation of LDL cholesTable 1. Characteristics of statins
Dose range (mg/dL)
Maximal LDL-C reduction (%)
Serum triglyceride reduction (%)
Serum HDL-C increased (%)
Penetration to CNS
Renal excretion (%)
Mechanism of hepatic metabolism
Hydro/lipophilic properties
Acta Cardiol Sin 2005;21:190-8
Atorvastatin
Lovastatin
Pravastatin Simvastatin
10-80
60
29
6
No
2
Cytochrome
p-450 3A4
10-80
40
16
8.6
Yes
10
Cytochrome
p-450 3A4
10-80
34
24
12
No
20
Sulfation
10-80
47
18
12
Yes
13
Cytochrome
p-450 3A4
lipophilic
lipophilic
hydrophilic
lipophilic
192
Fluvastatin
Rosuvastatin
20-80
5-40
24
55
10
43
8
9,2
No
No
<6
10
Cytochrome
Cytochrome
p-450 2C9
p-450 2C9
(small proportion) (small proportion)
lipophilic
hydrophilic
Pleiotropic Effects of Statins
LDL particle and/or by non-lipid (pleiotropic) effects of
the drug.23
upon endotheliumm, as was shown in study of Marchesi
et al. with atorvastatin and other statins.29,30
Statins and Antiinflammatory Effects
Recent research has shown that inflammation plays a
key role in coronary artery disease and other manifestations of atherosclerosis. Immune cells dominate early
atherosclerotic lesions, and activation of inflammation
can elicit acute coronary syndromes. Elevated markers
for inflammation such as CRP, interleukin-6, intercellular adhesion molecule-1 (ICAM-1), and serum
amyloid A have been associated with increased risk for
the first and reccurent cardiovascular events.31 Many experimental and clinical studies confirmed significant
reduction of CRP measured by high sensitive method (hs
CRP). The higher the baseline value of CRP, the higher
the decrease that has been observed, e.g. in the PROVE
IT study.32 In that study, decrease of hs CRP achieved
89% in the atorvastatin group and 85% in the pravastatin
group. Generally, the greatest decreases of hs CRP were
observed after treatment with atorvastatin or rosuvastatin. Increased levels of CRP were associated with
more pronounced monocyte migration and increased
LDL uptake by macrophages.33
PLEIOTROPIC EFFECTS – DEFINITION
Drugs usually have multiple effects; through an analogy with single genes which affect more than one
system or determine more than one phenotype, they are
currently referred to as “pleiotropic effects” (from the
Greek “pleion,” meaning more, and “tropos,” meaning
direction or turn). These may be related or unrelated to
primary mode of action of the drug. Pleiotropic effects
may emerge during preclinical and clinical studies in
drug development, but more often than not, they are discovered a posteriori long after the therapeutic agent is
marketed (the same situation occurs in use of statins).
They may be undesirable and recognized as adverse side
effects, they may be neutral, or they may be beneficial,
enhancing the desirable effect of a drug.24
ANTIATHEROGENIC PLEIOTROPIC
EFFECTS OF STATINS
Statins and Plaque Growth
Statins have antiproliferative effects and inhibit
transformation of contractile smooth muscle cells to
reparatory-type cells and their migration from arterial
media into intima. 34 Statins decrease synthesis of extracellular matrix and proteins Rac1, Rho A as well, and
by this means decrease plaque growth.35
Substantial differences have been found between the
statins. For example, in the ASAP study, it was shown
that at the highest therapeutic dose, two years of treatment with atorvastatin reduced the thickness of the
arterial wall, while after simvastatin treatment, the thickness of the arterial wall continued to increase.36 Similar
results were achieved in the ARBITER study when
atorvastatin and pravastatin were compared.37 In a very
recent study, REVERSAL, where intravascular ultrasound method was used to quantify atherosclerosis, after
18 months of therapy with atorvastatin 80 mg daily, volume of the atherosclerotic plaque slightly decreased,
while the volume of the plaque continued to increase
during therapy with pravastatin 40 mg daily.38
The most important pleiotropic antiatherogenic effects of statins are improvement of endothelial dysfunction, antioxidative properties, antiinflammatory, antiproliferative and antithrombotic effects and neoangiogenesis.25 Statins inhibit by blocking HMG-CoA reductase,
and also by blocking synthesis of geranylated proteins
responsible for proliferation and migration of smooth
muscle cells from vessel media to intima and their conversion from contractile to reparatory type which are
causes growth of atherosclerotic plaque. Also, synthesis
of farnesylated proteins is inhibited, that is why also activity of nuclear factor kappa B is decreased. This factor
plays very important role in the initiation of inflammatory process-atherosclerosis is inflammatory disease.26
Statins and Endothelial Dysfunction
Abnormal endothelium-dependent vasomotor responses predict the long-term progression of atherosclerosis and associated coronary events, as well as events
after vascular surgery.27,38 Statins are able to increase nitric oxide synthesis and improve blood flow dependent
193
Acta Cardiol Sin 2005;21:190-8
Daniel Pella et al.
Statins and Angiogenesis
Statins are able to activate proteinkinase Akt in endothelial cells and thereby stimulate activity of endothelial nitric oxide synthethase leading to increased NO
production and neoangiogenesis. Stimulation of proteinkinase Akt improves myocardial aerobic metabolism.
Statins increase also the level of angiopoetine.39
Given the fact that statins will be prescribed more
widely (“... statins to every patient with documented coronary artery disease...” Yusuf S, Lancet 2002), it is very
important to consider the safety of such therapy.45 Statin
therapy is long-term (even life-long, following evidence-based medicine), so the risk of adverse effects
might be increased. More clinical studies are needed in
order to confirm the beneficial effects of coenzyme Q10
substitution in long-term statin therapy. The International College of Cardiology, in its scientific statement,
recommended use of statins preferably in conjunction
with coenzyme Q10 in order to prevent possible myopathy.46
The recently published hypothesis by Moosmann
and Behl has identified a possible role of deficiency of
selenium and association with possible adverse effects of
statins, namely myopathy and polyneuropathy.47 They
noted that the pattern of side effects associated with
statins resembled the pathology of selenium deficiency,
and postulated that the mechanism lay in a wellestablished but often overlooked biochemical pathway –
the isopentylation of selenocysteine-tRNA. A negative
effect of statins on selenoprotein synthesis does seem to
explain many of the enigmatic effects and side effects of
statins, in particular, statin-induced myopathy.
In a recent study, Silver et al. evaluated left ventricular diastolic function with Doppler echocardiography
before and after statin therapy. Statin therapy worsened
diastolic parameters in most patients; coenzyme Q10
supplementation in patients with worsened diastolic
function with statin therapy improved parameters of diastolic function.48
Similar results were confirmed in the study of
Kumar et al. in more than 100 studied subjects (the study
of Silver et al. evaluated only 14 patients).49
What is very important to say is that statins are generally very well tolerated drugs and a remarkably safe class
of lipid lowering agents. These data probably lead to the
fact that in the United Kingdom simvastatin is now available in pharmacies without medical prescription.50
Statins and Plaque Rupture
Statins significantly reduce metalloproteinases activity, mainly of MMP1 and MMP3, which play important
roles in plaque rupture or fissuration. 40 Decrease of
blood pressure observed during long-term treatment with
statins lead to improvement of rheology and arterial
stiffness.41
Statins and Thrombosis
Statins have capacity to decrease global fibrinolytic
activity of the blood, decrease activity of PAI-1 and inhibit thrombine generation. Data regarding influence of
statins on fibrinogen levels are not so convincing.42
Statins and Plaque Stability
There were several pleiotropic effects of statins described which should be responsible for the stability of
the atherosclerotic plaque. Nevertheless, the most important finding for plaque stability is the combination of
lipid-lowering effects with pleiotropic ones (especially
decrease of plaque lipid core size and inhibition of inflammatory reaction).43
Possible Negative Pleiotropic Effects of Statins
Inhibition of HMG-CoA reductase leads not only to
decreased synthesis of cholesterol but also affects synthesis of other substances. Besides these positive pleiotropic effects, there is probably also a negative one,
namely, inhibition of geranyl pyrophosphate synthesis
and subsequently dekaprenyl-4-bensoate, which is a precursor of coenzyme Q10. Coenzyme Q10 (ubiquinone,
ubidekarenone) is a very important substance in myocardial energetic metabolism and the stability of cell
membrane as well; when deficient, myocytes could be
prone to damage in the form of myopathy or myositis, or
even rhabdomyolysis. 44 Deficiency of coenzyme Q10
will appear usually after longer duration of treatment and
may also be dependent on type of statin and its dosage.
Acta Cardiol Sin 2005;21:190-8
PLEIOTROPIC EFFECTS OF STATINS IN
NON-ATHEROSCLEROTIC DISEASE
Antiproliferative and antiinflammatory effects of
194
Pleiotropic Effects of Statins
Table 2. Possible beneficial pleiotropic effects of statins in non-atherosclerotic diseases
fibrosclerotic aortic stenosis
arterial hypertension
Alzheimer’s dementia
rheumatic diseases (rheumatoid arthritis)
sclerosis multiplex
sudden cardiac death prevention
deep venous thrombosis
regression of left ventricular hypertrophy
osteoporosis
vitiligo
Further study of pleiotropic functions of statins may
provide insights into the biology of atherosclerosis (and
other diseases e.g. osteoporosis, rheumatoid arthritis,
connective tissue diseases, etc.) that could yield benefits
in terms of targeting and developing novel strategies that
will address the residual burden of atherosclerotic complications that plague even those individuals who achieved current lipid goals.
statins have raised questions about possible use of statins
in diseases other than atherosclerosis, cardiovascular and
non-cardiovascular. Many clinical studies are in progress
which probably should enlighten us on their relative
clinical relevance and importance. Some of the diseases
involved in this research are listed in Table 2.51
CONCLUSIONS
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Statins have the same mode of action via inhibition
of HMG-CoA reductase activity but differ between each
other in the extent of this inhibition, which leads to different levels of LDL cholesterol lowering. Due to this
fact, not only cholesterol synthesis inhibited is but also
formation of inflammatory proteins, substances associated with smooth muscle cells proliferation and endogenous synthesis of coenzyme Q10.
Although the possibility that statins might have
pleiotropic effects was met at first with healthy scepticism, the vast amount of knowledge accrued over the
past few years has moved these effects into the spotlight.
Pleiotropic effects of statins are numerous and varied,
they may add to the desirable effect of a drug or be undesirable and interfere with the treatment. As the list of
pleiotropic effects effects of statins is expanding rapidly,
it will become essential to establish their relative biological significance and clinical relevance.
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current guidelines. Nevertheless, it will be important to
take action on the new indications which have emerged
from consideration of possible pleiotropic effects.
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Acta Cardiol Sin 2005;21:190-8
Review Article
Acta Cardiol Sin 2005;21:190−8
高血脂治療藥物 STATIN 的多重作用
Daniel Pella Rafael Rybar Viola Mechirova
1st Internal Clinic, Faculty of Medicine PJ Safarik University Kosice, Slovakia
近十年來，對於改善血脂肪異常與預防缺血性心臟病之間的研究逐漸開展。對於建立
新的治療標的與研發新的高血脂治療藥物也拓展臨床治療的選擇。不論病人是否具有冠狀
動脈心臟病，STATIN 已成為降低血膽固醇值與心血管疾病併發症最主要及最有效的藥物。
最近研究指出，STATIN 在治療心血管疾病的好處，不僅僅只從降低血膽固醇值方面解
釋。一些改善血脂肪異常以外的效果，如抗發炎、抗增生及抗血栓效果，以及改善內皮細
胞功能等，也扮演部份角色，本文將對這些改善血脂肪異常外之多重作用 (extra-lipid
pleiotropic effects) 作概略介紹。
關鍵詞：高血脂治療藥物、降血脂外多重作用、冠狀動脈心臟病。
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