Statins mechanism of action and effects

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					                                                                      J.Cell.Mol.Med. Vol 5, No 4, 2001 pp. 378-387


                    Statins: mechanism of action and effects

                                       Camelia Stancu, Anca Sima *

           "Nicolae Simionescu" Institute of Cellular Biology and Pathology, Bucharest, Romania

                            Received: November 12, 2001; Accepted: December 5, 2001

• Introduction                                                • Effects on
• Classification of statins                                        - cholesterol esterification and
     - How they are obtained                                         its accumulation in macrophages
     - Liver metabolism                                            - endothelial cell function
     - Physico-chemical properties                                 - inflammatory process
     - Specific activity                                           - proliferation, migration and
• Mechanisms for the action of statins                               apoptosis of arterial smooth muscle cells
     - Mechanisms involving lipids                                 - stability of the atherosclerotic plaque
     - Mechanisms involving intracellular                          - platelets activation
       signaling pathways                                          - coagulation process
• Beneficial effects of statins                               • Adverse effects of statins therapy
                                                              • Conclusions


The beneficial effects of statins are the result of their capacity to reduce cholesterol biosyntesis, mainly in the liver,
where they are selectively distributed, as well as to the modulation of lipid metabolism, derived from their effect of
inhibition upon HMG-CoA reductase. Statins have antiatherosclerotic effects, that positively correlate with the
percent decrease in LDL cholesterol. In addition, they can exert antiatherosclerotic effects independently of their
hypolipidemic action. Because the mevalonate metabolism generates a series of isoprenoids vital for different
cellular functions, from cholesterol synthesis to the control of cell growth and differentiation, HMG-CoA reductase
inhibition has beneficial pleiotropic effects. Consequently, statins reduce significantly the incidence of coronary
events, both in primary and secondary prevention, being the most efficient hypolipidemic compounds that have
reduced the rate of mortality in coronary patients. Independent of their hypolipidemic properties, statins interfere
with events involved in bone formation and impede tumor cell growth.

         Keywords: HMG CoA reductase • cell signaling • LDL oxidation • atherosclerosis • cancer •
                     osteoporosis • endothelial dysfunction • macrophage • smooth muscle cell

*Correspondence to: Dr. Anca SIMA                             8, B. P. Hasdeu Street, Bucharest 79691, Romania.
"Nicolae Simionescu" Institute of                             Tel.: (+401) 411.5240; Fax: (+401) 411.1143
Cellular Biology and Pathology                                E-mail:
                                                                              J.Cell.Mol.Med. Vol 5, No 4, 2001

Introduction                                             only for cholesterol, but also for many other non-
                                                         steroidal isoprenoidic compounds, inhibition of this
Statins, inhibitors of 3-hydroxy-3-methylglutaryl-       key enzyme may result in pleiotropic effects. They
coenzyme A (HMG-CoA) reductase, have revolu-             have been divided into two categories, involving:
tionized the treatment of hypercholesterolemia. They     directly lipids, or intracellular signaling pathways.
are the most efficient agents for reducing plasma        The first category includes: inhibition of cholesterol
cholesterol, being also appreciated for their good to-   biosynthesis, increased uptake and degradation of
lerance. Angiographic studies have demonstrated          low density lipoproteins (LDL), inhibition of the
that these compounds reduce the progression and          secretion of lipoproteins, inhibition of LDL
may induce the regression of atherosclerosis. These      oxidation, and inhibition of the scavenger receptors
effects were translated in significant cardiovascular    expression [3]. Statins modulate a series of processes
morbidity and mortality reductions in many clinical      leading to reduction of the accumulation of esterified
trials (WOSCOPS, AFCAPS/TexCAPS, HS, CARE,               cholesterol into macrophages, increase of endothelial
LIPID, HPS) [1]. The beneficial effects of the HMG-      NO synthetase, reduction of the inflammatory
CoA reductase inhibitors are usually attributed to       process, increased stability of the atherosclerotic
their capacity to reduce the endogenous cholesterol      plaques, restoration of platelets activity and of the
synthesis, by competingly inhibiting the principal       coagulation process [3].
enzyme involved [2]. Since mevalonate, the product           In addition, statins can inhibit tumor cells growth
of HMG CoA reductase reaction, is the precursor not      and enhance intracellular calcium mobilization. It

Fig. 1 Chemical structure of the statins and HMG-CoA.

was observed that inhibitors of HMG-CoA reductase          CYP 2C9 pathway, and pravastatin is metabolized
induce a reduction of the formation of osteoclasts in      differently [6]. The majority of the statins have a low
rodents [3]. Human subjects treated with statins have      circulation concentration: 12% for atorvastatin, 17%
shown a reduction in the number of bone fractures [4].     for pravastatin, 20-30 % for fluvastatin, 5% for
   The discovery of statins has led to an important        simvastatin and lovastatin. Cerivastatin has a
progress in the primary and secondary prevention           circulation distribution of more than 60%.
of coronary heart disease. Although angiographic
modifications following statin therapy were mo-            Physico-chemical properties
dest, clinical benefits that accompanied the therapy
have been significant. Numerous clinical studies           Pravastatin is extremely hydrophilic, fluvastatin has
have correlated the reduction of blood cholesterol         intermediar characteristics, lovastatin, simvastatin,
induced by these compounds with the reduction of           atorvastatin and cerivastatin are hydrofobic [7].
the number of major coronary events, as well as
general mortality in coronary patients [1].
                                                           Specific activity

                                                           Atorvastatin, cerivastatin, fluvastatin and
Classification of statins                                  pravastatin are administered as active compounds
                                                           (acid form). Lovastatin and simvastatin are
There are a number of classification criteria for          administered as inactive forms (lactone), which
statins, including: 1) how they are obtained, 2) liver     have to be enzymatically hydrolized to generate
metabolism, 3) physico-chimical properties, 4)             active forms [7].
specific activity.

How they are obtained                                      Mechanisms for the action of statins
Some of the statins are obtained after fungal              Mechanisms involving lipids
fermentation: lovastatin (Mevacor), pravastatin
(Lipostat, Pravachol) and simvastatin (Zocor), others      Dyslipidemia and hypercholesterolemia are
by synthesis: fluvastatin (Lescol), atorvastatin           controled by the liver. Hepatocytes take up from the
(Sortis, Lipitor), and cerivastatin (Baycol, Lipobay).     circulation ~ 50% of LDL cholesterol. An increase
    It must be stressed that on August 8, 2001, Bayer      in the activity of LDL receptor in hepatocytes could
AG voluntarily withdrew cerivastatin (Baycol,              be an efficient method to decrease plasma LDL
Lipobay) from the world pharmaceutical market,             cholesterol level.
after 31 patients died by acute renal failure caused
by rhabdomyolysis. FDA supported this decision.            Inhibition of HMG CoA reductase
As a result, only five statins are, at this moment, in     Statins target hepatocytes and inhibit HMG-CoA
clinical use: lovastatin, simvastatin, pravastatin,        reductase, the enzyme that converts HMG-CoA into
atorvastatin and fluvastatin.                              mevalonic acid, a cholesterol precursor. The statins
                                                           do more than just compete with the normal substrate
Liver metabolism                                           in the enzymes active site. They alter the
                                                           conformation of the enzyme when they bind to its
All statins have the liver as target organ. The            active site. This prevents HMG-CoA reductase from
percentage of the dose retained by the liver is as         attaining a functional structure. The change in
follows: > 70% for fluvastatin and lovastatin, >80%        conformation at the active site makes these drugs very
for simvastatin and 46% for pravastatin [5]. There         effective and specific. Binding of statins to HMG-
are no available data for atorvastatin and cerivastatin.   CoA reductase is reversible, and their affinity for the
For their liver metabolism, lovastatin, simvastatin,       enzyme is in the nanomolar range, as compared to the
atorvastatin and cerivastatin follow the citocrom          natural substrate, which has micromolar affinity [8].
P450 (CYP 3A4) pathway. Fluvastatin follows the            The inhibition of HMG-CoA reductase determines

                                                                                   J.Cell.Mol.Med. Vol 5, No 4, 2001

Table 1 Role of prenylated proteins in cellular functioning [3].

* in mammalian cells, 0.5-1% of total cellular proteins are geranyl-geranylated.

the reduction of intracellular cholesterol, inducing the   Reduction of LDL susceptibility towards oxidation
activation of a protease which slices the sterol           At least 4 mechanisms were proposed to explain sta-
regulatory element binding proteins (SREBPs) from          tins’ antioxidant properties [16]. (1) The hypochole-
the endoplasmic reticulum. SREBPs are translocated         sterolemic effect, resulting in reduced lipoprotein
at the level of the nucleus, where they increase the       cholesterol, and thus, reduced level of oxidation
gene expression for LDL receptor. The reduction of         substrate [17]. (2) The decrease of cell oxygen pro-
cholesterol in hepatocytes leads to the increase of        duction, by inhibiting the generation of superoxide by
hepatic LDL receptors, that determines the reduction       macrophages. Recently, it was demonstrated that
of circulating LDL and of its precursors (intermediate     statins can attenuate the formation of superoxide an-
density - IDL and very low density- VLDL                   ion in endothelial cells, by preventing the prenylation
lipoproteins) [9]. All statins reduce LDL cholesterol      of p21 Rac protein [18]. Statins can also prevent LDL
non-liniarly, dose-dependent, and after administration     oxidation by preserving the activity of the endoge-
of a single daily dose [5]. Efficacy on triglyceride       nous antioxidant system, like superoxide dismutase
reduction parallels LDL cholesterol reduction [10].        [19]. (3) The binding of statins to phospholipids on
                                                           the surface of lipoproteins (fluvastatin and lovastatin
Direct effects of HMG CoA reductase inhibition             bind to LDL phospholipids) preventing the diffusion
Statins inhibit hepatic syntesis of apolipoprotein B-      towards the lipoprotein core of free radicals generated
100, determining a reduction of the synthesis and          during oxidative stress [16]. (4) The potent
secretion of triglyceride rich lipoproteins [11] and an    antioxidative potential of the metabolites (i.e.
increase of receptors production for apolipoproteins       atorvastatin and fluvastatin metabolites) also results
B/E [12]. This can explain why atorvastatin and            in lipoproteins protection from oxidation.
simvastatin are capable of reducing LDL in patients
with homozigous family hypercholesterolemia,               Inhibition of the expression of type A scavenger re-
where LDL receptors are not functional [13, 14].           ceptor in THP-1 cells and in human monocytes [20],
Statins have a modest effect on HDL increase, and          which decrease the receptor-mediated degradation of
no influence on lipoprotein(s) concentration [15].         oxidised LDL. Statins can also reduce mRNA level

and CD36 expression on the cell surface, as well as           The mevalonate pathway yields a series of
LDL binding to human U937 monocytes [21].                  isoprenoids which are vital for diverse cellular
                                                           functions. These isoprenoids include: isopentenyl
Mechanisms involving intracellular                         adenosine, present in some types of transfer RNA,
signaling pathways                                         dolichols required for glycoprotein synthesis, and
                                                           poly-isoprenoid side chains of ubiquinone and
Prenylated proteins and their role in cellular signaling   hemeA, involved in electron transport [23].
A variety of proteins have covalently attached
isoprenoid groups, mainly the C15 farnesyl and C20
geranylgeranyl residues. The most common isopreny-         Beneficial effects of statins
lation site in proteins is the C-terminal “CaaX”,
where “C” is Cys, “a” is often an aliphatic aminoacid      Effects on cholesterol esterification and its
residue, and “X” is any aminoacid. Proteins are farne-     accumulation in macrophages
sylated when “X” is Ala, Met or Ser and gera-              Studies done in mouse peritoneal macrophages
nylgeranylated when “X” is Leu. In both cases the          have shown that fluvastatin and simvastatin, but not
prenyl group is enzymatically linked to the Cys sulfur     pravastatin, inhibit cholesterol esterification
atom via a thioether linkage. The “aaX” tripeptide is      induced in cells by acetyl LDL [23]. The efficacy of
then proteolytically excized and the newly exposed         fluvastatin in inhibiting cholesterol esterification is
terminal carboxyl group is esterified with a methyl        more increased in cholesterol loaded cells than in
group [22]. Many prenylated proteins are associated        normal ones, effect that might be explained by the
with intracellular membranes and mutating their Cys        fact that the HMG CoA reductase is already
prenylation sites blocks their membrane localization.      inhibited in lipid-loaded cells, as compared with
The hydrophobic prenyl group can act to anchor its         unloaded ones [24].
attached protein to a membrane. Prenylated proteins
may interact with specific membrane- bound receptor        Effects on endothelial cell function
proteins and hence prenylation also mediates protein-      Endothelial dysfunction represents an early event in
protein interactions [22].                                 the initiation of atherosclerotic lesion, induced by
    The complex process of cell signaling is very          hypercholesterolemia. Nitric oxide (NO) regulates
important for intercellular communication.                 the anti-atherosclerotic function of the endothelium
Extracellular signaling molecules, which are water         [1]. Hypercholesterolemia reduces the capacity of
soluble and have high molecular weight need to             endothelial cells to produce NO, probably due to
bind to specific receptors on the cell surface, which      the reduced availability of L-arginine, the
transduce the extracellular signals into the cell by       physiologic substrate of NO syntase, and determins
intracellular signaling pathways (cascades). Many          an increased degradation of NO. Cholesterol
intracellular signaling molecules are prenylated           reduction by statins leads to a significant increase
proteins. The specific receptors on the cell surface       of the endothelial function. The effect of statins on
are associated with trimeric G protein, or have            the endothelial function can be              partially
Ser/Thr/Tyr kinases activities. The trimeric G             independent of the reduction of the lipid level.
protein has a geranylgeranylated subunit (gamma),          Simvastatin, as well as lovastatin, induce the
allowing this signaling protein to be inserted in the      transcriptional activation of eNOS gene in human
cell membrane near specific membrane receptors             endothelial cells in vitro [25]. Activation of eNOS
and to receive extracellular signals, which are then       by statins takes place post-translationally and is
transfered to the secondary signaling molecules in         prevented by isoprenoid derivatives, mevalonate
the cell. Another important class of prenylated            and geranylgeraniol [25]. The endothelial function
signaling molecules are the components of Ras              was increased in primates treated with pravastatin,
family, which are farnesylated and intermediate the        without the reduction of LDL cholesterol [25].
Ser/Thr/Tyr kinases activities of membrane                     Simvastatin administration to hyperlipemic
receptors from the cell surface. The important role        hamsters (HH) restores the antioxidant potential of
of all these prenylated signaling molecules for the        the serum [26]. Although the exact mechanism is
living cell is presented in Table 1.                       not known, this effect may be the result of a

                                                                             J.Cell.Mol.Med. Vol 5, No 4, 2001

decrease in cell oxygen production, binding of          their prenylation and thus reducing the
LDL to surface phospholipids or due to the              inflammatory response. Statins diminish leukocytes
antioxidant action of simvastatin metabolites [16].     recruitment in postcapillary venules, stimulated by
In addition, experiments done by Simionescu et al.,     a lipid mediator (platelets activation factor-PAF or
2001 [26] showed that simvastatin reduced               leukotriene B4) in hypercholesterolemic rats [31].
transcytosis of LDL and was able to restore the         In addition, statins are capable to inhibit
endothelial dependent relaxation, probably due to       transendothelial migration and chemotaxisis of
an increase in NO-synthesis. This latter assumption     neutrophiles,     which       can     explain    the
was based on two facts: (i) NO-synthase inhibitor,      antiinflammatory effect of these compounds.
L-NAME, inhibited the response of the arteries and      Another antiinflammatory effect of statins on
(ii) serum NO level increased in simvastatin-treated    monocytes and macrophages was the decrease of
HH. These data confirmed and extented previous          the expression of intercellular adhesion molecule -1
reports indicating that statins upregulate eNOS         and the secretion of interleukine-6 (IL-6), induced
expression, and prevent native LDL-mediated             by lipopolysacharides (LPS) [3].
down-regulation of eNOS expression.
    Simvastatin, as well as lovastatin, exerted a       Effects on proliferation, migration and apoptosis
protective, dose-dependent effect in an                 of arterial SMC
experimental model of cerebral infarction, a            All statins, except for pravastatin, reduce aortic
neuroprotective effect mediated rather by the           SMC proliferation [8]. Mevalonate, trans-farnesol
increased production of eNOS, than by the reduced       and trans-geranylgeraniol prevent the inhibitory
level of cholesterol [27]. The neuroprotective effect   effect of statins on SMC proliferation, suggesting
of statins is completly absent in mice defficient in    that this effect derives from the inhibition of the
eNOS, indicating that the increased activity of         mevalonate pathway [8]. Fluvastatin, simvastatin
eNOS induced by statins is the mechanism by             and cerivastatin, but not pravastatin, inhibit in a
which these compounds protect against cerebral          dose dependent manner, arterial SMC migration
lesions [27]. Recent results obtained by Wagner et      induced by fibrinogen [8].
al. (2000) [18] suggest that statins inhibit the           Preclinical observations and in vitro studies
formation of O2- by endothelial cells, producing        suggest that apoptosis can modulate the arterial
modifications in the          NO-/ O2- balance,         wall in restenotic or proliferative lesions, where
modification leading to the restoration of the          SMC are dominant [3]. It was reported that statins
endothelial cell function.                              can induce apoptosis of vascular SMC in culture.
                                                        Lesioned carotid arteries from rabbits that received
Effects on the inflammatory process                     fluvastatin or atorvastatin, 5 days prior to lesion
Adhesion to the endothelium and transendothelial        induction, presented an increased number of
diapedesis of circulating monocytes and of T            apoptotic SMC [32].
lymphocytes represent key events in the
atherosclerotic lesion formation [28]. Cytokines        Effects on the stability of
secreted by macrophages and lymphocytes can             the atherosclerotic plaque
modify endothelial function, smooth muscle cells        Coronary events are the result of unstable
(SMC) proliferation, collagen degradation and           atherosclerotic lesion rupture and thrombus
thrombosis [3]. Statins can reduce the expression       formation [33]. The plaque instability, manifested
and function of molecules on the leukocytes surface     as an ulceration of the fibrous cap, the rupture of the
[29]. Atorvastatin reduces the number of intimal        plaque and internal hemorrhage, are characteristics
macrophages, monocyte-chemoattractant protein-1         of the plaques with numerous lipid deposits and
(MCP-1) and the activation of nuclear factor NFkB       macrophages in the cap. Recently, it was
in hypercholesterolemic rabbits [30]. Cytokines         demonstrated that statins (fluvastatin, simvastatin)
receptors are coupled to GTP-bound proteins, and        can inhibit the gelatinolytic activity of
the binding of leukocytes to the endothelium is         metalloproteases, as well as their secretion by
regulated by G protein. Statins can affect small        human macrophages in culture [34]. Angiographic
GTP-ases or trimeric G proteins, by preventing          studies showed that statins reduce the progression

Fig. 2 Hypercholesterolemia favors entry of LDL particles into subendothelial space at lesion-prone arterial sites.
Monocyte chemotactic protein-1 (MCP-1) and oxidized-LDL act as chemoattractants to direct accumulation of
monocytes and their migration to the subendothelial space, where monocytes undergo phenotypic transformation into
macrophages. Concurrently, oxigen free radicals modify LDL. Oxidatively modified LDL is taken up by
nondownregulating macrophage receptors to form lipid-rich foam cells. Foam cells develop into fatty streaks,
precursor of atherosclerotic plaques. Statins exihibit pleiotropic effects on many components of atherosclerosis that
accompany hypercholesterolemia, including platelet coagulation abnormalities, abnormal endothelial function, and
determinants of plaque thrombogenicity such as plaque inflammation and proliferation.

and induce the regression of coronary                      as a function of the duration of simvastatin
atherosclerosis, reduce the formation of new               administration [36]. Although the duration of
lesions and the incidence of coronary events [35].         treatment (6 weeks) was short as compared with
Computer tomography provided evidence of the               other clinical trials, simvastatin acted efficiently
reduction in the volume of coronary calcified              as a scavenger for peroxyl radicals.
plaques after 12 months of statin treatment. It was
concluded that alterations in the composition of           Effects on platelet activation
lesions confers an increased stability [1].                Hypercholesterolemia is associated with
    Other reports show that simvastatin treatment          hypercoagulability, as well as with increased
determines an increase of the antioxidant                  platelet activation [1]. An increased level of LDL
potential in sera from stable (SA) and unstable            determines an increased platelets reactivity,
angina (UA) patients. Incubation of U937                   associated with an increased thromboxan A2
macrophages and human aortic SMC with sera                 biosyntesis. Recently it was elucidated a new
from simvastatin treated SA or UA patients led to          mechanism by which platelets activity is
a decreased accumulation of esterified cholesterol         increased in hypercholesterolemia, due to LDL

                                                                              J.Cell.Mol.Med. Vol 5, No 4, 2001

inhibiting the platelet antiport Na+/H+ [37]. In         mevalonate and geranylgeraniol prevented the
addition, platelet dependent thrombin generation         effects, suggesting that a nonsterol intermediate
is increased in hypercholesterolemic subjects, and       is probably required for the prenylation of GTP-
pravastatin treatment determines a restoration of        binding proteins that control cytoskeletal
thrombin formation. Statin therapy was                   reorganization, vesicle fusion and apoptosis,
accompanied by a reduction of platelet                   processes involved in osteoclasts activation and
aggregation induced by ADP, collagen or                  survival. In addition, it was demonstrated in vitro
fibrinogen, as well as of thromboxan production,         and in vivo in rodents, that statins enhance new
in parallel with LDL cholesterol reduction.              bone formation [3]. Statins administration is
                                                         associated with a decrease of bone fracture risk in
Effects on the coagulation process                       subjects over 50 years, probably because of the
Primary and secondary prevention studies                 increase of the mineral density of the bones [4].
demonstrate that statin therapy reduces                  Thus, subjects with hyperlipidemia known to
significantly thrombus formation. Recently, a link       present increased risk for osteoporosis (mostly
between the enhancement of endothelial                   post-menopausal women) could benefit from
fibrinolytic system and the         inhibition of        statin therapy.
mevalonate pathway was reported [38]. Statins
action involves an increase in tPA activity, as well
as a decrease in PAI-1 activity [38]. The tissue         Adverse effects of statin therapy
factor plays an important role in the initiation of
the extrinsec coagulation pathway and it was             Statins are generally well tolerated. The most
localized in lipid-loaded macrophages from               important adverse effects are liver and muscle
atherosclerotic plaque. Recently, Colli et al. [39]      toxicity. Myopathy can happen if inhibitors of
have shown that lipophylic statins (simvastatin          cytochrom P450 or other inhibitors of statins
and fluvastatin) reduce the expression and               metabolism are administered together with statins,
activity of the tissue factor in human monocyte-         determining the increase of their blood con-
derived macrophages in culture, effect prevented         centration. Such are the azole antifungals [40].
by the addition of mevalonate and trans-                 Fibrates and niacin enhance myopathy risk by a
geranylgeraniol.                                         mechanism not involving the increased statins blood
                                                         concentration. Other risk factors are: hepatic
Other beneficial effects of statins                      dysfunction, renal insufficiency, hypothyroidism,
The fact that mevalonate plays a key role in cell        advanced age and serious infections.
proliferation and that many malignant cells                  The already discussed suspension of cerivastatin
present an increased HMG-CoA reductase                   from the clinical use, because of fatal rhabdomyolysis
activity, suggests that a selective inhibition of this   in a number of patients confirms the muscle toxicity
enzyme could lead to a new chemotherapy for              of statins. On the other hand, it must be stressed that
cancer disease [3].                                      cerivastatin is at least 10 times more myotoxic than
   Results obtained in vitro have shown that             other statins and it was used in unusual high doses.
statins can inhibit tumor cell growth, a fact
confirmed by some in vivo experiments also. The
obtained reduction of sterols synthesis by statins,      Conclusions
suggests that inhibition of tumor cell growth can
be related to the reduction of nonsteroidal
                                                         Statins are widely used for the treatment of
isoprenoid compounds. This effect can influence
                                                         hypercholesterolemia. They inhibit HMG-CoA
Ras protein farnesylation, thus inhibiting Ras
                                                         reductase competitively, reduce LDL levels more
dependent tumor cell growth [3].
                                                         than other cholesterol-lowering drugs, and lower
   Recent experimental evidence support a role
                                                         triglycerides levels in hypertriglyceridemic patients.
for mevalonate pathway in murine and rabbit
                                                         Statins have antiatherosclerotic effects, that correlate
osteoclast formation and bone resorption.
                                                         positively with the percent decrease in LDL
Lovastatin inhibited both processes, while

cholesterol. In addition, they can exert antiathero-        10. Stein E.A., Lane M., Laskarzewski P., Comparison
sclerotic effects independently of their hypolipide-            of statins in hypertriglyceridemia, Am. J. Cardiol.,
mic action (fig. 2). Because the mevalonate metabo-             81: 66B-69B, 1998
lism generates a series of vital isoprenoids for diffe-     11. Ginsberg H.N., Le N.A., Short M.P.,
                                                                Ramakrishnan R., Desnick R.J., Suppression of
rent cellular functions, from cholesterol synthesis to
                                                                apolipoprotein B production during treatment of
the control of cell growth and differentiation, HMG-            cholesteryl ester storage disease with lovastatin:
CoA reductase inhibition has beneficial pleiotropic             implication for regulation of apolipoprotein B
effects. Consequently, statins significantly reduce the         synthesis, J. Clin. Invest., 80: 1692-1697, 1987
incidence of coronary events, both in primary and           12. Gaw A., Packard C.J., Murray E.F., Effects of
secondary prevention, being the most efficient                  simvastatin on apoB metabolism and LDL
hypolipidemic compounds that have reduced the rate              subfraction distribution, Arterioscler. Thromb., 13:
of mortality in coronary patients. Statins are well             170-89, 1993
tolerated and have an excellent safety record. Inde-        13. Marais A.D., Naumova R.P., Firth J.C., Penny C.,
pendent of their hypolipidemic properties, statins              Neuwirth C.K., Thompson G.R., Decreased
                                                                production of low density lipoprotein by atorvastatin
interfere with events involved in bone formation. In
                                                                after apheresis in homozygous familial
addition, it was demonstrated that HMG-CoA                      hypercholesterolemia, J. Lipid Res., 38: 2071-2078,
reductase inhibitors impede tumor cell growth.                  1997
                                                            14. Raal F.J., Pilcher G.J., Illingworth D.R., Pappu
                                                                A.S., Stein E.A., Laskarzewski P., Mitchel Y.B.,
                                                                Melino M.R., Expanded dose simvastatin is
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