Hóa Sinh Statin

CHAPTER FIVE
Biochemistry of Statins
Emmanuel Eroume A. Egom*,†,1, Hafsa Hafeez†
*Department of Clinical Medicine, Trinity College Dublin/The University of Dublin, Dublin, Ireland
†
Egom Clinical & Translational Research Services Ltd, Halifax, Nova Scotia, Canada
1
Corresponding author: e-mail address: egom@ectrs.ca
Contents
1. Introduction 128
2. Structure 129
3. Pharmacokinetics 131
4. Mechanism of Action 135
5. Administration 137
5.1 Timing of Administration 137
5.2 Alternative Dosing Regimens 138
5.3 Interchange (Switching Between Statin Drugs) 138
5.4 Drug Interactions 139
6. Efficacy 139
6.1 Effect on LDL Cholesterol 139
6.2 Effect on HDL 140
6.3 Effect on Triglycerides 140
6.4 Genetic/Ethnic Effects 140
6.5 Pleiotropic Effects 141
6.6 Prevention of Cardiovascular Disease 142
7. Side Effects 146
7.1 Muscle Injury 147
7.2 Hepatic Dysfunction 152
7.3 Renal Dysfunction 153
7.4 Behavioral and Cognitive 153
7.5 Cancer 154
7.6 Diabetes Mellitus 154
7.7 Other 155
8. Statin Intolerance 156
9. Conclusion 156
References 157
Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide.
Elevated blood lipids may be a major risk factor for CVD. Due to consistent and robust
association of higher low-density lipoprotein (LDL)-cholesterol levels with CVD across
experimental and epidemiologic studies, therapeutic strategies to decrease risk have
Advances in Clinical Chemistry, Volume 73 # 2016 Elsevier Inc. 127

ISSN 0065-2423 All rights reserved.
http://dx.doi.org/10.1016/bs.acc.2015.10.005
128 Emmanuel Eroume A. Egom and Hafsa Hafeez
focused on LDL-cholesterol reduction as the primary goal. Current medication options

for lipid-lowering therapy include statins, bile acid sequestrants, a cholesterol-
absorption inhibitor, fibrates, nicotinic acid, and omega-3 fatty acids, which all have var-
ious mechanisms of action and pharmacokinetic properties. The most widely prescribed
lipid-lowering agents are the HMG-CoA reductase inhibitors, or statins. Since their intro-
duction in the 1980s, statins have emerged as the one of the best-selling medication
classes to date, with numerous trials demonstrating powerful efficacy in preventing car-
diovascular outcomes (Kapur and Musunuru, 2008 [1]). The statins are commonly used
in the treatment of hypercholesterolemia and mixed hyperlipidemia. This chapter
focuses on the biochemistry of statins including their structures, pharmacokinetics,
and mechanism of actions as well as the potential adverse reactions linked to their
clinical uses.
1. INTRODUCTION
More than a century ago, a pathologist named Rudolf Virchow dis-
covered that cholesterol was found in the artery walls of people that died
from occlusive vascular diseases [2]. In the early 1950s, the relationship
between cholesterol and cardiovascular disease (CVD) had unfolded by
using an ultracentrifuge to separate plasma lipoproteins by flotation. It
was found that not only did CVD correlate with elevated levels of plasma
cholesterol, but also that the cholesterol was contained in low-density lipo-
protein (LDL). It was also observed that CVD was less frequent when the
blood contained elevated levels of high-density lipoprotein (HDL) [3–5].
The Framingham Heart Study was one of the early studies to relate choles-
terol to CVD; it began in 1948 and continued for decades. Among the par-
ticipants, the risks for developing CVD were found to be correlated, aside
from genetic factors, to physical inactivity, smoking, obesity, hypertension,
hyperglycemia, and high LDL-cholesterol (LDL-C).
CVD is still the leading cause of morbidity and mortality worldwide and
affects more than 83.6 million Americans [6]. Atherosclerosis may play a
major role in the development of certain CVDs—coronary heart disease
including myocardial infarction, angina, heart failure, and cerebrovascular
accident. Atherosclerotic CVD (ASCVD) affects 15.4 million Americans
[6]. Elevated blood lipids may be a major risk factor for ASCVD. Due to
the consistent and robust association of higher LDL-C levels with ASCVD
across experimental and epidemiologic studies, therapeutic strategies to
decrease risk have focused on LDL-C reduction as the primary goal. Current
medication options for lipid-lowering therapy include statins, bile acid
Biochemistry of Statins 129
sequestrants, a cholesterol-absorption inhibitor, fibrates, nicotinic acid, and

omega-3 fatty acids, which all have various mechanisms of action and phar-
macokinetic properties. The most widely prescribed lipid-lowering agents
are the HMG-CoA reductase inhibitors or statins. Since their introduction
in the 1980s, statins have emerged as the one of the best-selling medication
classes to date, with numerous trials demonstrating powerful efficacy in
preventing cardiovascular outcomes [1]. Currently, available statins include
atorvastatin, simvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin, and
in some countries pitavastatin. The statins are commonly used in the treat-
ment of hypercholesterolemia and mixed hyperlipidemia. As our under-
standing of LDL-C and ASCVD continues to grow, the concept of
“lower is better” has corresponded with a “more is better” approach to
statin-based treatment [1]. This chapter focuses on the biochemistry of sta-
tins including their structures, pharmacokinetics, and mechanism of actions
as well as the potential adverse reactions linked to their clinical uses.
2. STRUCTURE
The chemical structure of all statins, as illustrated in Fig. 1 [7], consists
of the pharmacophore and its moiety containing a ring system with different
substituents. The pharmacophore is shared among all statins, it is a
dihydroxyheptanoic acid segment which is very similar to the HMG-
CoA substrate [7]. The ring system consists of a complex hydrophobic struc-
ture covalently linked to the pharmacophore and it is involved in binding
interactions with the HMG-CoA reductase enzyme [8]. It has also been
shown that the HMG-CoA reductase is stereoselective and as a result all sta-
tins need to have the required stereochemistry of chiral carbon atoms, C3
and C5, on their pharmacophore [9]. The statin pharmacophore inhibits
the HMG-CoA reductase enzyme and it binds to the same active site as
the HMG-CoA substrate naturally would.
The statins differ from each other in their hydrophobic ring structure and
its substituents, covalently linked to the HMG-like moiety. These differ-
ences in structure affect the pharmacological properties of the statins [10],
such as the affinity to the active site of the HMG-CoA reductase enzyme,
the rates of entry into hepatic cells versus extrahepatic cells, the bioavail-
ability of the compounds, and the biochemical metabolism and excretion
mechanisms that affect the biologic half-life of the active compound [11].
The additional groups range in character from very hydrophobic (e.g.,
cerivastatin) to partly hydrophobic (e.g., rosuvastatin). Rosuvastatin has a
HO O HO O
O O
O O
HO
COOH
H3C H O H O
CH3 H3C CH3 H
C S-COA CH3
O
H3C H3C
HMG-CoA Lovastatin Simvastatin

HO HO F
COOH COOH
O− Na
+
OH OH OH OH
O
F O
O
H3C H H
CH3 CH(CH3)2 H3C
N O
CH3
HO H3C N
H3C CH3
Pravastatin Fluvastatin Cerivastatin sodium
H3C CH3
O CH
OH OH O
NHC N CH2 CH CH C
CH2 CH2 CH2 OH
Atorvastatin
Figure 1 Chemical structure of the statins and HMG-CoA.
unique polar ethane sulfonomide group, which is quite hydrophilic and

confers low lipophilicity. A unique polar interaction is formed between
the sulfonamide group and the HMG-CoA reductase enzyme. As a result,
rosuvastatin has stronger binding affinity to the HMGR enzyme compared
to the other statins, which relates to its higher efficiency in lowering
LDL-C [10]. The lipophilicity of the statins is considered important since
the hepatoselectivity of the statins is related to their degree of lipophilicity.
The higher the lipophilicity of statins, the greater level of exposure it gets to
non-hepatic tissues, while the more hydrophobic statins have a tendency to
be more selective for the liver. Whereas lipophilic statins passively and non-
selectively diffuse into both hepatocyte and non-heptatocyte. The more
hydrophobic statins largely rely on active transport into hepatocyte to exert
their effects [12,13]. The bulky hydrophobic substituents of statins poten-
tially pose a difficult binding situation, but statins exploit the conformational
flexibility of HMG-CoA reductase to create a hydrophobic binding pocket
near the active site. The HMG-like moiety of the statins is kinked at the
O5-hydroxyl group to allow it extend into a narrow HMG-binding pocket
in the enzyme where endogenous HMG-CoA is normally bound. The

HMG-binding pocket is characterized by a loop, referred to as “cis
loop” [14]. Several polar interactions are formed between the HMG-
moieties and residues that are located in the cis loop (Ser684, Asp690,
Lys691, and Lys692). Lys691 also participates in a hydrogen-bonding net-
work with Glu559, Asp767, and the O5-hydroxyl of the statins [14].
Hydrophobic side chains of the enzyme involving residues Leu562,
Val683, Leu853, Ala856, and Leu857 participate in van der Waals contacts
with the statins [14].
Statins exist in two forms, lactone (inactive) and open-ring hydroxy acid
(active) forms. The HMG-like moiety that all statins share, may present in the
inactive form as a lactone. Simvastatin and lovastatin are administered as lac-
tone prodrugs and subsequently transformed to active metabolites. The
remaining statins are formulated in the pharmacologically active form as a
β-hydroxy acid. In vivo, lactone prodrugs are enzymatically hydrolyzed to
their hydroxy acid pharmacophores in the liver to achieve pharmacological
activity [15]. On the other hand, the remaining statins, in β-hydroxy acid form
are already in their active form and possess two hydroxyl groups in an alkyl
chain at the β and δ positions with respect to the carboxylic acid group [16].
Statin drugs are also divided into two groups: naturally or fungal-derived
(type 1) and synthetic (type 2) [17]. Type 1 statins include simvastatin, prav-
astatin, and lovastatin. Type 1 statins contain a substituted decalin ring struc-
ture that resembles the first ever statin discovered, mevastatin (also known as
compactin). Type 2 statins are those that are fully synthetic and with larger,
fluorophenyl, groups linked to the HMG-like moiety. These include
fluvastatin, atorvastatin, rosuvastatin, and cerivastatin [16]. One of the main
differences between the type 1 and type 2 statins is the replacement of the
fluorophenyl group of type 2 statins with the butyryl group in type 1 statins.
These specific groups are responsible for additional polar interactions that
cause tighter binding to the HMGR enzyme. Functionally, the methylethyl
group attached to the central ring of the type 2 statins replaces the decalin of
the type 1 statins. The butyryl group of the type 1 statins occupies a region
similar to the fluorophenyl group present in the type 2 inhibitors [14]. The
next section of this chapter will focus on the pharmacokinetics of statins.
3. PHARMACOKINETICS
The pharmacokinetic properties of the statins are orchestrated by sev-
eral characteristics, including their absorption, metabolism, lactone, or
active form as well as their hydrophilic or lipophilic rate [8]. Statins are
administrated orally as active hydroxy acids (type 2 statins), except for type
1 statins (e.g., lovastatin and simvastatin), which are administered in their
inactive lactone form. The percentage of absorption is between 30% and
98% and the time to reach peak plasma concentration (Tmax) is within
4 h after administration [18]. The daily absorption may vary according to
the time of administration [19] and food intake [20]. Pravastatin and
fluvastatin are essentially completely absorbed after oral intake, whereas lov-
astatin and simvastatin are absorbed approximately 30–50% when taken
orally. Since majority of cholesterol synthesis occurs in the liver, statins
mainly target the liver as well. Therefore, an extensive first-pass uptake
would be more important than high bioavailability to achieve optimal statin
effect. A statin’s ability to produce an efficient first-pass extraction implies a
low systemic bioavailability.
The solubility profile is a fundamental characteristic that governs the
hepatoselectivity of the statins and their inhibitory effect on HMG-CoA
reductase. Statins, which are lipophilic, enter the hepatocytes through pas-
sive diffusion, whereas hydrophilic statins undergo a carrier-mediated
uptake [21,22]. Lipophilic statins show an efficient activity in both hepatic
and extrahepatic tissues, whereas hydrophilic statins are more selective for
the liver [21]. Among the statins, lovastatin, simvastatin, atorvastatin, and
fluvastatin are lipophilic in nature, whereas rosuvastatin and pravastatin
are characterized as essentially hydrophilic. The lipophilic properties of sta-
tins are accompanied by low systemic bioavailability because of an extensive
first-pass effect at the hepatic level, with the exception of pitavastatin [23].
Although this effect can be desirable, because the liver is the target organ, the
statins’ lipophilicity allows them to also passively penetrate the cells of extra-
hepatic tissues, potentially leading to side effects that may be undesirable.
Statins are dosed orally and enter the systemic circulation through intestinal
basolateral or apical membrane in polarized cells both passively and by active
transport via the ABC and SLC gene family transporters as illustrated in
Fig. 2 [24]. On the other hand, hydrophilicity depends on an active transport
process to carry the drug from the portal blood into hepatocytes via the
organic anion-transporting polypeptides (OATP), which give them better
potency and selectivity for the liver. Hydrophilic statins—such as
rosuvastatin and pravastatin—are more selective to the liver, because they
do not easily enter other tissues as lipophilic statins do. However, the balance
between desired and undesired effects of lipophilic and hydrophilic statins
remains not clearly established.
Figure 2 Representation of the superset of all genes involved in the transport, metab-
olism, and clearance of statin class drugs (pharmacokinetics of statins). Copyright
PharmGKB. Permission to reproduce this image was granted by PharmGKB and Stanford
University. https://www.pharmgkb.org/pathway/PA145011108.
Metabolism of statins is catalyzed by CYP and UGT gene family

enzymes (Fig. 2). The more hydrophilic compounds, which require active
transport into the liver, are metabolized less by the cytochrome P450 (CYP)
family, and exhibit more active renal excretion; whereas the less hydrophilic
compounds are transported by passive diffusion and are better substrates for
both CYP enzymes and the ABC-mediated transporters involved in biliary
excretion (Fig. 2; [24]). In the liver, statin lactones are hydrolyzed to their
open acid forms chemically or enzymatically by esterases or paraoxonases
(PONs), as opposed to CYP pathways [25]. The open acid form is converted
to its corresponding lactone via a CoA-dependent pathway and via
glucuronidation by UDP-glucuronosyl transferase (UGT). Both acyl glucu-
ronide and acyl CoA derivatives may return to statin acids by hydrolysis. In
addition, type 1 statins rapidly undergo oxidation through the microsomal
cytochrome P450 (P450) family of enzymes, whereas type 2 statins are irre-
versibly cleared by β-oxidation and glucuronidation processes [26]. Among
the cytochrome P450 (CYP) isoenzymes, CYP3A4 and CYP2C9 are most
dominantly involved in the oxidative metabolism of the statins. Specifically,
simvastatin, lovastatin, cerivastatin, and atorvastatin are predominantly
metabolized by the CYP3A4 isoenzyme [9,27]. CYP3A4 and CYP2C8 iso-
enzymes contribute to the metabolism of fluvastatin with CYP2C9 being
the most predominant [27]. Rosuvastatin is metabolized to a small degree
by CYP2C9 and to a lesser extent by CYP2C19 isoenzymes. Pravastatin
is not metabolized by CYP isoenzymes to any appreciable extent [10,27].
The statins that have the ability to be metabolized by multiple CYP isoen-
zymes may therefore avoid drug accumulation when one of the pathways is
inhibited by coadministered drugs [27].
Excretion of statins takes place via the ABC transporter-mediated biliary
excretion and some through urinary elimination. The effective elimination
half-lives of the hydroxy acid forms range from 0.7 to 3.0 h. The rather
extensive metabolism by different cytochrome P450 isoforms also makes
it difficult to characterize these drugs regarding tissue selectivity unless all
metabolites are well characterized [28]. The hepatic elimination of the statins
is limited by its uptake and controlled by the transporters on the basolateral
membrane of the liver. P-glycoprotein (P-gp) and multidrug resistance-
associated protein 2 are two of the major ATP-dependent efflux pumps
for statin excretion into the bile [29]. On the other hand, urinary excretion
of statins, with the exception for pravastatin, is quite low. Up to 60% of
intravenously administered pravastatin is excreted in the urine in humans,
unlike other statins [30]. Tubular secretion is the main mechanism involved
in the renal excretion of pravastatin and it is primarily mediated by the
OAT3 transporter. Although when renal elimination is low, statin activity
in the liver depends only on the sequestration clearance and is independent
of the activity of the uptake. The elimination of half-life of the most statins is
very short, in the range of 0.5–3 h and they do not accumulate in plasma
after repeated administrations [31]. The next section of this chapter will dis-
cuss the mechanism of actions of statins.
4. MECHANISM OF ACTION
Synthesis of cholesterol occurs in the cytoplasm and membrane of the
endoplasmic reticulum of virtually all tissues in humans including the liver,
intestine, adrenal cortex, and reproductive tissues. Most of the circulating
cholesterol comes from internal manufacture rather than the diet. The liver
produces about 70% of total cholesterol in the body and when the liver can
no longer produce it, blood cholesterol levels will subsequently fall [6]. As
illustrated in Fig. 3 [8], the chemical pathway producing cholesterol in all
cells begins with condensation of acetyl-CoA with acetoacetyl-CoA to form
HMG-CoA (β-hydroxy-β-methylglutaryl coenzyme A) in a reaction
Figure 3 The mevalonate pathway. Statins act by inhibiting HMG-CoA reductase, the
key enzyme of the mevalonate pathway. Statins could have pleiotropic effects possibly
through other products of the mevalonate pathway (e.g., i6A tRNA, prenylated proteins,
and other isoprenoids) that play central roles in cell signaling, protein synthesis, and
cytoskeletal organization.
catalyzed by HMG-CoA synthase. The HMG-CoA reductase enzyme then

converts HMG-CoA to mevalonate, which is the first rate-limiting step in
the pathway of cholesterol synthesis [7]. After mevalonate is generated, mul-
tiple reactions follow to finally produce cholesterol (Fig. 3).
As HMG-CoA reductase inhibitors, statins are competitive, reversible
inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol
biosynthesis [7]. This rate-limiting step is the conversion of HMG-CoA to
CoA and mevalonate by a four-electron reductive deacylation process. It is
catalyzed by HMG-CoA reductase in a reaction that proceeds as follows:
ðSÞ HMG CoA + 2NADPH + 2H +

! ðRÞ mevalonate + 2NADPH + + CoASH
In this step, the NADP+ is the oxidized form of nicotinamide adenine

dinucleotide, NADPH is the reduced form of NADP+, and CoASH is
the reduced form of CoA [14].
Statins mimic HMG-CoA, the natural substrate molecule, and compete
to bind to the HMG-CoA reductase enzyme. Production of mevalonate
product slows down leads to decrease cholesterol biosynthesis downstream.
Since the majority of cholesterol synthesis in the body occurs in hepatocytes,
HMG-CoA reductase inhibitors mainly target the liver. Statins do more
than just compete with the normal substrate in the enzyme active site; when
bound, they alter the conformation of the enzyme itself, preventing HMG-
CoA reductase from attaining a functional structure. The high efficacy and
specificity of statins are determined by their ability to make the enzyme con-
form their shape. Although the binding of statins to HMG-CoA reductase is
reversible, their affinity for the enzyme is approximately 1000–10,000-fold
stronger than for its natural substrate molecule, HMG-CoA [27]. When the
HMG-CoA binds to the enzyme, it interacts with the elongated NADP(H)
in the binding site, whereas no portion of this molecule is involved in the
binding of statins. All statins are competitive inhibitors of HMG-CoA
reductase with respect to binding of the substrate HMG-CoA, but not with
binding of NADPH [32]. For the statin–enzyme complexes, the Ki (inhibi-
tion constant) values range between 0.1 and 2.3 nM [15], whereas the
Michaelis constant, Km, for HMG-CoA is 4 mM [33].
The fine-tuning of cholesterol synthesis is partly controlled in vitro and
in vivo by the delivery of sterols to the cell via the LDL receptor pathway [34].
Esterified cholesterol is mainly delivered into the cell by LDL; lysosomes
provide the milieu for the enzymatic conversion of cholesteryl esters to free
cholesterol [34]. In addition to reducing de novo cholesterol synthesis with

the use of statins, liver cells sense the reduced levels of cholesterol produc-
tion, inducing the activation of protease that slices the sterol regulatory
element-binding proteins (SREBPs) from the endoplasmic reticulum. In
the nucleus, gene expression of LDL receptors is increased and translocation
occurs into the production of LDL receptors to be displayed on the cell sur-
face for uptake of LDL and its precursors (intermediate density—IDL and
very low-density lipoproteins—VLDL) [7]. Inhibiting the cholesterol syn-
thesis pathway created a multidimensional approach to lowering LDL, and
HMG-CoA reductase had become the ideal target, as the pathway’s first
committed rate-limiting enzyme [35]. Statins, therefore, result in a reduc-
tion in plasma cholesterol both by decreased cholesterol synthesis and by
increased catabolism of LDL [16].
By inhibiting the HMG-CoA reductase, statins also inhibit production of
specific prenylated protein metabolites downstream, such as geranylgeranyl
pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) [8]. GGPP and
FPP are lipid attachments that constitute key intermediates for posttransla-
tional events of several cell signaling proteins, including the Ras, Rac, and
Rho GTPase family members [36]. Isoprenylation, or the attachment of these
lipids, is fundamental for the activation and intracellular transport of these pro-
teins that act as molecular switches controlling multiple pathways and cell
functions such as maintenance of motility, cell shape, differentiation, factor
secretion, and proliferation [8]. Considering that the key role prenylated pro-
teins play, it is expected that statin effects may extend beyond their LDL low-
ering actions (pleiotropic effects). These pleiotropic effects of statins, which
are cholesterol independent, include reduction of the inflammatory process
and accumulation of esterified cholesterol into macrophages, increased stabil-
ity of the atherosclerotic plaques, increase of endothelial NO synthetase, res-
toration of platelets activity, and of the coagulation process [37,38]. The
cholesterol-dependent and -independent effects of statins create significant
reduction in coronary events, both as primary and secondary interventions.
Statins remain the most efficient hypolipidemic compounds that have reduced
the rate of mortality in coronary patients universally [7].
5. ADMINISTRATION
5.1 Timing of Administration
The vast majority of cholesterol synthesis appears to occur at night [39], so
statins with short half-lives are usually taken in the evening or at bedtime to
maximize their therapeutic effects. Studies have shown greater reductions in

total and LDL-C in the short-acting simvastatin taken at night rather than
the morning [40]. A small study of atorvastatin, which has a long half-life,
found no significant differences whether it was administered in the morning
or the evening [19].
5.2 Alternative Dosing Regimens

Although statin therapy has achieved significant reductions in cardiovascular
morbidity and mortality, as many as 10% of patients prescribed these drugs
experience myopathies [41]. Intermittent statin regimens ranging from
every-other-day to once-weekly dosing have emerged in an attempt to
maintain efficacy while moderating the incidence of adverse effects. Small
studies have compared daily statin use with alternate day dosing and mea-
sured effects on lipid parameters and, in some cases, attainment of cholesterol
goals over 6–12 weeks [42–46]. Clinical studies with atorvastatin,
fluvastatin, and rosuvastatin suggest that to yield similar LDL-C lowering,
the every-other-day dose needs to be on average nearly twice that of the
daily dose [42,43,45,47]. Although clinical experience indicates that alter-
nate day dosing may improve the tolerability of statins in patients unable
to tolerate daily statin therapy [41], larger scale randomized trials are neces-
sary to more clearly define the role of this strategy and the optimal choice of
regimen.
5.3 Interchange (Switching Between Statin Drugs)

Therapeutic interchange programs (whether temporary or long term) are
commonly implemented in various practice settings. Clinical studies evalu-
ated lipid-lowering efficacy and costs of statin therapeutic interchange pro-
grams and generally showed that conversion programs may achieve similar
effects on lipid levels when equipotent statins are chosen [48,49]. Before a
therapeutic interchange program can be instituted, a literature must be
located to guide the healthcare provider in estimating equivalent doses.
In addition, healthcare providers should recognize that literature only guides
the dose conversion process [50]. The following dosing equivalents can be
used as a conservative starting point for the temporary substitution policy:
rosuvastatin 5 mg ¼ atorvastatin 10 mg ¼ simvastatin 20 mg ¼ pravastatin
40 mg ¼ lovastatin 40 mg ¼ fluvastatin 80 mg [50].
5.4 Drug Interactions

Drug interactions, including with other lipid-lowering agents, may predis-
pose to statin-induced muscle toxicity. The risk of myopathy is increased
when statins are coadministered with drugs that inhibit their metabolism.
Atorvastatin, lovastatin, and simvastatin are CYP3A4 substrates and when
coadministered with potent CYP3A4 inhibitors, the incidence of myopathy
is increased by about fivefold [51]. The extent of interaction between ator-
vastatin and CYP3A4 inhibitors may be less than that with lovastatin and
simvastatin [52]. Pravastatin, fluvastatin, rosuvastatin, and pitavastatin may
be preferred when concurrent therapy with a strong inhibitor of CYP3A4
cannot be avoided. Atorvastatin, lovastatin, and simvastatin may also be sub-
strates for P-gp; therefore, drugs that inhibit P-gp including cyclosporine
and diltiazem, may increase levels of these statins through this mecha-
nism [53]. Rosuvastatin (as opposed to atorvastatin, lovastatin, and simva-
statin) may not be extensively metabolized by the hepatic isoenzyme
CYP3A4 [50]. Approximately, 10% of this drug is metabolized via
CYP2C9 [54]. Drug interaction studies with rosuvastatin in combination
with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and
erythromycin did not result in clinically significant reductions or increases
in rosuvastatin plasma concentrations [50]. However, rosuvastatin adminis-
tration results in clinically significant drug interactions with cyclosporine and
warfarin [50]. Despite not being significantly metabolized by CYP3A4,
rosuvastatin levels may be increased by the protease inhibitor combinations
lopinavir/ritonavir and atazanavir/ritonavir [55]. Fluvastatin may primarily
be metabolized by CYP2C9 [52,56]. Pitavastatin may mainly be eliminated
via glucuronide conjugation and to a minor extent by CYP2C9 and
CYP2C8 [57]. An OATP transporter carries these and most other statins
into the liver for metabolism; therefore, drug interactions can occur through
inhibition of this transporter [52,56–58].
6. EFFICACY
6.1 Effect on LDL Cholesterol
The statins are currently the most powerful approved drugs for lowering
LDL-C, with reductions in the range of 30–63% [59–62]. Rosuvastatin
may be somewhat more potent than atorvastatin [62,63], and both these
agents may be significantly more potent than simvastatin, lovastatin,
pravastatin, and fluvastatin [63,64]. There may be an additive hypolipidemic

effect when any of the statins is used in combination with a bile acid
sequestrant [18,65,66], or the cholesterol-absorption inhibitor ezetimibe.
6.2 Effect on HDL

The level of HDL cholesterol is inversely related to the presence or devel-
opment of ASCVD, but a causal relationship between the cholesterol con-
tent in HDL particles (HDL-C) has not been established [67]. Furthermore,
the evidence that raising HDL-C is of benefit in reducing cardiovascular
events has not been established. Simvastatin (40–80 mg/day) may be more
effective than atorvastatin (20–40 mg/day) for increasing serum HDL-C and
apolipoprotein A–I concentrations [68]. However, rosuvastatin may be even
more effective, raising HDL-C by up to 10% [63]. In patients with metabolic
syndrome, rosuvastatin (10–20 mg/day) may be more effective than atorva-
statin (10–20 mg/day) in increasing large HDL particles [69]. Whether this is
clinically important is still uncertain.
6.3 Effect on Triglycerides

The causal association between elevated triglycerides and cardiovascular risk
is still uncertain due to the association between other lipoproteins and other
conditions associated with increased ASCVD risk such as disorders of insulin
resistance. Atorvastatin and rosuvastatin may be more effective at lowering
triglycerides (14–33%) than other statins in patients with hypercholesterol-
emia [63,70–72]. The effects of atorvastatin and rosuvastatin on plasma tri-
glycerides may be dose dependent [63,71].
6.4 Genetic/Ethnic Effects

Evidence suggests that part of the variability in the response to and side
effects with statins may be related to genetic differences in the rate of drug
metabolism [73]. For instance, CYP2D6 is a member of the cytochrome
P450 super family of drug-oxidizing enzymes [73]. CYP2D6 may be func-
tionally absent in 7% of Caucasians and African-Americans, while deficiency
is rare among Asians [73]. The CYP2D6 phenotype appears to be important
in patients treated with simvastatin, as it can affect both the degree of lipid
lowering and tolerability [74]. Polymorphisms in the gene coding for
HMG-CoA reductase also appear to affect the LDL-C response to statins,
but not the HDL-C response [75]. Concerns have been raised that Asians
may have greater responses to low doses of statins than Caucasians [76].
Prescribing information for rosuvastatin recommends starting therapy at a

lower initial dose in Asians than in other groups, given observed differences
in pharmacokinetics [73]. There is no strong evidence supporting such an
approach with other statins [73].
6.5 Pleiotropic Effects

Several studies have shown that the benefit of statin therapy in terms of its
ability to lower serum LDL-C in patients with and without clinical evidence
of ASCVD. Evidence suggests that some of the benefits of statin therapy may
be mediated by their pleiotropic effects, including their stabilization of ath-
erosclerotic plaques, anti-inflammatory properties, improvement of endo-
thelial dysfunction, and anti-thrombotic effects, which may only be partly
accounted for by the cholesterol-lowering properties of these therapeutic
agents [38]. Variation in the reduction of ASCVD risk in statins trials
may only partially account for the changes in LDL-C, HDL-C, and
triglycerides [38].
In fact, animal models and human studies have shown that statin therapy
may reduce the rate of progression of atherosclerosis and stabilize atheroscle-
rotic lesions [77,78]. There is limited evidence on the exact timing of regres-
sion of atherosclerosis, particularly coronary atherosclerosis, after statin
treatment. This issue was addressed using high-resolution MRI to assess aor-
tic and carotid artery plaques. No changes were seen at 6 months, but pro-
gressive regression was noted at 12 and 24 months [79,80]. The earliest
change, seen at 12 months, was a reduction in plaque size followed by an
increase in luminal area due to arterial remodeling [80]. While lowering
of LDL-C levels followed by stabilization and regression of atherosclerosis
are accepted as the primary mechanism by which statins reduce ASCVD
events, the observed benefit of this intervention begins within months after
its initiation [38]. This makes regression an unlikely cause for this early ben-
efit. Other mechanisms thought to be involved include reduction of inflam-
mation, reversal of endothelial dysfunction, reduction of oxidative
modification of LDL, reduction in monocyte adhesion to the endothelium,
increased mobilization and differentiation of endothelial progenitor cells,
and decreased thrombogenicity [38].
In addition to their ability to lower LDL-C and increase HDL-C, statins
may cross-talk with the sphingosine-1-phosphate (S1P—a naturally occur-
ring bioactive lysophospholipid that regulates diverse physiological func-
tions in a variety of different organ systems) receptors, resulting in the
enhancement of S1P-induced anti-inflammatory and anti-atherothrombotic

effects independently of serum LDL-C, partly through the upregulation of
the expression of S1P receptors and the increase of plasma levels of S1P [38].
Statin-induced S1P signaling may, therefore, play a major role in mediating
the enhanced response to HDL, and may represent a feature of the pleiotro-
pic effects of statins through which they mediate improvement of endothe-
lial function, increased mobilization, and differentiation of endothelial
progenitor cells, bioavailability of NO, anti-inflammatory response, inhibi-
tion of oxidation, and anti-atherogenic and anti-thrombotic actions [38].
6.6 Prevention of Cardiovascular Disease

6.6.1 Primary Prevention
Treating hypercholesterolemia in patients who do not have clinical evidence
of ASCVD is called primary prevention. The rationale for this approach is
based upon epidemiologic data documenting a continuous, graded relation-
ship between the total plasma cholesterol concentration and ASCVD events
and mortality [81,82].
Although early trials of lipid-lowering therapy in primary prevention,
conducted with nonstatin medications did not find significant reductions
in cardiac mortality, statin trials in primary prevention, starting with the
landmark West of Scotland Coronary Prevention Study (WOSCOPS) trial,
have found substantial relative reductions in cardiovascular events without
an increase in noncardiovascular mortality [83]. These observations were
extended in the Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS), which showed that lovastatin reduced the
incidence of a first major coronary event (unstable angina pectoris, fatal
and nonfatal myocardial infarction, and sudden cardiac death) in low-risk
men and women without clinical evidence of CVD and LDL-C levels near
the average for the general population (150 mg/dL [3.9 mmol/L], range
130–190 mg/dL [3.4–4.9 mmol/L]) [84]. Similar results were observed in
the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial
(ASCOT-LLA), which studied atorvastatin (10 mg) in men and women
with relatively normal serum cholesterol levels but with hypertension and
at least three additional cardiac risk factors, there was a trend toward a reduc-
tion in all-cause mortality [85]. The potential beneficial effect of statin ther-
apy in primary prevention was also evaluated by the Justification for the Use
of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin
( JUPITER), which randomly assigned 17,802 apparently healthy men
and women with LDL-C levels of less than 130 mg per deciliter (3.4 mmol
per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or
higher to rosuvastatin, 20 mg daily, or placebo and followed them for the
occurrence of the combined primary end point of myocardial infarction,
stroke, arterial revascularization, hospitalization for unstable angina, or death
from cardiovascular causes [86]. The trial was stopped early after only
1.9 years of follow-up when the preliminary results showed that rosuvastatin
therapy led to significant reductions of 54% in myocardial infarction, 51% in
stroke, and 20% in total mortality in the treatment group [86]. A later analysis
of JUPITER data clarified that only 25% of the patients enrolled in the trial
are actually considered at low risk and three-quarters are at least in the
intermediate-risk category based on Framingham and Reynolds risk scores.
When stratified according to underlying coronary heart disease risk, no ben-
efit was observed in the low-risk patients. Only those in the intermediate-
risk category derived a significant 45–49% reduction in ASCVD events from
statin therapy [86].
A meta-analysis of 11 statin trials including data only on 65,229 partic-
ipants who were free from known ASCVD at baseline, conducted to assess
whether statins reduce all-cause mortality in the setting of high-risk primary
prevention populations, found a small statistically nonsignificant reduction
with statin therapy [87]. A subsequent 2012 individual patient data meta-
analysis found a similar reduction in all-cause mortality in patients without
known vascular disease that was statistically significant with an absolute
reduction in deaths of 0.09% per year (1.33% vs. 1.42% per year) [88]. These
data suggest that statin therapy may produce only a small absolute reduction
in all-cause mortality in a true primary prevention population.
In November 2013, the American College of Cardiology and the
American Heart Association (ACC/AHA) released new guidelines for statin
treatment initiation in primary prevention of ASCVD [89]. These recom-
mendations deemphasize LDL-C thresholds to focus on total ASCVD risk,
which is defined by the new Pooled Cohort Equations [90]. The ACC/AHA
new recommendations established four groups for statin therapy eligibility for
adults aged 40–70 years, including 10-year ASCVD risk of 7.5% or higher.
Using data from the National Health and Nutrition Examination Surveys
of 2005–2010, Pencina and colleagues estimated that the new ACC-AHA
guidelines for the management of cholesterol would increase the number
of adults who would be eligible for statin therapy by 12.8 million, with the
increase seen mostly among older adults without CVD [91]. The expansion
of the indications for statin therapy for the prevention of CVD under the
ACC/AHA guidelines has been controversial [92]. Critics have questioned
the Pooled Cohort Equations used in the guidelines arguing that it may sub-
stantially overestimate ASCVD risk, and thus expose millions of Americans to
unnecessary statin therapy costs and risks [93]. On the other side, many experts
have advocated the expansion of the indications for statin therapy for the pre-
vention of CVD under the ACC/AHA guidelines, citing evidence that statin
therapy is very effective for reducing risk regardless of LDL-C or total
ASCVD risk [94–96]. Greenland et al., in their editorial of the July 2015 issue
of JAMA, suggested that the new risk threshold is likely to be reasonable and
cost effective, and that even a risk calculator that overestimates ASCVD risk
may be reasonable to use in clinical practice [97]. Recently, Pursnani and col-
leagues conducted a longitudinal community-based cohort study, with partic-
ipants drawn from the offspring and third-generation cohorts of the
Framingham Heart Study, to determine whether the ACC/AHA guidelines
improve identification of individuals who develop incident CVD and/or have
coronary artery calcification compared with the National Cholesterol Educa-
tion Program’s 2004 Updated Third Report of the Expert Panel on Detec-
tion, Evaluation, and Treatment of High Blood Cholesterol in Adults
(ATP III) guidelines [98]. The authors found that, in this community-based
primary prevention cohort, the ACC/AHA guidelines for determining statin
eligibility, compared with the ATP III, were associated with greater accuracy
and efficiency in identifying increased risk of incident CVD and subclinical
coronary artery disease, particularly in intermediate-risk participants [98].
Although the primary prevention studies demonstrated that statins may reduce
the risk of coronary events, the use of statins for primary prevention may not
be widely adopted, in part because the number of persons who need to be
treated to prevent one clinical event is relatively large, and the use of the
Pooled Cohort Equations as well as the risk of statin-induced diabetes have
not yet been assessed in cost-effectiveness analyses [99]. Recently, Pandya
and colleagues performed a cost-effectiveness analysis of the ACC/AHA
guidelines to estimate ASCVD events prevented and incremental costs per
quality-adjusted life-year (QALY) gained [100]. The authors found that, in
the microsimulation model of US adults aged 45–70 years, the current
10-year ASCVD risk threshold (7.5% risk threshold) used in the
ACC/AHA cholesterol treatment guidelines has an acceptable cost-
effectiveness profile (ICER, $37,000/QALY), but more lenient ASCVD
thresholds would be optimal using cost-effectiveness thresholds of
$100,000/QALY (4.0% risk threshold) or $150,000/QALY (3.0% risk
threshold) [100].
6.6.2 Secondary Prevention

Secondary prevention refers to the treatment intended to avert the recur-
rence of a disease or event in a subject who already had such a condition.
Although the clinical significance and economic consequences of the use
of lipid-lowering agents for primary prevention remains uncertain, the ben-
efit of statin therapy in secondary prevention of ASCVD events is well
established. Although the evidence linking hypercholesterolemia and cere-
brovascular disease is not as robust as that linking hypercholesterolemia and
ASCVD, the stroke outcomes in most secondary trials have been favorably
affected with statin therapy [101].
The Scandinavian Simvastatin Survival Study (4S), which evaluated
4444 patients with established ASCVD (angina or previous myocardial
infarction) and baseline plasma total cholesterol levels between 5.5 and
8.0 mmol/L (212 and 309 mg/dL), was the first large randomized controlled
clinical trial to demonstrate such a benefit [102]. The patients were treated
with a lipid-lowering diet and then randomly assigned to therapy with pla-
cebo or with simvastatin (20–40 mg/day) in an attempt to reduce the level of
total cholesterol below 5.2 mmol/L (200 mg/dL). At the end of 5.4 years,
there was a significant reduction in total mortality in patients treated with
simvastatin compared with placebo. There were also highly statistically sig-
nificant reductions in major coronary events, cardiovascular deaths, revascu-
larization procedures, and fatal plus nonfatal cerebrovascular events.
The 4S was followed by the Cholesterol and Recurrent Events (CARE)
study, which was a double-blind trial lasting 5 years during which either
40 mg of pravastatin per day or placebo were administered to 4159 patients
(3583 men and 576 women) with myocardial infarction who had plasma
total cholesterol levels below 240 mg per deciliter (mean, 209) and LDL-
C levels of 115–174 mg per deciliter (mean, 139) [103]. At 5 years, benefits
with pravastatin treatment compared to placebo included significant reduc-
tions in the combined end of coronary death and nonfatal MI, the need for
revascularization, and the frequency of stroke.
The CARE trial, however, was unable to establish that statin therapy
reduces the risk of death. The mortality benefit of statins was subsequently
demonstrated by the Long-Term Intervention with Pravastatin in Ischemic
Disease (LIPID) study [104]. The LIPID study randomly assigned 9014 men
and women with a recent myocardial infarction or unstable angina with
serum cholesterol concentrations of 155–270 mg/dL to therapy with prav-
astatin or placebo. After a mean follow-up of 60 months, the study was
terminated prematurely because, compared with placebo, pravastatin was

associated with significant reductions in death from coronary heart disease,
total mortality, stroke, need for bypass surgery, and fatal and nonfatal myo-
cardial infarction [104].
Similar results were seen in the Heart Protection Study, a large random-
ized trial involving 20,536 UK adults (aged 40–80 years) with coronary dis-
ease, other occlusive arterial disease, or diabetes, randomly allocated to
receive 40 mg simvastatin daily or matching placebo [105]. After an average
follow-up of 5.5 years, patients treated with simvastatin had a 13% reduction
in all-cause mortality, an 18% reduction in deaths from heart disease or
related blood vessel disease, a 24% reduction in major cardiovascular
events [105].
In a meta-analysis of 25 clinical trials involving 69,511 individuals
with ASCVD with a mean pretreatment LDL-C level of 149 mg/dL
(3.85 mmol/L), it was estimated that statin therapy reduces reduced coro-
nary heart disease mortality or nonfatal myocardial infarction by 25%, all-
cause mortality by 16%, and coronary heart disease mortality by 23% [106].
After an extensive and independently review of randomized control trials
demonstrating the beneficial effect of statins on morbidity and total mortality
when used as primary or secondary prevention, four groups most likely to
benefit from statin therapy were identified in the 2013 ACC/AHA choles-
terol guidelines [89]: (i) patients with any form of clinical ASCVD (includ-
ing acute coronary syndrome, history of myocardial infarction, stable or
unstable angina, coronary or other arterial revascularization, stroke, transient
ischemic attack, or peripheral arterial disease presumed to be of atheroscle-
rotic origin); (ii) patients with primary LDL-C levels of 190 mg per dL (i.e.,
no secondary cause) or greater; (iii) patients 40–75 years of age who have
diabetes and LDL-C levels of 70–189 mg per dL; and (iv) patients 40–75
years of age who do not have diabetes but who do have an estimated
10-year ASCVD risk of 7.5% or greater.
As in the above-described trials, in clinical practice adverse effects are fre-
quently experienced by patients during statin therapy and may result in statin
discontinuation.
7. SIDE EFFECTS
Several clinical trials have demonstrated the efficacy and safety of statin
treatment. Nevertheless, a significant proportion of patients taking these
drugs may experience some degree of intolerance, which in turn may result
in statin discontinuation. Patient characteristics that may influence statin

safety include but are not limited to: multiple or serious comorbidities,
including impaired renal or hepatic function; a history of previous statin
intolerance or muscle disorders; concomitant use of drugs affecting statin
metabolism; a history of hemorrhagic stroke; and age >75 years. Asian
ancestry may also influence the initial choice of statin intensity [107].
Although several adverse effects are commonly reported by patients during
statin therapy, only muscle toxicity and hepatic enzyme elevations are con-
sistently statin related [108]. While these adverse effects will dominate this
chapter, many other purported effects may lead to medical assessment, diag-
nostic testing, and potential inappropriate discontinuation of treatment,
even though such complaints may be unrelated to statin use.
7.1 Muscle Injury

Although muscle toxicity remains a concern, severe myopathy is unusual,
affecting perhaps 0.1% of patients [109]. The clinical features of statin-
induced myopathy include symptoms such as muscle aches or myalgia,
weakness, stiffness, and cramps. Muscle symptoms usually occur within
the first 6 months of treatment, although they can begin months or even
years after initiation of therapy [110]. Statin-induced myopathy may resolve,
or substantially abate, within 2 months of statin discontinuation, which may
be helpful for determining the relationship of symptoms to statin use. Skel-
etal muscle-related adverse effects of statin therapy are most often catego-
rized as myalgias, myopathy, or rhabdomyolysis.
7.1.1 Mechanisms of Statin-Induced Myopathy

Although the mechanism by which statins cause muscle toxicity is not well
understood, evidence suggests that statins may produce myopathic reactions
in two distinct forms—toxic and immune mediated.
The cellular mechanisms accounting for the muscle toxicity of statins are
unknown but numerous hypotheses have been proposed [111]. Statin-
induced inhibition of HMG-CoA reductase results in the lowering of cho-
lesterol, which is an essential component of the cell membrane contributing
to its stability. The reduction of cholesterol may, therefore, result in changes
in membrane fluidity and modification of muscle membrane alterations
including ion channels function, subsequently damaging myocytes and caus-
ing myopathy [112]. Cellular hypoprenylation secondary to the inhibition of
HMG-CoA reductase and the resultant disruption of small G-protein func-
tion, due to reduced isoprenoid intermediaries (i.e., GGPP and FPP), may
also exert pleiotropic effects on numerous signaling pathways leading to

alterations in protein handling and gene expression [113].
Individual statins may have distinct effects on the synthesis of coenzyme
Q10 (CoQ10, ubiquinone), which may play an important role in muscle cell
energy production. This effect may be a function of lipoprotein reduction as
these proteins serve as carriers for coenzyme Q10 [114,115]. It has been
suggested that a reduction in ubiquinone in skeletal muscle may contribute
to statin-induced muscle injury. Some studies have found that statins
decrease skeletal muscle and plasma concentrations of ubiquinone
[116–118]; however, other studies have not [119], and studies have come
to different conclusions about whether statin treatment decreases levels of
ubiquinone in skeletal muscle [118,120,121]. Thus, it is not surprising that
the supplementation with CoQ10 to prevent or treat statin-induced myop-
athy revealed contradictory results [112]. In fact, current guidelines or posi-
tion statements do not recommend CoQ10 supplementation to increase
adherence to statin treatment [122,123].
Next to their effects on CoQ10 levels, statins may also exert direct effects
on the mitochondrial electron transport chain, as pravastatin accelerated the
age-dependent impairment of complex I function in rat muscle cells [124].
The triggering of MELAS-like (mitochondrial myopathy, encephalopathy,
lactic acidosis, and stroke-like episodes) syndromes in two patients on statin
therapy, in fact supports the contention that mitochondrial fidelity may be
sensitive to HMG-CoA reductase inhibitors [125,126]. The effects of statins
on muscle mitochondria have been studied in cell cultures, animal models as
well as in humans. Kaufmann and colleagues investigated mitochondrial
toxicity of four lipophilic stains (cerivastatin, fluvastatin, atorvastatin, and
simvastatin) and one hydrophilic statin (pravastatin) [127]. In L6 cells (rat
skeletal muscle cell line), all statins, except pravastatin, decreased
glutamate-driven state 3 respiration and respiratory control ratio, lowered
beta-oxidation and -induced mitochondrial swelling, cytochrome c release,
and DNA fragmentation [127]. In addition, Kwak et al. demonstrated that
simvastatin-induced myotube atrophy and cell loss associated with impaired
ADP-stimulated maximal mitochondrial respiratory capacity, mitochondrial
oxidative stress, and apoptosis in primary human skeletal myotubes [128].
Other investigators compared isolated primary mouse skeletal muscle
myocytes, C2C12 myotubes and liver HepG2 cells to detect differences that
could uncover why statins are toxic in skeletal muscle but less so in the liver
[129]. These authors found that simvastatin caused a decrease in mitochon-
drial respiration in the primary mouse myocytes and C2C12 myotubes, but
had no effect in the HepG2 cells. Although several studies in animal models
have confirmed muscle injury following statin therapy, they did not consis-
tently support the concept of muscle mitochondrial dysfunction. Treating
rabbits with simvastatin and pravastatin resulted in myopathy and decreased
muscle ubiquinone content, but did not affect mitochondrial enzyme activ-
ities of respiratory chain [130]. Consistently, Schaefer and colleagues dem-
onstrated that neither mitochondrial injury nor a decrease in muscle
ubiquinone levels was the primary cause of skeletal myopathy in
cerivastatin-dosed rats [131]. Nevertheless, Obayashi et al. demonstrated that
cerivastatin-induced type I fiber-predominant muscles injury, which was
associated with mitochondrial damage, in young male F344 rats [132].
Moreover, Bouitbir and colleagues demonstrated that in human as well as
in rat, statins might trigger transcriptional activation of mitochondrial bio-
genesis in myocardium as well as antioxidant capacities via a mechanism
implicating reactive oxygen species signaling pathway [133]. The authors
also found that in skeletal muscle of patients with statin-induced myopathy
as well as in rat skeletal muscle with low antioxidant capacities, statins
induced high-oxidative stress, responsible of transcriptional deactivation
of mitochondrial biogenesis as well as mitochondrial dysfunctions [133].
Multiple studies investigated the effect of statins on skeletal muscle of
patients treated with different statins at various doses. De Pinieux et al. eval-
uated the effect of lipid-lowering drugs on ubiquinone serum level and on
mitochondrial function assessed by blood lactate/pyruvate ratio [134]. Inter-
estingly, lactate/pyruvate ratios were significantly higher in patients treated
by statins than in untreated hypercholesterolemic patients or in healthy con-
trols, a finding that provided the first evidence that statins may be associated
with abnormal mitochondrial metabolism [134]. Phillips and colleagues
reported the biopsy-confirmed myopathy of four patients with muscle
symptoms that developed during statin therapy and reversed during placebo
use [135]. Muscle biopsies showed evidence of mitochondrial dysfunction,
including abnormally increased lipid stores, fibers that did not stain for cyto-
chrome oxidase activity, and ragged red fibers. Interestingly, these findings
reversed in the three patients who had repeated biopsy when they were not
receiving statins [135]. Comparing treatment of 80 mg/day simvastatin with
that of 40 mg/day atorvastatin for 8 weeks, in patients with hypercholester-
olemia, showed a 30% decrease of muscle CoQ10 in the simvastatin group
along with decreased respiratory chain enzyme activities and apparently,
39% lower plasma CoQ10 levels in the atorvastatin group [118]. Neverthe-
less, some studies failed to demonstrate the relationship between muscle
mitochondrial dysfunction and statin-induced myopathy. Laaksonen and

colleagues investigated the effect of 6 months of simvastatin treatment
(20 mg/day) on skeletal muscle concentrations of high-energy phosphates
and ubiquinone by performing biopsies in 19 hypercholesterolemic patients
[120]. The muscle high-energy phosphate and ubiquinone concentrations
assayed after simvastatin treatment were similar to those observed at baseline
and did not differ from the values obtained in control subjects at the begin-
ning and end of follow-up. While this was explained by the low dose of sim-
vastatin used, another albeit retrospective analysis of muscle biopsies
obtained from 23 patients with statin-related myopathy compared to those
of patients with statin-unrelated myopathy found no direct association with
statins [136]. Nevertheless, muscle mitochondrial DNA was lower in
patients with statin-induced myopathy, but there was no difference between
both groups in mitochondrial DNA deletion score or oxidative mitochon-
drial DNA damage, suggesting that the observed mitochondrial DNA
depletion did not lead to qualitative damage of muscle mitochondria [136].
Evidence also suggests increased levels of plant sterols in skeletal muscle
in patients treated with high-dose statins may contribute to statin-induced
myopathy [118]. Specifically, sitosterol may be increased by approximately
50%. The authors of the study postulated that these increased cellular levels
could contribute to the muscle toxicity of statins. Beta-sitosterol is an acti-
vator of AMP-activated protein kinase, which inhibits acetyl-CoA carbox-
ylase. This results in reduced fat synthesis and increased beta-oxidation.
Preliminary evidence suggests that statin-intolerant patients demonstrate
increased fatty acid oxidation (FAO) in response to lovastatin, implicating
an intrinsic FAO abnormality [137]. Statins may increase the expression
of mitochondrial carnitine acylcarnitine translocase and this effect may con-
tribute to the alteration in FAO [138].
Statins may also impair calcium handling in skeletal muscle. For instance,
simvastatin may trigger: (i) mitochondrial depolarization and Ca2+ efflux;
(ii) sarcoplasmic reticulum Ca2+-uptake and/or overload; and (iii) large-
amplitude Ca2+-transients [139]. Additionally, simvastatin-induced long-
lasting fura-2 Ca2+-transients in human skeletal muscle may lead to activation
of calpain and caspases 3 and 9. Calcium chelation and ryanodine, via in-
hibition of Ca2+-induced Ca2+ release, have been shown to abrogate these
effects [140].
Atrogin-1, a muscle-specific ubiquitin protein ligase, may also play an
important role in statin-induced muscle toxicity. Lovastatin may induce
expression of atrogin-1 in humans with statin myopathy and in several
in vitro models; in the models, myopathy could be prevented by knockdown
of atrogin-1 [141]. These and other proposed mechanisms require further

experimental confirmation.
Although the pathophysiological explanations of statin-induced myop-
athy have focused primarily on toxic mechanisms, an immune-mediated
form of necrotizing myopathy (NM) has recently emerged as a rare but ful-
minant form of statin myopathy [142]. It is still unclear whether the two
forms of myopathy can coexist or if a toxic, insult may trigger a secondary
immunologic event. Immune factors may, in fact, play a role in the devel-
opment of statin myopathy/myositis in a certain subset of patients. Indeed,
several reports have emerged demonstrating the induction of inflammatory
myopathies (i.e., polymyositis and dermatomyositis) by statins in a time-
frame consistent with a toxic effect [143–149]. In contrast to these studies,
which exhibited robust inflammatory infiltrates on muscle biopsy, an
immune myopathy may develop manifesting major histocompatibility-1
upregulation without inflammation [150]. Interestingly, statins may increase
plasma lipidic proinflammatory markers [151] potentially magnifying or per-
petuating an autoimmune response against HMG-CoA reductase, which
may be expressed at high levels in regenerating muscle fibers [152].
7.1.2 Implications of Statin-Induced Myopathy: Spotlight on Exercise

Capacity
Although the exact mechanisms of statin–exercise interactions are not fully
understood, the incidence of myopathy increases exponentially among statin
users who also exercise, limiting the cardiovascular benefit of this therapeu-
tic agent [153]. It is well established that the regular physical activity or exer-
cise has numerous beneficial effects on the cardiometabolic risk profile [154]
and decrease the incidence of morbidity and mortality from CVD [155].
Chomistek and colleagues showed that participating in 3 h of high-intensity
physical activity is associated with a 22% lower risk of myocardial infarction
among men [156]. Regular physical activities have also been shown to
induce beneficial changes in blood pressure, blood lipids, inflammatory
markers, and insulin sensitivity [156] as well as improving wellness, attenu-
ating age-related decline, and reducing risk of premature death [157]. More-
over, Cotter et al. demonstrated that a higher sense of control, more social
support, and more social strain are related to more physical activity [158]. It
should, therefore, be encouraged and desirable for patients with CVD who
are on statin therapy to participate in regular physical activities to benefit
from these two interventions.
Several studies support the concept that aerobic exercise of adequate
intensity, duration, and volume increases HDL-C concentration as well
as attenuates the reductions in HDL-C usually observed with low-fat diets

[159]. Thus, in light of the evidence suggesting that the effects of statin on
HDL-C levels may be type and dose dependent [160], regular physical
activity may serve as an invaluable adjuvant therapy. In a prospective cohort
study of 10,043 dyslipidemic veterans, the combination of statin treatment
and increased fitness resulted in substantially lower mortality risk than
either intervention alone or reinforcing the importance of physical activity
for individuals with dyslipidemia [159]. However, statins not only may
induce muscle pain and weakness, reducing regular physical activity partic-
ipation and ultimately affecting exercise performance, but also they may
directly compromise aerobic exercise capacity and training adaptations
[133,161,162]. Mikus and colleagues examined the effects of simvastatin
on changes in cardiorespiratory fitness and skeletal muscle mitochondrial
content in response to aerobic exercise training in 37 sedentary overweight
or obese adults with at least two metabolic syndrome risk factors [161]. Car-
diorespiratory fitness increased by 10% (P < 0.05) in response to exercise
training alone, but it was blunted by the addition of simvastatin resulting
in only a 1.5% increase (P < 0.005 for group by time interaction). The
authors also found that skeletal muscle citrate synthase activity were
increased by 13% in the exercise only group (P < 0.05), but were decreased
by 4.5% in the simvastatin plus exercise group (P < 0.05 for group by time
interaction) [161]. Despite conflicting reports, some experimental evidence
suggests that physical activity, especially when it involves eccentric contrac-
tions, may aggravate statin-induced myopathy, whereas statin therapy might
predispose to exercise-induced myopathy [153]. Sinzinger et al. showed that
only about 20% of professional athletes with familial hypercholesterolemia
were able to tolerate statin treatment without side effects or a decrease in
performance [163]. Interestingly, it has been estimated that 38% of statin-
treated patients with myalgia avoid even moderate physical activity during
everyday life and as many as 25% of the patients who exercise experience
muscle-related symptoms [153]. It is therefore evident muscle pain and
weakness may reduce endurance performance, while the consequent reduc-
tion in exercise participation may negatively affect aerobic capacity and
long-term adaptations [153].
7.2 Hepatic Dysfunction

Clinical studies of statins have demonstrated a 0.5–3.0% occurrence of persis-
tent elevations in aminotransferases in patients receiving statins. This has
primarily occurred during the first 3 months of therapy and is dose dependent.
While many drugs may cause liver disease, the evidence indicates that signif-
icant liver pathology attributable to statins is rare [164]. These rare episodes of
more severe liver injury may, predominantly, occur 3–4 months after initia-
tion of statin therapy [165], with a range in one study of 1 month to 10 years
[166]. However, these are sufficiently uncommon that overall the incidence
of hepatic failure in patients taking statins appears to be no different from the
incidence in the general population [167]. Thus, when the serious hepatotox-
icity is encountered in a statin-treated patient, undiagnosed, and nonstatin-
related liver diseases should be strongly considered in the differential diagnosis
[142]. The pattern of more severe hepatotoxicity attributed to statins has
included hepatocellular, cholestatic, and autoimmune injury [166]. The most
commonly reported hepatic adverse effect is the phenomenon known as
“transaminitis” in which liver enzyme levels are elevated in the absence of his-
topathological changes [142]. Although the underlying mechanism remains
unclear, it may result from altered lipid components within the hepatocyte
membrane, leading to increased permeability and subsequent “leakage” of
liver enzymes [142,168]. In fact, the phenomenon is observed with all classes
of lipid-lowering drugs including resins, which are not absorbed [142]. There-
fore, this effect may be due to the lipid-lowering process itself and may not be
specific to statins [142]. When it occurs, it is usually hepatocellular and only
very rarely cholestatic [142]. Most cases of “transaminitis” resolve spontane-
ously without the need for drug discontinuation [142].
7.3 Renal Dysfunction

Reports of rosuvastatin-induced renal toxicity, largely proteinuria and
hematuria, initially caused widespread concern [169]. As a result, submission
data for all statins were reviewed by the FDA, which eventually concluded
that statins, including rosuvastatin, did not cause renal toxicity [169]. There
have been a number of reports about proteinuria with statins, particularly in
patients receiving rosuvastatin or simvastatin [170]. However, it is believed
that proteinuria with statins is a benign finding [171]. Statins may cause pro-
teinuria through tubular inhibition of active transport of small-molecular-
weight proteins [172,173].
7.4 Behavioral and Cognitive

Early research suggested that lowering cholesterol concentrations may be
associated with an increase in violent or suicidal deaths [174]. Other studies
showed that both chronically low and medically lowered serum cholesterol
may be associated with an increased incidence of depression [175,176].
Although concerns have been raised, statins do not appear to be associated
with an increased risk of suicide or depression [177]. There have been case
reports of patients developing severe irritability and aggression associated
with the use of statins [178]. It is not known whether the statin use caused
these symptoms, but very rare idiosyncratic reactions of this sort may be mis-
sed in controlled trials.
Concerns have also been raised in the media and popular press about
cognitive dysfunction and memory loss associated with statin use. Evans
and colleagues conducted a patient survey-based analysis, to characterize
the adverse cognitive effects of statins in 171 patients (age range 34–86 years)
who self-reported memory or other cognitive problems associated with
statin therapy while participating in a previous statin effects study [179].
The authors found that cognitive problems associated with statin therapy
have variable onset and recovery courses, a clear relation to statin potency,
and significant negative impact on quality-of-life [179]. Interestingly, a sys-
tematic review of randomized trials and observational studies found that
published data do not suggest that statins harm cognition; however, the qual-
ity of the evidence was felt to be only low-to-moderate, particularly with
regard to high-intensity statin therapy [180].
7.5 Cancer
Preclinical studies found that very high-dose statin therapy increased the risk
of liver tumors in rodents [181]. Some [182–185], but not all [186–189],
observational studies have also raised the possibility that use of statins may
decrease overall risk of cancer and of specific cancers. In contrast, meta-
analyses of randomized trials have consistently shown no effect of statins
on cancer incidence or cancer mortality [190–193]. 10-Year follow-up of
the 4S trial and the West of Scotland Coronary Prevention Study
(WOSCOPS) and 11-year follow-up of the Heart Protection Study
(HPS) showed no increases in cancer deaths [194–196]. In summary, there
is no convincing evidence that statins increase or decrease the risk of cancer.
7.6 Diabetes Mellitus

Statins may have effects on glucose metabolism that might influence the
development of diabetes mellitus in nondiabetics or affect glycemic control
in patients with existing diabetes. Experimental evidence has been
conflicting about whether statins as a group improve glucose metabolism or

whether some statins show beneficial effects while others show harmful
effects [197–202]. It appears likely that statins may confer a small increased
risk of developing diabetes, and that the risk is slightly greater with intensive
statin therapy than moderate statin therapy [107]. Recently, Mansi and col-
leagues conducted a retrospective cohort study of tricare beneficiaries who
were evaluated between October 1, 2003 and March 1, 2012, to examine
the association between statin use and new-onset diabetes, diabetic compli-
cations, and overweight/obesity [203]. A total of 25,970 patients (3982
statin users and 21,988 nonusers) were identified as healthy adults at baseline.
Of these, 3351 statins users and 3351 nonusers were propensity score mat-
ched. Statin users had higher odds of new-onset diabetes (odds ratio [OR]
1.87; 95% confidence interval [95% CI] 1.67–2.01), diabetes with compli-
cations (OR 2.50; 95% CI 1.88–3.32), and overweight/obesity (OR 1.14;
95% CI 1.04–1.25) [203]. Diabetes, diabetic complications, and over-
weight/obesity were, therefore, more commonly diagnosed among statin
users than similar nonusers in a healthy cohort of adults. The authors con-
cluded that short-term clinical trials might not fully describe the risk/benefit
of long-term statin use for primary prevention [203]. Despite the above evi-
dence, some experts still claim that the potential for an ASCVD risk-
reduction benefit outweighs the excess risk of diabetes in all but the
lowest-risk individuals [107,204,205].
7.7 Other
In preclinical toxicity testing, dogs developed cataracts when given doses of
statins much higher than human doses [206]. While most large case–control
and cohort studies [207–209], as well as a small randomized trial [210], may
not have found an increased risk of cataract, large cohort studies from
England and Wales and from the United States military health system have
found that statin use was associated with an increased risk of cataract
[211,212]. A small number of epidemiologic and case studies have suggested
an association between statin and peripheral neuropathy, although this causal
association has yet to be proven [164]. Some [213,214], but not all [215],
studies suggest that statins may lower androgen levels in men, although it
appears unlikely that this effect is clinically significant [216]. Statins may also
reduce androgen levels in women, including in women with androgen
excess [202]. In the United States, statins are rated category X in pregnancy,
and the recommendation is to discontinue their use prior to conception if
possible [73]. Animal studies suggest that at maternally toxic doses statins
may be associated with adverse fetal outcomes, but limited human data indi-
cate that statins may not be major human teratogens [217]. Data on statin
safety in breastfeeding are very limited. In the absence of adequate safety
data, use of statins by breastfeeding mothers is discouraged [73].
8. STATIN INTOLERANCE
Although data from clinical trials suggest low rates of statin side effects
leading to discontinuation, it is not uncommon to find patients who are
intolerant of one or more statins because of myalgias or other muscular
symptoms. Less commonly, aminotransferase elevations require making
changes in the statin, the statin dosage, or changes to another class of
cholesterol-lowering therapy [73]. As an increasing number of patients
become eligible for lipid-lowering therapy, this is becoming a more prev-
alent issue. There are several measures that healthcare providers and their
patients can take to reduce the risk of statin intolerance. These may include
comprehensive pretreatment assessment, patient counseling, and ongoing
monitoring [142]. For patients who demonstrate actual intolerance to statin
therapy, there are several therapeutic options that may be considered,
including the use of different or lower dose statins [142]. In addition, non-
statin alternatives or adjuncts for lowering LDL-C may be warranted [142].
Interventions to alleviate the symptoms of myalgia while continuing to take
statins have also been considered [142].
9. CONCLUSION
Cholesterol is an essential natural component of all mammalian cell
membranes and plays an important role in the functioning of all human
organs. Nevertheless, LDL-C was found to be responsible for the develop-
ment of ASCVD. Statins remain one of the most important advances in the
therapy of dyslipidemia and for the reduction of ASCVD event risk. The
extensive experience with this class of drugs has substantiated its efficacy
and safety. This chapter provided a foundation for understanding the clinical
use of statins as well as factors that may limit their pharmacological
applications.
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CHAPTER FIVE

Advances in Clinical Chemistry, Volume 73 # 2016 Elsevier Inc. 127

focused on LDL-cholesterol reduction as the primary goal. Current medication options

sequestrants, a cholesterol-absorption inhibitor, fibrates, nicotinic acid, and

HMG-CoA Lovastatin Simvastatin

Pravastatin Fluvastatin Cerivastatin sodium

unique polar ethane sulfonomide group, which is quite hydrophilic and

in the enzyme where endogenous HMG-CoA is normally bound. The

Metabolism of statins is catalyzed by CYP and UGT gene family

catalyzed by HMG-CoA synthase. The HMG-CoA reductase enzyme then

ðSÞ HMG CoA + 2NADPH + 2H +

In this step, the NADP+ is the oxidized form of nicotinamide adenine

cholesterol [34]. In addition to reducing de novo cholesterol synthesis with

maximize their therapeutic effects. Studies have shown greater reductions in

5.2 Alternative Dosing Regimens

5.3 Interchange (Switching Between Statin Drugs)

5.4 Drug Interactions

pravastatin, and fluvastatin [63,64]. There may be an additive hypolipidemic

6.2 Effect on HDL

6.3 Effect on Triglycerides

6.4 Genetic/Ethnic Effects

Prescribing information for rosuvastatin recommends starting therapy at a

6.5 Pleiotropic Effects

enhancement of S1P-induced anti-inflammatory and anti-atherothrombotic

6.6 Prevention of Cardiovascular Disease

6.6.2 Secondary Prevention

terminated prematurely because, compared with placebo, pravastatin was

in statin discontinuation. Patient characteristics that may influence statin

7.1 Muscle Injury

7.1.1 Mechanisms of Statin-Induced Myopathy

also exert pleiotropic effects on numerous signaling pathways leading to

mitochondrial dysfunction and statin-induced myopathy. Laaksonen and

of atrogin-1 [141]. These and other proposed mechanisms require further

7.1.2 Implications of Statin-Induced Myopathy: Spotlight on Exercise

as attenuates the reductions in HDL-C usually observed with low-fat diets

7.2 Hepatic Dysfunction

7.3 Renal Dysfunction

7.4 Behavioral and Cognitive

7.6 Diabetes Mellitus

conflicting about whether statins as a group improve glucose metabolism or

[22] K. Nezasa, K. Higaki, M. Takeuchi, M. Nakano, M. Koike, Uptake of rosuvastatin

high-resolution, noninvasive magnetic resonance imaging, Circulation 104 (2001)

[130] K. Nakahara, M. Kuriyama, Y. Sonoda, H. Yoshidome, H. Nakagawa, J. Fujiyama,

[146] F.H. Khattak, I.M. Morris, W.A. Branford, Simvastatin-associated dermatomyositis,

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