Review article S W I S S M E D W K LY 2 0 0 6 ; 1 3 6 : 4 1 – 4 9 · w w w . s m w .

c h 41
Peer reviewed article

The role of statins in clinical medicine –

LDL – cholesterol lowering and beyond
Jonas Rutishauser
Innere Medizin B, Universitätsspital, Basel, Switzerland

Summary
In the past years, statins have emerged as the other drugs must be considered. Recently, charac-
most important class of lipid lowering agents. teristics unrelated to LDL lowering have been in-
Through inhibition of HMG-CoA reductase, they tensively studied. These pleiotropic statin effects
restrict the rate-limiting step of cholesterol syn- result from decreased levels of isoprenoid interme-
thesis, which leads to upregulation of LDL recep- diates of cholesterol synthesis. They include –
tors on the cell membrane and thus reduction of among others – anti-inflammatory, anti-prolifera-
atherogenic LDLs. This effect translates into clin- tive, and immunomodulatory actions. Pleiotropic
ical benefit by reducing cardiovascular events both effects favourably influence pathomechanisms of
in primary and secondary prevention settings. As plaque formation. Furthermore, they may prove
an approximate rule, statin therapy leads to a rela- beneficial in the prevention or treatment of dis-
tive risk reduction of 25–30% in most of the large eases unrelated to atherosclerosis, eg rheumatoid
randomised controlled trials. Stroke risk is re- arthritis, multiple sclerosis, or cancer.
duced to a similar degree. Despite initial concerns,
the currently available statins have a favourable Key words: statins; HMG-CoA reductase inhi-
safety profile; however, potential interactions with bitors; cholesterol; LDL; effects, pleiotropic

Introduction
The identification of hypercholesterolaemia cant elevation of non-cardiac deaths during the
as a key cardiovascular risk factor fuelled intensive treatment phase which levelled off after treatment
research for compounds that would inhibit the was terminated [4]. The Lipid Research Clinics
rate-limiting enzyme in cholesterol synthesis, study with cholestyramine [5] and the Helsinki
3-hydroxy-3-methylglutaryl-coenzyme A (HMG- heart study with gemfibrozil [6] also found an ele-
CoA) reductase. In 1971, Japanese chemists initi- vated non-coronary death rate, compared with
ated a project which led to the isolation of the first placebo, particularly due to accidents and violence,
statin, mevastatin, from 600 litres of penicillium but the increases were not significant. Neverthe-
citrinum culture filtrate [1]. The compound low- less, as late as 1992 the British Medical Journal
ered serum cholesterol in hens, dogs and primates, asked: “Should there be a moratorium on the
including humans, and led to the development of use of cholesterol lowering drugs?” [7]. But at that
other HMG-CoA reductase inhibitors [2]. Lovas- time, the statins had already begun their tri-
tatin, simvastatin, and pravastatin were approved umphant success, and since the early 1990s, tens
and marketed by 1990, and since then, fluvastatin, of thousands of individuals have been allocated
atorvastatin, cerivastatin, and rosuvastatin have to statin treatment in many randomised con-
followed. Interestingly, during the early days of the trolled trials. According to an internet source
statin era the safety of cholesterol lowering ther- ([Link]/[Link]), 126 million
apy in general was questioned [3]. The WHO trial, subscriptions have been filled for statins in 2004,
No financial a primary prevention study with clofibrate in 30% more than in 2003. These figures underscore
support declared.
hyperlipidaemic patients, had reported a signifi- the socioeconomic significance of these drugs.
The role of statins in clinical medicine 42

Cardiovascular risk reduction

The foremost effect of all statins is the lower- LDL-cholesterol levels of 3.59 mM [17]. Treat-
ing of blood atherogenic LDL levels. LDL reduc- ment with pravastatin led to a relative risk reduc-
tion by the available statins may range from ~20% tion for coronary events of 24% compared to
to maximally ~55%; elevation of HDL levels is placebo. The LIPID study with pravastatin
clearly less pronounced with 0% to ~10% reported showed similar relative risk reductions for cardio-
[8, 9]. Several early as well as recent studies re- vascular events in a secondary prevention setting
ported reduction of progression or even regression with patients after myocardial infarction or unsta-
of coronary lesions as measured by angiography ble angina [18, 19]. Furthermore, LIPID also doc-
[10–14]. Similarly, in venous coronary bypass umented a significant reduction in overall mortal-
grafts, lowering of LDL-cholesterol with lovas- ity [18]. The same is true for HPS (Heart Protec-
tatin slowed the progression of graft atheroscle- tion Study), a large trial evaluating simvastatin ver-
rosis as measured by angiography [15]. The “4S” sus placebo in over 20 500 very high-risk patients
study with simvastatin, published in 1994, was the with or without known CAD and mean pre-treat-
first placebo-controlled megatrial to demonstrate ment LDL-levels of 4.3 mM [20]. The PROSPER
a reduction of cardiac mortality and morbidity as trial looked at an elderly population aged 70–82
well as overall mortality in a high-risk population years, about 45% of which had a history of vascu-
with established coronary artery disease (CAD) lar disease [21]. In these patients, lowering LDL-
and an elevated mean LDL cholesterol level of cholesterol by approximately one third over three
4.87 mM [16]. Other large trials followed. The years reduced cardiac events by 19%; overall mor-
CARE trial was a secondary intervention study in tality was unchanged.
patients after myocardial infarction with mean

Primary prevention studies

A large body of clinical data suggests that the disease. Recently, the ASCOT-LLA trial looked at
benefit of statin treatment is not limited to patients over 10000 hypertensive patients with ≥3 addi-
with known CAD. In the West of Scotland Coro- tional cardiovascular risk factors, but without
nary Prevention Study (WOSCOPS) none of the known CAD [24]. These individuals had mean
nearly 6600 high-risk males with elevated LDL LDL-cholesterol levels as low as 3.4 mM.
levels (mean, 4.96 mM) had a history of myocar- Nonetheless, atorvastatin treatment resulted in a
dial infarction, and only 5% reported angina. In relative reduction of major cardiovascular events
these individuals, pravastatin reduced the relative by 36%. In the CARDS trial, which studied nearly
risk for coronary events (including cardiac death) 3000 type 2 diabetics without CAD, treatment
by ~30%, and for overall mortality by 22% as com- with atorvastatin resulted in an equal relative risk
pared to placebo [22]. Even more astonishing, the reduction for major cardiovascular events [25].
AFCAPS/TexCAPS trial demonstrated that lovas- However, although statins in the setting of pri-
tatin reduces the relative cardiac risk to a similar mary prevention effectively reduce cardiovascular
degree also in individuals with average LDL cho- events, the economic consequences of this therapy
lesterol levels (mean, 3.89 mM) and without a pro- must be kept in mind. Thus, it was concluded from
nounced coronary risk profile [23]. In the HPS, a cost-effectiveness analysis that statin treatment
35% of patients reported no prior CAD, and only in primary prevention should be limited to high-
~45% of the participants in PROSPER had a his- risk individuals [26].
tory of coronary, cerebral, or peripheral vascular

Specific patient groups, clinical settings and outcomes

Diabetes mellitus AFCAPS/TexsCAPS, a total of 13200 persons were

Subgroup analyses in the large secondary pre- studied, of which ~300 diabetics. This was not
vention trials have been of limited meaning, because enough to draw a conclusion about the benefit of
the number of included patients with diabetes mel- statin treatment in diabetic patients in the primary
litus was low (~1590 of a total of >17600 subjects prevention setting. Similarly, the ASCOT-LLA pri-
studied in 4S, CARE, and LIPID). Nevertheless and mary prevention study was underpowered and/or
not surprisingly, the data from these studies sug- had too short a follow-up (median, 3.3 years) to
gested a similar cardiovascular benefit for diabetics prove a benefit for diabetics [24]. These issues were
as for non-diabetics (eg [27] for the CARE trial). clarified by the HPS. 5963 diabetics were included,
In the primary prevention trials, WOSCOPS and 3982 of which without CAD and 2912 without any
 S W I S S M E D W K LY 2 0 0 6 ; 1 3 6 : 4 1 – 4 9 · w w w . s m w . c h 43

known arterial disease. These patients benefited sig- between hypercholesterolaemia and CAD. Thus, a
nificantly from treatment with simvastatin with re- meta-analysis of 45 studies with 450000 patients
gard to coronary and cerebrovascular events and failed to demonstrate a relationship between total
revascularisations (relative risk reduction for any cholesterol levels and stroke rate, except in patients
major vascular event, 22%) over a wide range of <45 years old [34]. However, most of the cited stud-
specified variables such as age, duration and type of ies reported fatal strokes only, and the distinction be-
diabetes, HbA1c level, presence or absence of hyper- tween ischaemic and haemorrhagic stroke was not
tension, waist circumference, and creatinine levels made. The 4S study showed no benefit on stroke
[28]. The risk reduction occurred irrespective of the mortality, which was a component of the composite
pre-treatment LDL-levels. The CARDS study [25] primary endpoint. However, in a post-hoc analysis,
exclusively studied diabetic patients, in which the the relative risk for fatal and non-fatal stroke was
baseline mean LDL concentration was somewhat 70% in those patients allocated to simvastatin [16].
lower than in the HPS study population (3 vs 3.4 Subgroup analyses of the LIPID and CARE trials
mM, respectively). CARDS corroborated the find- demonstrated a relative risk reduction of 19% and
ings of HPS. Treatment with atorvastatin reduced 31%, respectively [17, 18]. In the primary preven-
the risk of a first major cardiovascular event by 37%. tion setting of WOSCOPS, the relative risk reduc-
Thus, these data warrant statin treatment of diabetic tion was only 11%, and the low absolute risk resulted
patients even in a setting of primary prevention. in a very high number needed to treat (642 to avoid
Although direct evidence exists for simvastatin and 1 stroke event for the mean follow-up period of 4.9
atorvastatin only, there is no reason to believe that years; >3000 per year). The overall beneficial effect
other statins will not yield a comparable benefit. in all three pravastatin studies resulted entirely from
Should all type 2 diabetics be treated with statins? a reduction in non-haemorrhagic strokes [35]. Thus,
This question is under debate [29] and may well be the more studies became available, the more evident
negated. Multiple factors such as age, comorbidity, was the benefit of statin treatment on stroke risk [36,
and socio-economic situation must be taken into 37]. However, so far, no data exist on statin benefits
account when making a treatment decision. The in the secondary prevention of stroke in patients
UKPDS risk engine represents a helpful tool to pre- without known CAD. PROSPER, although focused
dict CHD and stroke risk in type 2 diabetes and may on a high-risk elderly population surprisingly
thus facilitate treatment decisions ([Link] showed no reduction on stroke rate [21]. This find-
[Link]/[Link]?maindoc=/riskengine). ing may be explained by the low stroke incidence ob-
served in the study population and the relatively
Acute coronary syndrome short follow-up of 3.2 years. In the HPS, the relative
and percutaneous coronary interventions reduction in ischaemic strokes (28%) paralleled that
In 3000 patients with unstable angina or non-Q- in major coronary events [20, 38]. Based on the meta-
wave acute myocardial infarction, the MIRACL analyses of the large statin trials, the authors calcu-
study demonstrated a 16% relative risk reduction by lated a 21% risk reduction for every 1 mM reduction
treatment with high-dose atorvastatin, compared to in LDL levels. CARDS even reported a 48% risk re-
placebo, for a composite cardiac endpoint during duction for strokes in diabetics, higher than that for
16 weeks after randomisation [30]. The LIPS trial acute coronary events [25]. Taken together, most of
looked at statin-mediated benefits in >1600 patients the available clinical data clearly support a beneficial
with coronary catheter interventions [31]. Fluvas- effect of statins on ischaemic stroke risk, in a range
tatin significantly reduced the risk for a major car- comparable to that on coronary events.
diac event during 4 years of follow-up. A subgroup
analysis of the PRISM trial in acute cardiac is- Chronic kidney disease
chaemia also confirmed the benefit of statins in the So far, one trial has studied the effect of ator-
acute ischaemic episode by demonstrating that dis- vastatin on cardiovascular events in ~1200 type
continuation of statin therapy in pre-treated patients 2 diabetics undergoing chronic haemodialysis, a
is related to an increased risk of recurrent events dur- population with very high cardiovascular risk [101].
ing the follow-up of 30 days [32]. Recently, the Surprisingly, despite a marked drop in LDL choles-
PROVE-IT trial compared high-dose (80 mg) ator- terol of 42% in the atorvastatin group, no reduction
vastatin versus standard-dose (40 mg) pravastatin was found in the composite primary cardiovascular
therapy in 4162 patients with acute coronary syn- endpoint as compared with placebo over a follow-up
drome [33]. Although designed as a non-inferiority of four years. Overall and CHD mortality did not
trial, the study found a benefit of the aggressive ther- change either. In marked contrast to the studies
apy regarding a composite endpoint including death mentioned above, there was even a two-fold risk for
from any cause and stroke. The findings of PROVE- fatal strokes in the atorvastatin- compared to
IT will be further discussed below in the section on placebo-treated patients. The lack of therapeutic
the pleiotropic statin effects. benefit in this study may result from differing
pathogenetic mechanisms of cardiovascular dis-
Effect on stroke risk ease in patients on haemodialysis, but the negative
The causal relationship between dyslipidaemia findings remain essentially unexplained.
and stroke risk is less clearly documented than that
The role of statins in clinical medicine 44

Pleiotropic effects of statins

Whether the favourable effect on the serum is crucial for the correct function and localisation
LDL concentration is the sole explanation for the of these molecules. They are involved in the reg-
clinical benefit of the HMG-CoA reductase in- ulation of the cell cycle, endothelial nitric oxide
hibitors is an interesting and intensively studied synthase expression, smooth muscle cell migra-
question. Although acute lowering of LDL con- tion, tissue plasminogen activator (tPA) / tPA in-
centrations by a single apheresis improves en- hibitor expression, NAD(P)H oxidase activity, and
dothelial-dependent vasodilation as assessed by other cellular functions relevant in the prolifera-
forearm blood flow measurement [40], several tive and oxidative processes of plaque formation
lines of evidence suggest that statins have features [42]. In plaques obtained and analysed from hu-
that cannot be explained by lowering of the LDL mans ex vivo, pravastatin treatment has been
levels alone. These cholesterol-independent, so- shown to increase collagen content and reduce
called pleiotropic effects [41] on non-hepatic tis- metalloproteinase activity, thereby counteracting
sues have been observed with various statins, even factors that lead to plaque destabilisation and rup-
the hydrophilic pravastatin, which penetrates ture [44]. In a mouse model of focal cerebral is-
poorly through cell membranes of non-hepatic chemia, simvastatin and lovastatin reduced infarct
cells. It has therefore been hypothesised that size via up-regulation of endothelial NO synthase
pleiotropic statin effects could in part be mediated [45], which, among other effects, promotes vasodi-
by a reduction in circulating levels of hepatic cho- lation and inhibits platelet aggregation. Thus, the
lesterol precursors [42]. impact of statins on atherosclerotic lesions exceeds
In the absence of a clear-cut causal relation be- their effect on plaque size by mere reduction of
tween LDL elevation and stroke risk, the statin lipid contents.
benefit on stroke incidence may be viewed as indi-
rect evidence for pleiotropic effects. These may Anti-inflammatory
concern either neuronal cells or, in the case of the and immunomodulatory effects
hydrophilic pravastatin, which in therapeutic con- The CRP level has been identified as inde-
centrations does not pass the blood-brain barrier, pendent predictor for future cardiovascular events
endothelial cells (see below). Another clue for [46–48]. The post-hoc analysis of the CARE trial
pleiotropic effects comes from the 10-year report demonstrated that pravastatin treatment led to a
of the POSCH trial [43], which studied the effect decrease of CRP levels, which rose continuously in
of partial ileal bypass surgery on cardiac events. the placebo-treated group [49]. The lowering of
POSCH demonstrated a 37% reduction, com- CRP was independent of the effect on LDL levels.
pared to the non-operated control group, of coro- This finding was confirmed in the prospective
nary morbidity and mortality along with changes PRINCE study with pravastatin [50]. Moreover, in
in lipid profiles similar to those achieved by statin the AFCAPS/TexCAPS study, lovastatin reduced
therapy. However, while in many statin trials the the CRP level significantly, and there were more
effects were fully discernible after three years of first coronary events in patients with CRP levels
treatment, leading to premature termination of the higher than median even when LDL levels were
studies in some instances, the event curves in the low [51]. In the PROVE-IT study, the achieved
POSCH study started to separate only at ~3 years CRP levels predicted the cardiac outcome irre-
and continued to do so until approximately 10 spective of the achieved LDL levels [52]. A post-
years of follow-up. The relatively early benefit of hoc analysis of the REVERSAL trial, which had
the statin treatment could thus result from addi- demonstrated a reduced coronary atheroma pro-
tional pleiotropic effects. gression with 80 mg atorvastatin compared to
40 mg pravastatin [14], reported that the decrease
Plaque stabilization in CRP levels was correlated independently with
and endothelial homeostasis atheroma progression. The atheroma size regress-
The MIRACLE trial demonstrated that ag- ed in the patients with the greatest reductions
gressively dosed statin therapy significantly re- in CRP levels, but not in those with the greatest
duced recurrent coronary events within 16 weeks LDL reductions [53]. These hypothesis-generating
in patients with acute coronary syndrome [30]. In studies suggest that the anti-inflammatory action
the PROVE-IT study, the advantage of the high of statins, whatever mechanism responsible, could
over the standard statin dose led to a separation of translate into a clinical benefit irrespective of that
the event curves as early as three weeks after the achieved by lowering the LDL levels. It should be
initiation of treatment. Moreover, the reduction of kept in mind, however, that CRP levels in patients
the hazard ratio became significant already after with CAD fluctuate substantially [54]. This may
180 days [33]. How could such rapid effects be ex- hamper the use of CRP as a parameter for risk
plained? Via inhibition of HMG-CoA reductase, stratification and treatment monitoring. So far,
statins lower concentrations of intermediate prod- there have been no studies using CRP levels as
ucts of cholesterol synthesis, the isoprenoids. Post- primary target to guide statin treatment. The
translational modification through isoprenylation JUPITER trial will include up to 15 000 subjects
of GTP-binding proteins, such as Rho, Ras or Rac, with low (<3.36 mM) LDL and elevated (>2 mg/L)
 S W I S S M E D W K LY 2 0 0 6 ; 1 3 6 : 4 1 – 4 9 · w w w . s m w . c h 45

high-sensitive CRP levels to test the effect of found equal fracture rates in the pravastatin- and
rosuvastatin on cardiovascular events in a primary placebo-treated group [69]. Thus, the benefit of
prevention setting [55]. statins on fracture risk remains uncertain, and con-
Immunomodulatory effects of various statins trolled trial designed for this endpoint are lacking.
have been investigated in vitro and in vivo. Inter-
feron g-induced expression of major histocompat- Effects on risk for dementia
ibility complex II molecules on human endothelial Observational studies have suggested signifi-
and macrophages is inhibited specifically and in a cant reductions in the risk for various forms of de-
dose-dependent manner by atorvastatin, lovas- mentia [70, 71] as well as for Alzheimer’s disease
tatin, and pravastatin [56]; thus, statins may be re- [72]. However, these results may be influenced by
garded as potentially immunosuppressive. Indeed, indication and cessation bias and have been subject
in an earlier study in patients with cardiac trans- to debate [73]. A placebo-controlled randomised
plants, those treated with pravastatin not only had study with simvastatin over 6 months in 35–70
less graft vasculopathy and intimal thickness, but year-old adults even found adverse effects on neu-
also less severe rejections than those receiving ropsychological tests [74]. In the PROSPER and
placebo [57]. However, none of the large statin tri- HPS studies, no differences on cognitive function
als has reported an increased risk of serious infec- were seen between the treatment groups [20, 21].
tions, which could be expected if statins were po- Effects on cognition were, however, not part of the
tent immunosuppressors. Although fluvastatin was primary and secondary endpoints.
shown to lower cardiac event rates in kidney trans-
plant recipients [58], it failed to reduce the rate of Statins and cancer
allograft rejection in a randomised, placebo-con- By reducing the intracellular isoprenoid pool,
trolled trial [59]. lovastatin has been shown in cell culture experi-
Interesting clinical observations were made in ments with various tumour cells to induce apopto-
patients with autoimmune diseases. Two open- sis, initiate cell cycle arrest, induce differentiation,
label pilot studies using simvastatin and lovastatin and regulate various signalling pathways involved
reported regression of gadolinium-enhancing le- in tumour growth (reviewed in [75]). Cerivastatin
sions in patients with relapsing-remitting multiple inhibits proliferation and invasiveness of cultured
sclerosis [60, 61]; however, clinical disability scores breast cancer cells [76]. On the other hand, in the
were unchanged. In contrast, in a randomised, CARE study, the incidence of female breast cancer
placebo-controlled trial in patients with rheuma- rose in the pravastatin group, and the PROSPER
toid arthritis, the TARA study, atorvastatin, given trial reported a significantly higher number of new
in combination with standard disease-modifying cancer diagnoses in the pravastatin compared to
drugs, not only lowered markers of inflammation the placebo group [21], with the highest hazard ra-
but had a modest, but significant effect on clini- tios for breast and gastrointestinal tumours (1.65
cally defined disease activity [62]. and 1.46, respectively). A meta-analysis of the can-
cer incidence in the major pravastatin trials, how-
Effects on bone and fracture risk ever, was performed in the PROSPER report
Through interference with isoprenylation of which failed to detect an elevated cancer risk. A
GTP-binding proteins, lovastatin has an in- 10-year follow-up of the 4S study found no differ-
hibitory effect on osteoclasts in vitro [63]. Addi- ences in mortality and cancer incidence in the orig-
tionally, a stimulating effect on bone formation in inal simvastatin and placebo groups [77]. Recent
mice has been demonstrated for simvastatin, lovas- case-control studies even found slight decreases in
tatin, mevastatin, and fluvastatin; simvastatin in- breast cancer risk in postmenopausal women [78]
creases expression levels of bone-morphogenetic and a 20% relative risk reduction for various can-
protein-2 via action on its gene promoter [64]. cers in a mixed population [79]. In a population
Statins may thus have a therapeutic potential in os- from northern Israel, the use of statins for 05 years
teoporosis prevention and/or treatment [65]. In was associated with a 47% relative risk reduction
observational studies, statin use was associated for colorectal cancer [80]. However, due to the low
with a decreased fracture risk in postmenopausal incidence and hence absolute risk, the number
women [66] as well as mixed populations [39, 67]. needed to treat to prevent one case is >4800. Taken
In these studies, the adjusted odds ratios for statin together, the epidemiological data – in the absence
users were as low as ~50%. On the other hand, an of prospective endpoint studies – suggest that
analysis using the same data base as in ref. [67] statin use is safe or may even have a protective ef-
found no beneficial effect of statin use on fracture fect on cancer incidence.
risk [68], and a post-hoc analysis of the LIPID trial
The role of statins in clinical medicine 46

Target LDL levels: how low is low enough?

The question of how intensely LDL choles- mM. Moreover, TNT, which compared two doses
terol should be lowered has been addressed from of atorvastatin, achieved 2 mM in the high dose
both a socioeconomic and a biological point of (80 mg) group, for a relative risk reduction of 22%
view [81, 82]. While an earlier post-hoc subgroup of total major cardiovascular events. Notably, in
analysis of the CARE trial suggested that no fur- TNT, overall mortality did not differ between
ther benefit resulted if LDL levels were lowered to treatment groups [84]. In the light of recent clini-
<3.21 mM [83], recent trials clearly draw a differ- cal data, the executive summary on the detection,
ent picture. The HPS in particular demonstrated evaluation, and treatment of high blood choles-
that a distinct LDL-threshold cannot been de- terol in adults (ATP III), which dates from 2001
fined, as the relative risk reduction of ~25% was [85], has been amended with a recent guideline
preserved even in participants whose LDL was [86]. LDL goals are defined according to the car-
lowered to <2 mM [20]. In PROVE-IT, cardiovas- diovascular risk category. For high risk patients (10
cular benefit was achieved by lowering LDL to 1.6 year risk estimated >20%), LDL <1.8 mM is given
as “optional goal”, with <2.6 mM remaining the
standard. For practical purposes, scores to calcu-
Figure 1
late an individual patient’s risk category are avail-
able (eg, the PROCAM scheme [87]).
The absolute cardiac
risk reduction by Thus, the therapeutic goals have become more
statin treatment is ambitious, particularly for high-risk patients. Nev-
shown as a function
of mean baseline LDL ertheless, the indication and goals of statin therapy
levels in various clin- must be evaluated critically. Although the log-lin-
ical trials. Primary
prevention studies
ear relationship between LDL-levels and cardio-
are presented in vascular risk predicts an equal relative risk reduc-
italics tion irrespective of the baseline LDL level [81, 86],
the absolute risk reduction abates with decreasing
baseline LDL (see figure). Consequently, the num-
ber needed to treat increases. Thus, as the motiva-
tion to initiate statin treatment rises, so do the
costs, and the advantages and disadvantages of
statin therapy must therefore be weighed for every
patient individually.

Table 1 Lovastatin Simvastatin Pravastatin Fluvastatin Atorvastatin Rosuvastatin

Pharmacological CYP Metabolism 3A4 3A4 not significant 2C9 3A4 2C9
properties of statins.
Lipophilia yes yes no yes yes no
Approx. elimination half life (h) 2 3 3 3 14 19
Approx. equivalence dose* (mg) 40 20 40 >40 10 <10
* for LDL reduction; cf. refs. [8, 9]

Adverse events and drug interactions

Statin toxicity is in part idiosyncratic, but treated groups in the large trials. The TNT study,
clearly shows dose-dependency as well. Myopathy however, demonstrated the dose dependency of
may manifest as myalgia only but may also present this adverse event, which occurred in 0.2% of pa-
as severe rhabdomyolysis. Elevation of kreatine ki- tients treated with 10 mg atorvastatin and 1.2% of
nase (>10x upper limit of normal) was very rare in those treated with 80 mg [84]. Similar observations
the large statin trials and occurred to a similar de- were made in the PROVE-IT trial [33]. Recently,
gree under placebo (eg, 30 cases under statin treat- the safety of rosuvastatin, the most potent HMG-
ment, 29 under placebo in >30 000 participants CoA reductase inhibitor currently available, has
of the CARE, LIPID, WOSCOPS, 4S, and AF- been debated for higher risk rates of renal toxicity
CAPS/TexCAPS trials [88]). The pathogenesis of and rhabdomyolysis than other statins [90, 91].
statin-induced myositis is unclear (mitochondrial Case-reports [92] and a case-control study [93]
toxicity? Selenoprotein deficiency [89]?). Eleva- have described axonal peripheral neuropathy
tion of liver transaminases to >3x upper limit of under statin use, and thrombotic thrombocy-
normal occurred in the percent range and not topenic purpura has been observed as well [94, 95].
more often in the statin- than in the placebo- When suspecting statin-associated adverse
 S W I S S M E D W K LY 2 0 0 6 ; 1 3 6 : 4 1 – 4 9 · w w w . s m w . c h 47

events, it is important to consider a patient’s co- ability (~60%, compared to ~5–20% in other
morbidity and comedication. Since statins are statins). Many of the patients who developed fatal
eliminated partly by the kidney, doses need to be rhabdomyolysis were treated simultaneously with
adapted in patients with severe renal insufficiency. gemfibrozil. The combination of these factors led
Special attention should be paid to pharmaco- to 52 deaths among cerivastatin-treated patients
logical interactions [96]. With the exception of and consequently the withdrawal from the market
pravastatin, statins are metabolised by the cy- in 2001. Simvastatin and atorvastatin are substrates
tochrome P 450 (CYP 450) enzymes (table 1). In- of P-glycoprotein, a transport protein involved in
hibitors of CYP 3A4 include macrolide antibiotics, biliary and renal excretion of drugs and drug
azoles, protease inhibitors, verapamil, diltiazem, metabolites. Therefore, simvastatin and atorvas-
amiodarone, warfarin and grapefruit juice. CYP tatin may increase plasma concentration of other
2C8/9 is inhibited by gemfibrozil, phenytoine, P-glycoprotein substrates, such as digoxin [99].
losartan, diclofenac, ibuprofen, and tolbutamide. Overall, statins proved to have a favourable
These agents potentially augment statin toxicity. safety profile both according to data reported in
Gemfibrozil and cyclosporine A inhibit the hepatic large trials and in post-marketing surveillance.
statin transporter, OATP-C, thereby potentially The initial fears of increased non-cardiac death
increasing their bioavailability [97]. Gemfibrozil rates have been abolished, and if individual factors
also inhibits glucuronidation of statin metabolites such as age, hepatic and renal function, and co-
[98]. The case of cerivastatin highlights the impor- medication are given adequate thought, treatment
tance of pharmacological aspects in statin toxicity. is safe for patients in a wide age range.
It has a high intrinsic activity and a high bioavail-

Conclusion and outlook

Statins have become the mainstay of choles- the miracle cure for all vascular problems, they
terol lowering treatment. Their benefit on cardio- have great clinical potential, and their fascinating
vascular event rates, including ischaemic stroke, pleiotropic effects may open the field for novel
has been demonstrated in many large-scale ran- therapeutic indications in the future.
domised controlled trials. On the other hand, lim-
itations of statin effects have also become evident, Correspondence:
eg they do not influence the progression of calcific Jonas Rutishauser, M.D
aortic stenosis [100], and a recent atorvastatin Innere Medizin B
study with diabetics receiving haemodialysis failed Universitätsspital
to show a benefit on a composite CAD and stroke Petersgraben 4
endpoint [101]. CH-4031 Basel
In summary, although statins do not represent [Link]@[Link]

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