International Journal of Cardiology 96 (2004) 131 – 139

www.elsevier.com/locate/ijcard

Review
Does aggressive statin therapy offer improved cholesterol-independent
benefits compared to conventional statin treatment?
Sandeep Gupta *
Department of Cardiology, Whipps Cross and St Bartholomew’s Hospitals, Whipps Cross Road, Leytonstone, London E11 1NR, UK
Received 10 August 2003; accepted 29 October 2003

Abstract

There is currently intense research interest in the properties of HMG-CoA reductase inhibitors (statins) beyond their well-documented
lipid-lowering action. Studies have consistently demonstrated that administration of statin therapy decreases levels of the inflammatory
marker C-reactive protein (CRP), a marker associated with an increased risk of cardiovascular events. This effect appears to be independent
of the extent of reduction in total or LDL-cholesterol. Statins also appear to improve endothelial dysfunction by increasing endothelium-
dependent vasodilatation. There is also evidence that statins inhibit fibrin formation and thrombus development, an effect that which would
be clinically beneficial following plaque fissure or rupture. Early preclinical and clinical evidence suggests that there are quantitative
differences between statin regimens in terms of their cholesterol-independent properties. Trials comparing equipotent doses of different
statins, based on lipid-lowering efficacy, have not reported any differences in cholesterol-independent properties. However, the current
evidence base indicates that more aggressive statin regimens are associated with an enhanced anti-inflammatory effect. Intensive lipid-
lowering using statin therapy generates a greater reduction in mortality than standard lipid management, and it is possible that enhanced
cholesterol-independent effects may account for some of this excess benefit.
D 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: C-reactive protein; CRP; Inflammation; Statin; Simvastatin; Pravastatin; Atorvastatin

1. Introduction process, involving a chronic inflammatory response within

The clinical benefits of HMG CoA reductase inhibitor
(statin) therapy for primary [1] or secondary [2,3] prevention
of cardiovascular events, even in at-risk patients with average
or lower-than-average cholesterol levels [4], are well-docu-
mented. The effectiveness of statin therapy in treating dysli-
pidaemia has been demonstrated conclusively, and there is a
clear relationship between the magnitude of total cholesterol
[5] and LDL-cholesterol [6] lowering and event reduction.
Beyond the well-documented lipid-lowering action of
statins, however, there is now a considerable weight of
evidence to indicate that this class of drug exerts a range of
other effects that inhibit the atherosclerotic process (Table
1). Historically, the process of atherogenesis was generally
seen as the deposition of lipids within the arterial wall.
Instead, however, atherosclerosis is a far more complex
* Tel.: +44-20-8535-6442; fax: +44-20-8500-9352.
E-mail address: sgupta111@aol.com (S. Gupta).
the arterial wall [7] and endothelial dysfunction prior to the
development of the atherosclerotic plaque [8]. To varying
degrees, it has now been shown that statin therapy inhibits
local inflammatory mechanisms (Fig. 1), ameliorates endo-
thelial dysfunction (Fig. 2), and reduces thrombotic risk
after plaque rupture. The most conclusive evidence relates
to the effect of statins on C-reactive protein (CRP), a marker
for inflammation that appears to be an independent predictor
of cardiovascular events, and which may indeed be a more
accurate prognostic marker than LDL-cholesterol [9]. A
number of large studies have shown conclusively that statins
reduce CRP levels, particularly in patients with high CRP
levels at baseline who are, accordingly, at greatest risk of
experiencing a cardiovascular event [10 –12].
It seems likely that these ‘cholesterol-independent’
effects may, at least in part, account for the apparent
disparity between angiographic and clinical findings follow-
ing statin therapy. While clinical outcomes are substantially
improved [1– 3], only slight regression of atherosclerosis is
detected by quantitative angiography.

0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2003.10.013
132 S. Gupta / International Journal of Cardiology 96 (2004) 131–139
Table 1
Main effects of statin therapy other than plasma lipid regulation
Inhibition of inflammation
Reduction in inflammatory markers
Inhibition of inflammatory cell migration
Reduction in cellular adhesion molecules
Impact on endothelial function
Increased endothelium-mediated arterial responsiveness
Increased NO bioavailability in endothelial cells
Inhibition of leukocyte and platelet adhesion
Antithrombotic effects
Reduced formation of fibrin
Inhibition of PAI-1 and increase in t-PA
Inhibition of matrix metalloproteinases
PAI-1, plasminogen activator inhibitor type-1 (PAI-1). t-PA, tissue type
plasminogen activator.
Statins display considerable variation in ability to lower
cholesterol. In general, newer agents such as atorvastatin
lower total cholesterol and LDL-cholesterol levels to a
greater degree than conventional statins such as pravastatin
and simvastatin [13 – 15]. What is less certain is whether the
non-lipid-lowering (‘pleatrophic’) properties of statins also
vary between agents, either qualitatively or quantitatively.
Research into a possible correlation between the extent of
lipid lowering and the degree of cholesterol-independent
effects generally indicates that reduction in CRP level
during statin therapy does not correlate with the extent of
LDL-cholesterol reduction [10,11,16,17].
This raises a question of potentially significant clinical
impact: does more aggressive statin therapy, either through
use of a more potent agent or higher dose, generate
additional cholesterol-independent benefits compared to
conventional statin treatment? To assess this issue, a com-
prehensive Medline search was undertaken. Based on the
search findings, this article reviews the available data
concerning the anti-inflammatory and other non-lipid-low-
ering effects of statins, and examines the evidence for
differences in the extent of cholesterol-independent effects
between aggressive and less aggressive statin therapy.
2. Cholesterol-independent effects of statins
2.1. Inhibition of inflammation
The existence of an inflammatory component in the
atherosclerotic process is now well established [6] and the
prognostic significance of sensitive inflammatory markers
for cardiovascular risk has been assessed in a number of
large-scale studies [18]. These have consistently reported
that even a relatively small increase in the inflammatory
marker CRP is associated with an increased risk of cardio-
vascular events in healthy individuals [19] or in those with
pre-existing cardiovascular disease [20,21] (Table 2). There
still remains a question over whether CRP is a primary local
phenomenon, or whether it reflects generalised inflamma-
tion or even chronic infection, which have been indepen-
dently linked with atherosclerosis [22]. A predictive role has
been reported for other acute-phase proteins such as serum
amyloid [21] and fibrinogen [23,24], but evidence to date is
less conclusive.
The impact of statin therapy on inflammatory markers, in
particular CRP, has been demonstrated by Albert et al. [11]
in a prospective trial of 1702 patients with no prior history
of cardiovascular disease who were randomised to pravas-
tatin or placebo. In the pravastatin cohort, median CRP
levels fell by 17% over 24 weeks, while in the placebo-
treated arm median CRP remained unchanged. This effect
appears to be maintained long-term: patients receiving
pravastatin in the Cholesterol and Recurrent Events (CARE)
study sustained a significant fall in CRP levels over a 5-year
period [10]. Other researchers have reported similar findings
using other statins [17,25,26].
Some investigators have proposed that the presence of
aggressive inflammation within atherosclerotic plaque in
human coronary and peripheral arteries is associated with
increased plaque temperature [27,28]. This can be detected
by thermister probes inserted using a thermography catheter.
Thermographic imaging has shown that patients receiving
statin treatment produce less ‘‘heat’’ from unstable athero-
sclerotic plaques in coronary vessels than untreated patients,
indicating that local inflammatory activity is reduced [29].
Further evidence that statins inhibit local inflammatory
processes has come from evidence suggesting statins may
inhibit leukocyte recruitment in a mouse model of local
inflammation by suppressing production of monocyte che-
motactic protein-1 (MCP-1) [30]. Oral administration of
lovastatin or pravastatin at a dose of 10 mg/kg reduced
MCP-1 release and leukocyte migration by 50% [30].
The ability of statins to reduce inflammatory markers is
not equal in all patients. Riesen et al. [31] conducted an
open-label study of 155 hypercholesterolaemia patients, all
of whom were treated with atorvastatin. Patients were
stratified into quartiles depending on their baseline CRP
level. Within the quartile of patients with the highest level of
CRP, 73% showed a significant reduction in CRP after 1
month of treatment compared to 49% of patients in the
lowest quartile (Fig. 3). By 3 months, median CRP had
Fig. 1. Inflammatory mechanisms in the atherosclerotic process.
 S. Gupta / International Journal of Cardiology 96 (2004) 131–139 133

Fig. 2. The interplay of inflammatory mediators, LDL-cholesterol and endothelium—a target site for statins.

fallen from 7.82 to 4.95 mg/l ( p < 0.01) but there was no
significant change in patients within the lowest quartile.
This variation in response may account for reports that statin
therapy does not consistently reduce median CRP levels in
patients with familial hypercholesterolaemia [32,33], in
whom CRP levels tend to be in the normal range or only
slightly increased. Given the preferential effect of statins on
high CRP levels it would seem reasonable to hypothesise
that the patient populations included in these studies may
not have been in a heightened inflammatory condition.
At the clinical level, a large observational trial of patients
with severe coronary heart disease (CHD) has demonstrated
that the reduction in cardiovascular risk associated with
statin therapy is greatest among those with elevated CRP at
baseline compared to those with normal CRP levels [34]. A
retrospective substudy of data from the CARE trial reported
a similar finding [35].
2.2. Improvement in endothelial cell function
The endothelium is intrinsically involved in the athero-
sclerotic process through a variety of mechanisms. Pro-
duction of oxidized LDL-cholesterol within endothelial
cells impairs relaxation of the arterial wall [36], and
atherosclerosis is characterised by impaired endothelium-
mediated vasoditation [37]. Moreover, nitric oxide (NO)
synthesis by the endothelium appears to relate to the

Table 2
Clinical trials evaluating effect of statin therapy on CRP levels in
hypercholesterolaemia patients
Statin Patient type (n) Study duration Effect on Reference
CRP
Pravastatin No history of 24 weeks Decreased [10]
CVD (1702) 17%
Atorvastatin No history of 1 year Decreased [24]
CVD (103) 43%
Atorvastatin Unstable angina 16 weeks Decreased [56]
or non-Q-wave 75%
MI (2322)
Pravastatin Pre-existing 24 weeks Decreased [10]
CVD (1182) 13%
Pravastatin Previous MI 5 years Decreased [9]
(472) 19%
Simvastatin Previous CVD 4 months Decreased [11]
event (95) 21%
Atorvastatin Type II 20 weeks Decreased [61]
diabetes (186) up to 47%
Atorvastatin Type II 6 months Decreased [41] Fig. 3. Frequency in CRP change according to baseline CRP level among
diabetes (80) 17% 155 patients with stable CHD and hypercholesterolaemia after treatment
CVD, cardiovascular disease. MI, myocardial infarction. with atorvastatin for 1 month [28].
134 S. Gupta / International Journal of Cardiology 96 (2004) 131–139

presence of low-grade chronic inflammation [38] and CRP of nitrotyrosine, a marker for protein modification by NO-
levels correlate with markers of endothelial dysfunction derived oxidants [45]. This potentially beneficial effect was
[39], suggesting that there may be a relationship between independent of reductions in total cholesterol, LDL-choles-
endothelial activity and local inflammatory processes. terol and CRP following atorvastatin therapy.
Again, low-grade infections such as Chlamydia pneumo-
niae may act as the signal for this inflammatory activity 2.3. Antithrombotic effects
[40].
In addition to the well-documented effect of statin Acute coronary events are usually associated with rup-
therapy on inflammatory processes, there is evidence to ture or fissuring of an atheromatous plaque, followed by a
indicate that statin therapy ameliorates endothelial dys- thrombotic response to the plaque contents as they enter the
function in patients. Two controlled clinical studies have circulation. The clinical manifestation depends on the se-
used quantitative coronary angiography to evaluate the verity of the thrombotic response; limited plaque rupture
effect of pravastatin [38] and lovastatin [41] on coronary with only a mild thrombotic response can be asymptomatic
endothelial responses to local infusions of acetylcholine while more significant ruptures can result in a response that
(Table 3). These each showed a significant increase in partially or fully occludes the vessel and presents as angina
endothelium-mediated arterial responsiveness compared to or myocardial infarction. Although less well researched,
placebo. More recently, a similar improvement in endo- there is evidence that statin therapy can affect the fibrino-
thelium-dependent vasodilatation has been reported in lytic system. Statins in vitro reduce fibrin formation and
diabetic patients treated with atorvastatin [42]. thrombus development by inhibiting production of the
Improvement in endothelium-mediated vasoditation may prothrombotic marker plasminogen activator inhibitor
be due, at least in part, to an increase in NO bioavailability type-1 (PAI-1) in endothelial and smooth muscle cells and
in endothelial cells in the presence of statins. Loss of increasing production of tissue type plasminogen activator
endothelium-derived NO is an important factor in athero- (t-PA) [46]. These effects influence the local fibrinolytic
genesis [43]. When endothelial cells are stimulated in vitro balance such that fibrinoloysis is more dominant, and
by application of a NO agonist, electrochemical micro- accordingly the extent of thrombus formation after plaque
sensors detect enhanced release of NO in the presence of rupture would be expected to be less severe.
statins [44]. Clinically, administration of low-dose atorvas- Statins appear to decrease markers of fibrin generation
tatin to patients with hypercholesterolaemia has recently (D-dimer and fibrin monomer) preferentially in patients with
been shown to result in a 25% reduction ( p < 0.02) in levels the highest level of fibrinolytic activity at baseline [47],
similar to the selective anti-inflammatory effect of statins on
Table 3 high levels of CRP. Interestingly, it has also been shown that
Trials evaluating effect of statin therapy on endothelial function statins inhibit activity of the protease enzymes matrix
Statin Patient type (n) Effect of statin Reference metalloproteinases [48], which play an important role in
or model degrading connective tissue proteins that maintain the
Pravastatin Hypercholesterolaemia Decreased [37] integrity of plaques. This effect is likely to result in a
(9) acetylcholine- reduced propensity for advanced plaques to rupture.
induced
vasoconstriction
in epicardial artery. 2.4. Other effects
Increased
acetylcholine- As research continues, it seems realistic that other
induced coronary cholesterol-independent effects of statins may be confirmed.
artery blood flow
Lovastatin CVD (23) No difference to [40]
Rather intriguingly, statin-induced change in endothelial
placebo at 12 days. function and arterial wall composition may also potentially
Increased translate to a benefit in terms of blood pressure, although
endothelial data on this is still preliminary. A cross-over study of 22
responsiveness patients with systolic hypertension randomised to atorvas-
at 5 months
Atorvastatin Type II diabetic (80) Increased [41]
tatin therapy or placebo has shown that systolic and diastolic
endothelial- blood pressure were each significantly lower following
dependent therapy, and that this was associated with improved system-
vasodilatation ic arterial compliance [49]. Similar results have been
Various In vitro endothelial Increased NO [43] reported in another cross-over study in which pravastatin
cells bioavailability
Fluvastatin Rabbit carotid Tissue factor [55]
significantly reduced blood pressure in 25 patients with
artery expression untreated hypertension: mean systolic pressure was reduced
decreased by 8 mm Hg and diastolic pressure by 5 mm Hg (both
by 50% p < 0.001) [50]. This effect was not related to total or LDL-
CVD, cardiovascular disease. cholesterol reduction by pravastatin. An uncontrolled study
 S. Gupta / International Journal of Cardiology 96 (2004) 131–139
of fluvastatin has also demonstrated a reduction in blood
pressure among hypertensive individuals over 3 months [51]
and in an observational study of 113 renal transplant
patients, blood pressure fell significantly in statin-treated
patients over 12 months, during which time there was no
change in a group of matched controls [52]. A large-scale
prospective trial is justified to investigate the antihyperten-
sive effect of statins more thoroughly.
There is also data to suggest that use of statins may
influence insulin resistance and the development of diabetes
mellitus. Patients enrolled in the West of Scotland Coronary
Prevention Study (WOSCOPS) who were non-diabetic at
baseline were studied retrospectively [53]. Out of 5974
individuals, 139 became diabetic over the course of the
study. Pravastatin therapy was associated with a significant-
ly reduced risk of developing diabetes mellitus (Hazards
Ratio 0.70, 95% CI 0.50 –0.98, p < 0.05). When risk of
diabetes mellitus was adjusted for confounding variables in
a multivariate analysis, the predictive value of pravastatin
for reduced diabetic risk was unchanged. The authors
commented that reduced triglyceride level associated with
pravastatin therapy was likely to contribute to this effect, but
that anti-inflammatory and endothelial properties may also
play a role. In a prospective 8-week study of 195 Type II
diabetic patients randomised to simvastatin, atorvastatin or
placebo, statin therapy significantly improved insulin resis-
tance [54]. This study suggested that any statin effect on
metabolic control may be related to lipid-lowering potency:
the extent of triglyceride reduction was significantly corre-
lated to metabolic improvement.
3. Cholesterol-independent effects of ‘‘conventional’’
statins
The potential benefits of statin therapy beyond lipid-
lowering was first demonstrated by the large-scale CARE
trial, a five-year study in which patients were randomised to
pravastatin or placebo [10]. In a subpopulation of 472
patients, plasma concentrations of CRP were measured as
a marker for increased vascular risk. Randomisation to
pravastatin resulted in significant reduction in CRP levels,
while during the same period patients receiving placebo
showed a tendency to increased CRP (Fig. 4). It has since
been shown [34] that the clinical benefits of statins are most
pronounced in patients with elevated CRP at baseline.
These findings prompted further investigations into the
impact that statins exert on the inflammatory and other non-
lipid elements of the atherosclerotic process. The most
extensive research has been carried out using pravastatin
and simvastatin. The effect of pravastatin on CRP levels has
been demonstrated convincingly by The Pravastatin Inflam-
mation/CRP Evaluation (PRINCE) study, in which 1702
patients with no history of cardiovascular disease were
randomised to pravastatin 40 mg/day or placebo [11]. A
significant reduction in CRP level was seen as early as 12
135
Fig. 4. Changes in median CRP level at baseline and at 5 years among 472
patients with a history of myocardial infarction randomised to pravastatin
therapy or placebo [6].
weeks in the pravastatin group (15% reduction compared to
placebo, p < 0.001), an effect that increased slightly by the
end of the 24-week study period. In a separate, open-label
study, 1182 patients with known cardiovascular disease
treated with pravastatin 40 mg/day showed a 13% reduction
in CRP versus placebo [11]. Similarly, in a subpopulation of
129 secondary prevention patients enrolled in the Scandina-
vian Simvastatin Survival Study (4S) study, simvastatin
reduced CRP levels significantly compared to baseline
[12]. Reduction of CRP levels appears to be maintained
long-term [10].
Moreover, these anti-inflammatory effects appear to be
independent of lipid lowering, a finding that has been
supported by results from animal studies. When simvastatin
was administered daily to mice deficient in apoE for 6 weeks,
plasma lipids remained unaltered but the cholesterol content
of the aorta was significantly decreased [55]. A study of pigs
with experimental hypercholesterolaemia randomised to
normal diet or high cholesterol diet with or without simvas-
tatin showed that addition of simvastatin overcame the
attenuation of vasorelaxation caused by the high cholesterol
diet, despite the fact that there was no difference in LDL-
cholesterol level between the three groups over the 12-week
study period [56]. Similarly, the anti-thrombotic effects of
conventional statins appear to occur in the absence of lipid
lowering. Fluvastatin reduces expression of tissue factor
(which is involved in thrombogenicity associated with ath-
eroma) by 50% in rabbit carotid intimal lesions while having
no effect on the increase in plasma cholesterol level arising
from a cholesterol-rich diet [57].
4. Cholesterol-independent effects of ‘‘newer’’ statins
To date, the majority of research into the cholesterol-
independent anti-atherogenic effects of newer statins has
been carried out using atorvastatin, with less data currently
136 S. Gupta / International Journal of Cardiology 96 (2004) 131–139
available regarding other agents such as rosuvastatin and
pitavastatin.
In a large secondary prevention study of 2322 patients
with unstable angina or non-Q-wave MI randomised to
atorvastatin or placebo, CRP levels were significantly lower
at 16 weeks in the atorvastatin-treated cohort versus the
group receiving placebo [58]. Reduction of CRP in atorvas-
tatin-treated patients with no history of cardiovascular
events has also been reported over a period of 1 year [25],
and in obese individuals during short-term therapy [59].
Although more data are required, there are indications
that the effect of atorvastatin on CRP and markers for fibrin
generation is established quickly after initiation of treat-
ment, a finding that may have implications for the manage-
ment of acute coronary syndromes. In a study of 155
patients receiving atorvastatin, there was a reduction of
CRP concentration of 28% after 1 month and 35% after 3
months [31]. There is also early evidence that the reduction
in D-dimer and fibrin monomer is complete by one month
after start of atorvastatin therapy [47].
Several studies have investigated the cholesterol-inde-
pendent effects of atorvastatin in diabetic patients, a group
at high risk of cardiovascular disease. Mean CRP level is
higher in both Type I [60] and Type II [61] diabetics than in
non-diabetic individuals, and vasodilatation has been shown
to be reduced in Type I diabetes mellitus compared to
matched non-diabetic controls [62]. An anti-inflammatory
effect or an improvement in endothelial dysfunction may
therefore be of particular clinical relevance in this group. A
placebo-controlled study in 80 patients with Type II diabetes
mellitus has shown that six months after initiation of
atorvastatin therapy, plasma CRP decreased significantly
compared to baseline in the atorvastatin group, together
with endothelium-dependent vasodilatation [42]. A similar
response has been reported in another double-blind study of
Type II diabetic individuals, in which median CRP levels
fell by 15% and 47% over 20 weeks in patients receiving 10
and 80 mg atorvastatin, respectively [63]. Finally, a study in
normocholesterolemic young patients with Type I diabetes
mellitus has shown that brachial artery flow-mediated dila-
tation was significantly increased following 6 weeks of
atorvastatin 40 mg/day [62].
5. Comparative analysis of statin regimens
5.1. Preclinical comparative evaluations of different statins
The literature contains relatively few studies comparing
cholesterol-independent effects of different statin agents in
vitro or in vivo. Wiesbauer et al. [46] evaluated the relative
impact of six statins (cerivastatin, fluvastatin, lovastatin,
atorvastatin, pravastatin and simvastatin) on the fibrinolytic
system in vascular endothelial cells and smooth muscle and
found qualitative and quantitative differences in the
responses of individual components of the fibrinolytic
system to the various agents. All the statins except for
pravastatin significantly decreased levels of PAI-1 in both
cell types, and t-PA in smooth muscle cells, but only
simvastatin and lovastatin affected t-PA production in en-
dothelial cells. The authors speculated that the lack of
efficacy of pravastatin within in vitro studies may be due
to its lipophilic properties, which could limit penetration
through cell membranes.
Stimulation of endothelium-derived NO release by statin
administration to a single endothelial cell also shows some
variation between different agents, with the greatest degree
of stimulation seen with simvastatin and the lowest with
lovastatin [44].
5.2. Clinical evaluation: aggressive versus conventional
statin therapy
Available evidence from relatively small-scale studies
suggests that more aggressive use of statin therapy confers
increased anti-inflammatory and other cholesterol-indepen-
dent effects.
The relative impact of intensive LDL-cholesterol re-
duction (atorvastatin 10 – 80 mg/day, reduction goal < 2.1
mmol/l) and less intensive treatment (lovastatin 5 –10 mg/
day, reduction goal < 3.4 mmol/l) has been assessed in a
group of 110 patients with stable angina pectoris with
inducible myocardial ischaemia [17]. In this randomised,
placebo-controlled trial, the reduction in mean CRP was
significant with intensive LDL-lowering over 12 months
(from 2.6 to 1.7 mg/l, p = 0.002) but not with the less
intensive treatment goal (Fig. 5). Half of the CRP reduction
had occurred within four weeks of starting therapy within the
atorvastatin group. Median CRP level in this secondary
prevention population was 2.9 mg/l at baseline, demonstrat-
ing that aggressive therapy can be effective in reducing even
relatively high levels of CRP. Differences in CRP reduction
between statin regimens have also been reported among
lower risk populations with more moderate CRP levels.
The effects of a conventional statin (simvastatin: 40 mg
increased to 80 mg after 6 weeks) and a more potent statin
(atorvastatin: 20 mg for 6 weeks, 40 mg for 6 weeks and then
80 mg) have been compared in a 36-week placebo-controlled
study of 47 hypercholesterolaemia patients, of whom only
four had early CHD (angina pectoris or MI) [64]. Median
CRP level at baseline was approximately 1.6 mg/l in both
cohorts. In the atorvastatin-treated patients, CRP fell signif-
icantly from baseline at all time points, but there was no fall
in the simvastatin-treated patients. Similarly, levels of the
inflammatory marker serum amyloid A fell significantly with
atorvastatin but not with simvastatin. Neither treatment
group showed a consistent effect on IL-6 or intercellular
adhesion molecule-1 (ICAM-1).
Use of aggressive statin therapy has also been shown to
confer enhanced anti-inflammatory benefits in patients with
familial hypercholesterolaemia. Van Wissen and colleagues
conducted a 2-year double-blind trial in which 325 patients
 S. Gupta / International Journal of Cardiology 96 (2004) 131–139
were randomised to atorvastatin 80 mg (aggressive therapy)
or simvastatin 40 mg (conventional therapy) [65]. At
baseline, median CRP values were 2.1 and 2.0 mg/l,
respectively. After 2 years, these had fallen to 1.1 and 1.5
mg/l, representing a fall of 40% in the atorvastatin group
and 20% in the simvastatin arm. This difference was
significant ( p = 0.02). The authors showed by univariate
analysis that reduction in intima media thickness of carotid
artery segments over the 2-year period correlated signifi-
cantly with the decrease in CRP level, suggesting that
increased CRP reduction using aggressive statin therapy
appears to be associated with a slowing of the atheroscle-
rotic process.
Other randomised studies have compared the effect of
different statin drugs on levels of CRP and other inflamma-
tory markers, but used only low doses of more potent
agents, with the goal of achieving equipotency, instead of
comparing aggressive and conventional therapeutic regi-
mens [26,32,66]. These trials have reported no differences
in CRP reduction between patients randomised to atorvas-
tatin 10mg, simvastatin 20 –40 mg or pravastatin 40 mg.
It would thus appear that aggressive statin treatment, for
example using moderate or high doses of a potent statin
agent or adjusting dose to target a relatively low LDL-
cholesterol level, is required for enhanced anti-inflammatory
Fig. 5. Mean CRP level among patients with stable angina pectoris with
inducible myocardial ischaemia, randomised to intensive LDL-cholesterol
reduction (atorvastatin 10 – 80 mg/day, reduction goal < 2.1 mmol/l) or less
intensive treatment (lovastatin 5 – 10 mg/day, reduction goal < 3.4 mmol/l).
Adapted from Kinlay et al. [16].
137
Fig. 6. Median CRP levels among hyperlipidemic patients without manifest
CHD receiving 10 mg atorvastatin (n = 10), 80 mg atorvastatin (n = 64) or
placebo (n = 55). p values refer to difference from placebo; *p < 0.005,
**p < 0.001.
activity. This is further supported by evidence from a
double-blind trial of 186 dyslipidemic patients with Type
II diabetes mellitus but no CHD, who were randomised to
10 or 80 mg atorvastatin for 30 weeks [63]. At the end of the
study period, the reduction in CRP levels was significantly
greater with 80 mg than 10 mg atorvastatin (Fig. 6). During
the same period, median CRP increased by 7% in the
placebo group. Among patients with relatively high baseline
CRP level (>3.0 mg/l), who would be considered at in-
creased risk for cardiovascular disease, 56% in the 80 mg
atorvastatin group and 23% in the 10 mg group fell to below
this threshold by 30 weeks ( p < 0.01). Further research to
assess the comparative effects of varying doses of a given
statin within other patient populations is required.
6. Conclusions
With the effectiveness of statins in lowering cholesterol
levels now firmly established, attention is turning to other
anti-atherogenic properties of this class of drug. Reduction
of various inflammatory markers by statins has been dem-
onstrated, albeit to a varying degree of certainty. While
reduction of raised CRP levels has been reported relatively
consistently, more extensive work is required to confirm an
effect on other markers such as TNFa, and results to date
suggests that IL-6 production remains largely unaffected by
statin therapy. Similarly, it seems probable that components
of the fibrinolytic system are affected to varying extents by
different statins. The weight of evidence appears to point to
an important role for cholesterol-independent anti-athero-
genic effects of statins.
It appears likely that the potency of a statin regimen
determines the extent of cholesterol-independent effects;
use of intensive statin therapy seems to confer additional
anti-inflammatory benefit compared to conventional regi-
138 S. Gupta / International Journal of Cardiology 96 (2004) 131–139
mens. Intensive lipid-lowering with statin therapy is
known to reduce total and coronary mortality compared
to standard lipid management [67] and at this stage it
would seem reasonable to hypothesise that increased
cholesterol-independent statin effects may contribute to
this mortality benefit to some extent. The challenge now
is to determine the significance of these effects within the
overall physiological impact of statin therapy. Exciting
research lies ahead.
Acknowledgements
Caroline Dunstall for invaluable help in preparation of
the manuscript.
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