J. Lipid Nutr. Vol.19, No.

1 (2010)

RECENT CHOLESTEROL-LOWERING DRUG TRIALS:

NEW DATA, NEW QUESTIONS
Michel de Lorgeril and Patricia Salen
Laboratoire Cur & Nutrition, Universit Joseph Fourier - Grenoble 1,
CNRS, TIMC-IMAG, UMR 5525, Facult de Mdecine, Grenoble, France.
Correspondence : Michel de Lorgeril, MD, Cur & Nutrition, Facult de Mdecine, Domaine
de la Merci, 38706 La Tronche, France
(e-mail: michel.delorgeril@ujf-grenoble.fr).

ABSTRACT
The cholesterol-lowering drug trials published in 2008-2009 were either negative
(ENHANCE, SEAS, GISSI-HF, AURORA) or obviously biased and therefore not credible
(JUPITER). How can we explain this wave of negative cholesterol-lowering drug trials? In
this article, authors review and comment the results of these recent trials. It is also
noteworthy that most cholesterol-lowering drug trials published between 2005 (the year
of the Vioxx affair and of enforcement of new clinical trial regulations) and 2007 were also
negative or ambiguous. Taken together, these recent trials, including those of 2008-2009,
strongly suggest that the results of previous, highly positive trials with statins
particularly in the secondary prevention of coronary heart disease published between
1994 and 2004 and that were used to issue guidelines for medical practitioners should
be carefully re-examined by experts independent from the pharmaceutical industry. The
next question would be whether it is not time for a full reappraisal of the theory according
to which cholesterol-lowering results in a significant protection against cardiovascular
morbidity and mortality.
Short title : Recent cholesterol-lowering drug trials
Introduction

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The years 2008 and 2009 have been very disappointing for cholesterol experts and
the cholesterol drug industry, for at least four reasons. In fact, three events as important
in terms of media coverage as of science and medicine are held each year around the
issue of cholesterol: the annual meeting of the American College of Cardiology (ACC) in
March, the annual meeting of the European Society of Cardiology (ESC) in August, and
the American Heart Association (AHA) meeting in November. Because thousands of
cardiologists from all continents are at the same place at the same time, each of these
meetings is an opportunity to roll out cholesterol drug marketing campaigns. Today,
marketing is primarily based on the publication of results of randomized trials. Thus every
year, the three cardiology world meetings are the best time for the pharmaceutical
industry and friends to re-launch the cholesterol-lowering drug machine. However, the
years 2008 and 2009 have been sad years because trials results obviously did not
support the theory according to which cholesterol-lowering results in significant benefits
in the prevention of coronary heart disease (CHD), including the so-called the lower the
better theory. To understand this course of events, a chronological account of events is
needed.
Chapter One: The ACC meeting in March 2008
The results of the ENHANCE study conducted in patients with familial
hypercholesterolemia (1) were published in March 2008and were disappointing.
Familial hypercholesterolemia is supposed to be a cholesterol-driven disease, with
dramatically high LDL cholesterol levels. In ENHANCE, an association of ezetimibe, a
cholesterol-lowering drug acting by decreasing the absorption of cholesterol in the
digestive tract, and simvavastin, a statin that acts by decreasing the endogenous
synthesis of cholesterol, was tested. For those who believe that cholesterol is the main
cause of CHD, ENHANCE was designed not to fail. Actually, the association of the two
drugs in the same patient results in a drastic reduction of cholesterol levels, in particular
LDL cholesterolthe so-called bad cholesterollevels. The test was not performed by
measuring hard clinical endpoints such as cardiac death or myocardial infarction, but by
repeated measurements of carotid intima-media thickness (IMT), a supposed marker of
atherosclerosis progress.
Unexpectedly, the combination of the two drugs failed to provide incremental benefits
over simvastatin alone, despite a drastic reduction of cholesterol (1). In addition, both
treatments did not result in significant effects on the primary endpoints: not only did the
change in IMT not differ over time, from baseline to 24 months, between the two study

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groups, but there was a slight increase in IMT in both groups: at 2 years, the estimates
were of +0.00950.0040 mm in the simvastatin-only group (P=0.02 vs. baseline) and
+0.01210.0038 mm in the combined-therapy group (P<0.01 vs. baseline), which
suggests that the lower the cholesterol, the greater was the increase in IMT (1). These
surprising and very disappointing data might explain why the results of ENHANCE were
hidden from the medical community for nearly two years, while the drug was being used
by millions of patients over the world, hoping that it was protecting their arteries and
hearts (2-4).
Very surprisingly, after ENHANCE many cholesterol experts declared that familial
hypercholesterolemia is not the adequate population to test the effects of
cholesterol-lowering (2-4). Instead, a scientist would have concluded that if this potent
association of drugs does not work in familial hypercholesterolemia, it can hardly be
expected to work in any other case. Hence, ENHANCE was, by itself, a cause of
confusion and debate among cholesterol experts. The data of ENHANCE led an ACC
panel to urge physicians to only prescribe cholesterol-lowering medications with proven
clinical effectiveness, i.e. proven effects on hard clinical CHD endpoints such as cardiac
death, myocardial infarction and stroke (5). As a matter of fact, ezetimibe was approved
and marketed in 2002 based solely upon a 20% reduction of cholesterol, but not on data
related to its effectiveness on any clinical endpoint (6), as if cholesterol levels by
themselves could be a surrogate of CHD. In addition, the effectiveness of the
ezetimibe+simvastatin combination against hard clinical endpoints has never been
demonstrated, as discussed below about the SEAS trial. As a consequence, many
physicians and scientists rightly questioned why the combination tablet already was on
the market if there was no proven effect on clinical CHD complications (4,5).
Finally, during the 2008 ACC meeting, a press release announced the premature
termination of JUPITER, a trial testing rosuvastatin, presumably the most effective statin
in terms of cholesterol-lowering, against a placebo in the primary prevention of CHD (7,8).
With this announcement, the pharmaceutical company probably wanted to communicate
that rosuvastatin, contrary to ezetimibe+simvastatin, resulted in an unequivocal
evidence of reduction in cardiovascular morbidity and mortality as written in the press
release (7,8). This was quite strategic for cholesterol experts at that particular time,
because several trials testing cholesterol-lowering had been published during the
previous years in various clinical circumstances ASPEN, 4D, PREVENT IT, IDEAL,
ILLUMINATE (9-13) and also ENHANCE (1), and all of them reported no convincing

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protective effect against CHD complications (1,9-13). The failure of ENHANCE, in

particular, generated unprecedented media coverage, patient and physician concerns,
and the involvement of the US Congress over the use of cholesterol-lowering drugs to
reduce CHD risk (2-5).
Following the publication of ENHANCE, two studies of cholesterol-lowering
treatments following protocols approved by the FDA were either not published or abruptly
terminated (14,15). CASHMERE tested atorvastatin in postmenopausal women. The trial
results were unearthed by capital market analyst Robert Hazlett and showed no effect at
all on IMT (14). ACHIEVE tested a novel combination tablet associating niacin and
laropiprant (a prostaglandin D2 blocker used to prevent the flushing induced by niacin) in
familial hypercholesterolemia (15). The trial was prematurely stopped because after the
failure of ENHANCE in the same category of patients, sponsors and investigators
thought that there was no hope to demonstrate a benefit (15). This indicated that even in
2008, trials that were obviously negative or tended in the wrong direction were still not
publicly discussed by investigators and sponsors and sometimes were halted before
completion. This gives an idea of what was being done before the new clinical research
regulation came into force in 2005-2006, after the Vioxx affair (16), with the obligation of
declaring all the clinical trials and of publishing the results even when they are not
favorable to the tested drug (17,18). All these attempts to mislead the medical and
scientific community have highlighted the fact that the alleged effectiveness of
cholesterol-lowering to prevent CHD complications is very questionable for anyone
wanting to open their eyes.
Chapter Two: The ESC meeting in August 2008
During the August ESC meeting, the results of two important trials were reported:
SEAS and GISSI-HF (19,20).
The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was a randomized,
placebo-controlled study evaluating ezetimibe+simvastatin, like ENHANCE (1). This time,
however, cholesterol-lowering was tested (against a placebo) by evaluating its effects on
hard clinical endpoints, including aortic valve replacement and CHD complications in
patients with aortic stenosis (19). The main assumption was that disease progression in
aortic stenosis is strongly influenced by hypercholesterolemia (21,22) and often
associated with CHD complications (23,24). Thus, double benefits were expected in
these patients: first, by preventing CHD complication and second, by preventing aortic

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valve complications. The primary endpoint of the trial was therefore a combination of
CHD and aortic valve complications.
To summarize SEAS results, drastic cholesterol-lowering had no significant effect on
the primary endpoint (19). While the authors tried to present the SEAS data in a positive
light by claiming that cholesterol-lowering had a significant effect on secondary endpoints
such as coronary revascularization, SEAS actually confirmed the negative results of
ENHANCE, but this time for of hard clinical endpoints (19).
From a scientific point of view, SEAS is a critical study for several reasons.
First, SEAS confirmed previous recent trials (9-13), including ENHANCE (1), and the
inability of cholesterol-lowering to reduce the risk of CHD complications in certain
populations. This raised the question of whether the failure of ezetimibe+simvastatin was
due to some unknown side effects of the combined treatment or to the fact that
cholesterol-lowering actually is beneficial in certain populations or patients and not in
others. In fact, some experts have claimed that previous positive trials were not the result
of cholesterol-lowering but of other properties of statins, the so-called pleiotropic effects
(25). At this point in the controversy, cholesterol experts appeared to be divided into two
groups: those who were claiming that cholesterol-lowering is still important whatever the
results of ENHANCE and SEAS, and those claiming that cholesterol-lowering is not
important as long as patients receive intensive statin treatment in order to induce
pleiotropic protection (2-4,26).
Second, the control group in SEAS received a placebo, whereas in ENHANCE the
comparison group received simvastatin alone. This means that the difference in LDL
cholesterol between the experimental and the control group was huge in SEAS, close to
50%, but still did not provide any protection. Thus, ENHANCE and SEAS taken together
should have logically led to reject the the lower the better theory that states that the
lower the cholesterol, the better the protection (27,28).
Third, it is noteworthy that in SEAS, patients with low cholesterol levels in the
experimental group had more cancers and died more frequently from cancers than those
receiving the placebo (19). Although it can be speculated that the increased cancer rate
was a chance effect (29,30), this raises another critical question: may intensive
cholesterol-lowering increase the risk of cancers in certain patients? No one can answer
that question today. Given the millions of patients receiving intensive cholesterol-lowering
treatment without any unambiguous cardiovascular benefits, the next critical question is
whether we should not follow precautionary principles on this public health issue and at

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least fully inform the public about these questions.

The results of another important statin trial were reported during the 2008 ESC
meeting.
GISSI-HF was a double-blind randomized trial testing whether 10 mg rosuvastatin
compared with a placebo could reduce mortality and cardiac complications in patients
with chronic heart failure (CHF) from various causes (20). Large observational studies,
small prospective studies and post-hoc analyses (including meta-analyses) of large
randomized trials have indeed suggested that cholesterol-lowering could be beneficial in
CHF patients. Despite a 36% reduction of LDL cholesterol in the statin group compared
with placebo, there was no difference between groups for total mortality (657 deaths
versus 644 in the placebo group) and for other cardiovascular endpoints in GISSI-HF
(20).
GISSI-HF thus confirmed the results of a previous trial published less than one year
before, the CORONA trial (31). In CORONA, 10 mg rosuvastatin also were tested
against placebo in patients with CHF aged 60 and more. Contrary to GISSI-HF, all
patients in CORONA were CHD patients who had survived a previous myocardial
infarction and presented left ventricular dysfunction. In other words, CORONA was a
secondary prevention trial in high-risk patients because left ventricular dysfunction
significantly increases the risk of CHD complications and cardiac death. Before
CORONA, statin experts claimed that the higher the risk of cardiac death was, the higher
the benefits of intensive cholesterol-lowering would be (32,33). Official and international
guidelines state that a statin should be given to all patients whatever their cholesterol
level in high-risk secondary prevention, whereas in primary prevention, when the risk
of cardiac death is lower, prescription should depend on the cholesterol level (28,34,35).
In CORONA, the primary composite outcome was cardiac death, nonfatal infarction and
nonfatal stroke (31). LDL cholesterol was reduced by 45% and CRP (an inflammatory
marker) by 37% in the rosuvastatin group compared with placebo. CORONA was
therefore designed not to fail. However, no significant difference was recorded for the
primary composite outcome. Moreover, there were 488 and 487 cardiovascular deaths in
the rosuvastatin and placebo groups, respectively. The numbers of deaths due to
worsening heart failure were 191 and 193 in the placebo and statin groups, respectively.
Thus, the unequivocal lessons of CORONA were that both drastic cholesterol-lowering
and the supposed pleiotropic (anti-inflammatory) effect of the statin had no effect at all in
the secondary prevention of CHD in high-risk patients.

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CORONA and GISSI-HF therefore provided exactly the same information in two
different populations, namely that cholesterol-lowering does not improve the prognosis
for high-risk CHD patients. The theory that the higher the risk notably in secondary
prevention of CHD the higher the benefit of cholesterol-lowering (28,32-35) should
logically be rejected. Also, the theory according to which statin pleiotropy could have a
significant clinical impact appears to be very elusive after GISSI-HF and CORONA.
Both GISSI-HF and CORONA raised many questions. The main, one however, was
why the most recent statin trials conducted in secondary prevention and high-risk
patients, including the patients with familial hypercholesterolemia recruited in ENHANCE
and those with aortic valve disease recruited in SEAS, have been negative. An
alternative question was whether there were some technical problems and potential
biases in these 4 trials that could have explained the failure. If not, the same question
should have been raised about the previous trials reporting high protection with statins, in
particular those conducted during the 1990s, before the Vioxx affair and the new clinical
research regulations (16,17). How can we explain the discrepancy between these older
positive trials, in one hand, and CORONA, GISSI-HF, ENHANCE and SEAS, on the
other hand?
Lastly, are the methods and results of previous trials reporting high benefits of
cholesterol lowering verifiable today? Did the new regulations introduced after the Vioxx
affair result in such a striking improvement of trial conduct that all trials are now negative?
Chapter Three: The 2008 AHA November meeting and the JUPITER trial
JUPITER tested the effects of 20 mg rosuvastatin in subjects without cardiovascular
disease, normal cholesterol levels but relatively high CRP (36). The authors report a 50%
decrease in LDL cholesterol, a 37% decrease in CRP and a decrease by about 50% in
cardiovascular complications. However, there are methodological problems and major
clinical inconsistencies in JUPITER.
The main methodological problem in JUPITER regards the premature trial termination
(36). Investigators made the awkward decision to stop the trial after 393 cases of
complications, before the calculated number of at least 520 events calculated in their
analysis plan was reached (36). Taking only the hard complications of fatal and non fatal
myocardial infarction and stroke into account, they actually stopped the trial after only
240 events! The ethical argument according to which patients in the placebo group could
no longer be left untreated is not relevant, and even the opposite, as many scientific

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articles constantly stress (37,38) Scientific rigueur is the primary ethical rule that has to
be followed in clinical research. Ethics required that the trial should not have been
discontinued prematurely, as evidenced by the inconsistency of clinical results (see
below).
The results of JUPITER are reproduced in the Table. They look dramatic. The primary
endpoint (1st line) is a mix of diverse complications listed in the bottom lines of the table,
although some of them such as revascularization are irrelevant because they are not
complications but medical decisions. This being said, we actually observe an impressive
difference between the two groups in terms of hard clinical complications, myocardial
infarction and stroke (157 against 83, line 9). However, there are no clear data on
cardiovascular mortality in the Table as well as the text of the article. One may infer from
the Table (although this is not indicated in the text) that fatal myocardial infarction is the
difference between any myocardial infarction and nonfatal myocardial infarction,
giving total numbers of 9 (31 less 22) in the rosuvastatin group and 6 (68 less 62) in the
placebo group. We can make the same calculation for fatal stroke (the difference
between any stroke and nonfatal stroke), resulting in total numbers of 3 (33 less 30) in
the rosuvastatin group and 6 (64 less 58) in the placebo group. Cardiovascular mortality
(fatal stroke+fatal myocardial infarction) is therefore identical in the two groups (12
against 12).

The lack of effect on cardiovascular mortality associated with a miraculous effect on

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nonfatal complications is puzzling and should have led to suspect a bias and to the
continuation of the trial instead of a premature ending. In addition, the numbers of fatal
myocardial infarction in both groups (9 and 6) were unexpectedly low compared to
nonfatal infarction (62 and 22), suggesting that JUPITER patients, particularly in the
placebo group, withstood the consequences of myocardial ischemia and infarction
extremely well. This was apparent even within the first hour following the first symptoms
(the definition of sudden cardiac death), since curiously no sudden cardiac death was
reported in the trial. Almost no (non sudden) cardiac deaths were reported either during
in the following hours, days and weeks.
We were clearly facing a major clinical inconsistency.
Mortality from myocardial infarction is known to be very high. In fact, the case fatality
rate in epidemiological reports has been reported in many populations with very different
risks (39). Out of 100 patients who have a myocardial infarction, an average of 50 die
immediately or within the 3-4 weeks that follow, and almost never less than 40 out of 100
even in populations with low cardiovascular mortality (39). In JUPITER, mortality during
infarction (6 divided by 68 multiplied by 100) is 8.8% in the placebo group. This is
extremely low, and here we have another major clinical inconsistency! But where does
the error lie? Which are the false figures? The case fatality rate in the rosuvastatin group
(9 divided by 22 multiplied by 100) is 29%, a figure that fits better (although not perfectly)
with the expected variations but raises another question: would rosuvastatin have tripled
myocardial infarction-related mortality?
Is this clinically consistent?
Another way to measure the trial's clinical consistency is to compare cardiovascular
and total mortality. In most countries, cardiovascular mortality represents 45 to 60% of
total mortality, rarely less than 35%. Yet in JUPITER, it represents only 6% of total
mortality (12 divided by 190 x 100; see Table) in the statin group and 5% (12 divided by
235 x 100) in the placebo group. How incredibly low! This is another major
epidemiological inconsistency.
Pending confirmation of JUPITER by a new trial that willhopefullyfollow traditional
and validated clinical trial methods, the obvious conclusion is that JUPITER results are
not clinically consistent and therefore not credible. We must bear in mind that two
previous trials with rosuvastatin (CORONA and GISSI-HF) were negative for CHD
prevention (20,31). Thus, no clinical trial so far had been published showing an
unequivocal clinical benefit of rosuvastatin when JUPITER was published. And this right

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at the time where other anti-cholesterol drugs (tested in ENHANCE and SEAS) showed
totally ineffective whatever the type of hard or surrogate endpoints used to test the effects
of cholesterol-lowering (1,19).
Chapter Four: The 2009 ACC meeting and JUPITER follow-up
During the March ACC meeting, the results of one important trial, named AURORA,
were reported (40). It was an international, multicenter, randomized, double-blind,
prospective trial involving 2776 patients who were undergoing maintenance hemodialysis.
These patients are known to be at very high risk of CHD complications and a
meta-analysis based on subgroup data extracted from previous trials did claim that
cholesterol-lowering is effective to reduce CHD complications in these patients (41). In
AURORA, patients were randomly assigned to receive rosuvastatin, 10mg daily, or
placebo. The combined primary endpoint was death from cardiovascular causes,
nonfatal myocardial infarction, or nonfatal stroke. Secondary endpoints included death
from all causes. The mean reduction in LDL-cholesterol levels was 43% in patients
receiving rosuvastatin. During a median follow-up period of 3.8 years, 396 patients in the
rosuvastatin group and 408 patients in the placebo group reached the primary endpoint
(9.2 and 9.5 events per 100 patient-years, respectively; p=0.59). There was also no
significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years;
p=0.51). Thus, in chronic kidney disease patients undergoing hemodialysis,
cholesterol-lowering with rosuvastatin had no effect at all (40). This was not unexpected
and confirmed the results of a previous negative trial in similar kidney disease patients
where atorvastatin, instead of rosuvastatin, had been tested (10). Together the two trials
confirmed that the failure of cholesterol-lowering was not medicament-specific but the
consequence of the lack of effect of both cholesterol-lowering itself and of any
pleiomorphic effect of statins.
At the same 2009 ACC meeting, JUPITER investigators presented data from
secondary endpoints, symptomatic venous thromboembolisms (42). They were claiming
on the basis of very weak data that rosuvastatin significantly reduces the occurrence of
venous thromboembolisms forgetting that they were not included among the endpoints
used to calculate the a priori hypothesis tested in the trial (36). It is perplexing to see
leading medical journals publishing trials results which could lead naive practitioners to
the foolish conclusion that rosuvastatin might have some anticoagulant properties.
During the same 2009 ACC meeting, JUPITERs investigators reported analyses

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aimed at testing the hypothesis that the benefits observed in JUPITER were primarily the
results of lowering both LDL cholesterol and high-sensitivity C-reactive Protein (CRP). It
is not useless to recall that the JUPITERs principal investigator has a personal conflict of
interest as a co-holder of the patent for the CRP test (36). Authors reported that, although
LDL and CRP reductions were only weakly correlated in individual patients, participants
who achieved striking reductions of both LDL (less than 1.8mmol/L) and CRP (less than
1mg/L) had a 79% reduction of event rates (43). To further celebrate the magic
usefulness of CRP testing in clinical practice, they also claimed that achieved CRP
concentrations were predictive of event rates irrespective of the lipid endpoint used (43).
Unfortunately, these weak data using subgroups extracted from an apparently biased
dataset (see above) were in total contradiction with recent studies showing that CRP
measurements are useless for improving our ability to evaluate CHD risk. For instance, a
large study involving 28,112 cases and 100,823 controls showed a lack of concordance
between the effects on CHD complications of CRP genotypes and CRP levels (44). This
also strongly argued against a causal association of CRP with CHD (44).
The issue regarding subgroup analyses is particularly interesting regarding the effects
of cholesterol-lowering in chronic heart failure patients. Indeed, cholesterol-lowering was
claimed to be very effective in these high-risk and fragile patients on the basis of
meta-analyses using subgroup data of previous trials (45). This was unchallenged by the
medical community until the publication of well-designed negative trials (20,31) leading to
opposite conclusions and rejection of the theory that cholesterol-lowering with statins is
useful in this condition.
The heart and/or renal failure patients story is also an indication that meta-analyses,
although often considered as golden-standard of medical sciences, can be strikingly
flawed and misleading. An illustration of this is a recent article in the British Medical
Journal (46) where JUPITER data were surprisingly included in a meta-analysis
although they are obviously not validated to support the use of statins in primary
prevention of CHD complications (46). Also in that study, authors wrongly used selected
subgroup data to make their meta-analysis (46). It is worrisome to realize that the very
process of reviewing and publishing itself can be biased, even in leading medical
journals.
Conclusion
For cholesterol experts and the cholesterol industry, 2008 and 2009 have definitely

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been very disappointing years. The trials results reported at the four world cardiology
meetings (ACC 2008, ESC, AHA and ACC 2009) were either negative (ENHANCE,
SEAS, GISSI-HF, AURORA) or not clinically consistent and probably biased (JUPITER)
because of premature termination. Taken together, in the light of other recent negative
trials (CORONA, ASPEN, 4D, PREVEND IT, IDEAL, ILLUMINATE) published after the
Vioxx affair in 2005 and the following new clinical research regulations, the 2008-2009
trials are puzzling. They suggest that the positive trials published before 2005 and the
Vioxx affair should be urgently re-examined. A minimum would be that experts
independent from the industry and free of conflict of interests should be committed to
carefully check all the raw data recorded in the datasets and redo the statistical analyses.
The next question would then be: is it not time for a full reappraisal of the cholesterol
theory?
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191(2010)

Michel de LorgerilPatricia Salen

463-8521 2-1723

20082009
ENHANCESEASGISSI-HFAURORA
1JUPITER

2005
2 2007
2008 2009
1994 2004

3
4

1
2 1999 80
8,000 2,750 2004
4
2000
2004 FDA
FDA 5
28,000

3 HMG-CoA
4

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J. Lipid Nutr. Vol.19, No.1 (2010)

2008 2009

3
3 ACC8
ESC11 AHA

2008
2009

1 2008 3 ACC
ENHANCE 6(1)
2008 3
LDL
ENHANCE
78

ENHANCE
LDL
9
10IMT

6 LDL LDL

7
2007 8
8 1 1991 12
9

10 (IMT) 1.0mm 1.1mm

()

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191(2010)

(1)
11 IMT
24 IMT
IMT
0.00950.0040 mm P=0.02 vs.

0.01210.0038 mm P<0.01 vs.

IMT (1)ENHANCE

(2-4)
ENHANCE

(2-4)

ENHANCE
ENHANCE

(5)

20 2002 (6)
SEAS

(4,5)
2008 ACCJUPITER
(7,8)JUPITER
1213

(7,8)
11

12

13

2005 4

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J. Lipid Nutr. Vol.19, No.1 (2010)

ASPEN
4DPREVENT ITIDEALILLUMINATE(9-13) ENHANCE(1)

(1,9-13)ENHANCE

(2-5)
ENHANCE FDA14
(14,15)
CASHMERE 15
IMT
(14)ACHIEVE 16
2
(15)
ENHANCE
(15)2008

(16) 2005-2006

(17,18)

2 2008 8 ESC
8 SEAS
GISSI-HF (19,20)
17 SEAS
ENHANCE(1)
18
14

15
16
17
18

2000 5
B

( 5)

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191(2010)

(19)19
(21,22)
(23,24)

SEAS
(19)SEAS
20
SEAS
ENHANCE ENHANCE
IMT
(19)
SEAS
SEAS ENHANCE(1)(9-13)

21
(25)ENHANCE SEAS

(2-4,26)
SEAS ENHANCE
SEAS LDL
50
ENHANCE SEAS

(27,28)
SEAS
(19)
19
20
21

NO

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J. Lipid Nutr. Vol.19, No.1 (2010)

(29,30)

2008 ESC

GISSI-HF 2210

(20)2324
25
GISSI-HF
LDL 36
657 644
(20)
GISSI-HF CORONA (31)
CORONA 60 10
GISSI-HF CORONA

CORONA
CORONA

(32,33)

(28,34,35)CORONA
(31) LDL
45CRP ) 37
22

23
24
25

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191(2010)

CORONA
488
487 193
191 CORONA

CORONA GISSI-HF

(28,32-35)

GISSI-HF CORONA
GISSI-HF CORONA
ENHANCE
SEAS

1990
(16,17)
CORONAGISSI-HFENHANCESEAS

3 2008 11 AHA JUPITER

JUPITER 20mg
CRP (36)
LDL 50CRP 37 50
JUPITER

JUPITER (36)
26 520 393

26

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J. Lipid Nutr. Vol.19, No.1 (2010)

(36)
240

(37,38)

JUPITER
1

(83 157
8 )

9 (3122=9) 6 (6862=6)
3 (33
30=3) 6 (6458=6)(
)(12 12)

(9 6 )
(22

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191(2010)

62 )JUPITER

1
1

(39)
100 50 3-4
100 40 (39)
JUPITER 8.86/68100
2
299/22100

45-6035
JUPITER
612/190100
512/235100

JUPITER
JUPITER

CORONA GISSI-HF(20,31)

JUPITER

ENHANCE SEAS

(1,19)
4 2009 3 ACC JUPITER
3 AURORA
(40)
2776

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J. Lipid Nutr. Vol.19, No.1 (2010)

(41)AURORA
10mg

27LDL
43% 3.8 396
408
9.2 9.5 100
p=0.59

13.5 14.0100
p=0.51

(40)

(10)

2009 JUPITER
(42)

(36)

2009 JUPITER JUPITER

LDL C CRP
JUPITER
CRP
(36)LDL CRP
LDL 1.8mmol/L CRP 1mg/L
79(43) CRP

CRP (43)

CRP
28,112 100,823
CRP CRP

27

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191(2010)

(44)CRP
(44)
28

(45)
(20,31)

JUPITER (46)

(46)

2008 2009
(ACC 2008 ESCAHA
ACC 2009 )(ENHANCESEAS
GISSSI-HFAURORA)
(JUPITER)2005
ASPEN4
PREVENT ITIDEALILLUMINATE20082009
2005

Michel de Lorgeril
http://www-timc.imag.fr/article780.html?lang=fr
Patricia Salen
28

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J. Lipid Nutr. Vol.19, No.1 (2010)

http://www-timc.imag.fr/article730.html?lang=fr
Michel de Lorgeril
1950 1976
1988 1990
1989 Experimental Cardiology

Laboratory2007

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