ArticlePDF Available

Beyond confusion and controversy, can we evaluate the real efficacy and safety of cholesterol-lowering with statins?

Authors:
  • Swiss-mc medical center

Abstract and Figures

A strong controversy has emerged about the reality of safety and efficacy of statins as stated by company-sponsored reports. However, physicians need credible data to make medical decisions, in particular about the benefit/harm balance of any prescription. This study aimed to test the validity of data on the company-sponsored statin trial by comparing them over time and then comparing statins with each other. Around the years 2005/2006, new stricter Regulations were introduced in the conduct and publication of randomized controlled trials (RCTs). This would imply that RCTs were less reliable before 2006 than they were later on. To evaluate this, we first reviewed RCTs testing the efficacy of statins versus placebo in preventing cardiovascular complications and published after 2006. Our systematic review thereby identified four major RCTs, all testingrosuvastatin. They unambiguously showed that rosuvastatin is not effective in secondary prevention, while the results are highly debatable in primary prevention. Because of the striking clinical heterogeneity and the inconsistency of the published data in certain RCTs, meta-analysis was not feasible. We then examined the most recent RCTs comparing statins to each other: all showed that no statin is more effective than any other, including rosuvastatin. Furthermore, recent RCTs clearly indicate that intense cholesterol-lowering (including those with statins) does not protect high-risk patients any better than less-intense statin regimens. As for specific patient subgroups, statins appear ineffective in chronic heart failure and chronic kidney failure patients. We also conducted a MEDLINE search to identify all the RCTs testing a statin against a placebo in diabetic patients, and we found that once secondary analyses and subgroup analyses are excluded, statins do not appear to protect diabetics. As for the safety of statin treatment – a major issue for medical doctors – it is quite worrisome to realize that it took 30 years to bring to light the triggering effect of statins on new-onset diabetes, manifestly reflecting a high level of bias in reporting harmful outcomes in commercial trials, as has been admitted by the recent confession of prominent experts in statin treatment. In conclusion, this review strongly suggests that statins are not effective for cardiovascular prevention. The studies published before 2005/2006 were probably flawed, and this concerned in particular the safety issue. A complete reassessment is mandatory. Until then, physicians should be aware that the present claims about the efficacy and safety of statins are not evidence based.
Content may be subject to copyright.
Journal of Controversies in Biomedical Research 2015; 1(1):67-92.
Doi: http://dx.doi.org/10.15586/jcbmr.2015.11
Review Article
Beyond Confusion and Controversy,
Can We Evaluate the Real Efficacy and
Safety of Cholesterol-Lowering with Statins?
Michel de Lorgeril,1 Mikael Rabaeus2
1TIMC-IMAG CNRS UMR 5525, Laboratoire Cœur et Nutrition, Université Joseph Fourier, Grenoble,
France; 2Clinique La Prairie, Clarens-Montreux, Switzerland.
Abstract
A strong controversy has emerged about the reality of safety and efficacy of statins as stated
by company-sponsored reports. However, physicians need credible data to make medical
decisions, in particular about the benefit/harm balance of any prescription. This study aimed
to test the validity of data on the company-sponsored statin trial by comparing them over
time and then comparing statins with each other. Around the years 2005/2006, new stricter
Regulations were introduced in the conduct and publication of randomized controlled trials
(RCTs). This would imply that RCTs were less reliable before 2006 than they were later on. To
evaluate this, we first reviewed RCTs testing the efficacy of statins versus placebo in
preventing cardiovascular complications and published after 2006. Our systematic review
thereby identified four major RCTs, all testing rosuvastatin. They unambiguously showed that
rosuvastatin is not effective in secondary prevention, while the results are highly debatable in
primary prevention. Because of the striking clinical heterogeneity and the inconsistency of the
published data in certain RCTs, meta-analysis was not feasible. We then examined the most
recent RCTs comparing statins to each other: all showed that no statin is more effective than
any other, including rosuvastatin. Furthermore, recent RCTs clearly indicate that intense
cholesterol-lowering (including those with statins) does not protect high-risk patients any
better than less-intense statin regimens. As for specific patient subgroups, statins appear
ineffective in chronic heart failure and chronic kidney failure patients. We also conducted a
MEDLINE search to identify all the RCTs testing a statin against a placebo in diabetic
patients, and we found that once secondary analyses and subgroup analyses are excluded,
statins do not appear to protect diabetics. As for the safety of statin treatment a major issue
for medical doctors it is quite worrisome to realize that it took 30 years to bring to light the
triggering effect of statins on new-onset diabetes, manifestly reflecting a high level of bias in
reporting harmful outcomes in commercial trials, as has been admitted by the recent
confession of prominent experts in statin treatment. In conclusion, this review strongly
suggests that statins are not effective for cardiovascular prevention. The studies published
before 2005/2006 were probably flawed, and this concerned in particular the safety issue. A
complete reassessment is mandatory. Until then, physicians should be aware that the
present claims about the efficacy and safety of statins are not evidence based.
Keywords: atorvastatin, cholesterol, chronic heart failure, chronic kidney failure, diabetes,
myocardial infarction, pravastatin, rosuvastatin, simvastatin.
Received: 13 November 2015; Accepted after revision: 04 December 2015: Published: 12 January 2016.
Author for correspondence: Michel de Lorgeril, MD, TIMC-IMAG CNRS UMR 5525, Laboratoire Cœur et Nutrition,
Université Joseph Fourier, Grenoble, France. Email: michel.delorgeril@ujf-grenoble.fr
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 68
How to cite: de Lorgeril M, Rabaeus M. Beyond Confusion and Controversy, Can We Evaluate the Real Efficacy
and Safety of Cholesterol-Lowering with Statins?. Journal of Controversies in Biomedical Research 2015; 1(1):
67-92. Doi: http://dx.doi.org/10.15586/jcbmr.2015.11
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
Introduction
There is a growing controversy affecting
several drugs about their efficacy and
safety, triggered by increasing signs of
altered validity of numerous company-
sponsored trials. One example is the
neuraminidase inhibitors for treating
influenza (1, 2). The 5-year battle needed to
access the raw trial data led to a reversed
picture of the drugs: benefits had been
overestimated and harms under-reported
in the company-sponsored trial reports (1,
2). Ultimately, the benefit/harm balance
was not in favor of the drugs; this is a
critical issue for physicians, in particular
when they are in charge of fragile patients.
One probable cause of the failure is that
none of the trials was independent of the
drug’s manufacturers. Several experts
conclude that the “Tamiflu story” may
suggest that the entire ecosystem of drug
evaluation and regulation could be flawed
(3, 4).
These concerns were strongly reinforced by
the recent “confession” by Dr. Rory Collins
from Oxford University, a prominent expert
investigator in the field of cholesterol
epidemiology and cholesterol-lowering
statins. He stated bluntly in the lay press
that the evaluation of statins during the last
two decades had not been done correctly (5).
He admitted that “the nature and importance
of their adverse effects have to be reassessed
(5). The Cochrane statins review group also
admitted that they do not have proper data
to evaluate statin safety (5). Curiously, this
occurred just 1 year after a rather unusual
dispute between several “experts” about
adverse effects of statins (6-11).
Dr. Rory Collins being the head of several
consortiums publishing huge meta-
analyses through the Clinical Trial
Service Unit (CTSU) or The Cholesterol
Treatment Trialists’ (CTT) Collaboration, for
instance the whole story does raise major
concern, for the simple reason that these
meta-studies repeatedly claimed that
statins are particularly safe (12-15); not
forgetting that they served as a scientific
basis for “lipid treatment guidelines”
released by several national and
international institutions (16, 17).
How then are physicians supposed to act
when it is admitted today by the experts
themselves that their evaluation works
were not done correctly? Can we trust and
follow the guidelines? In other words, what
is the true benefit/harm balance of statins
(18, 19)?
The most adequate way to solve the issue
would be to “open the doors” so that
independent experts do have full access to
the company-sponsored trial data sets i.e.,
clinical raw data of each randomized patient
in each trial to examine their validity in
terms of safety and efficacy. This has led to
an intense debate about randomized
controlled trial (RCT) transparency (20-30).
Prestigious scientists recently stated that
modern medical scientific data are generally
irreproducible (31-33), often wrong (34-38),
going as far as claiming that an estimated
85% of research resources are wasted(31,
32). As raw clinical data are still not
available (lack of transparency), the US
Food and Drug Administration (FDA) and
the European Medicines Agency (EMA)
cannot fully ensure that industry
adequately conduct RCTs and fully report
drug data regarding both efficacy and safety
(20-41). One key measure to ensure RCT
quality is the concealment of patient
allocation and double-blinding. Not
respecting one of these obligations may
introduce unintentional bias in RCTs, in
particular when clinical efficacy is based on
“soft outcomes” such as revascularization
or hospitalization for chest pain, when
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 69
evaluating cardiovascular drugs or
“composite outcomes” mainly including soft
outcomes (42). A clear possibility of such an
unintentional “unblinding bias” has been
recently described (43). All these contribute
to the emerging skepticism affecting the
credibility of RCT data among both public
and health professionals (44, 45).
There have been two periods in the modern
history of RCTs: before and after the
2005/2006 New Clinical Trial Regulations.
These were implemented by the Health
Authorities in Europe and USA following
the Vioxx and Celebrex incidents among
others in order to bring more
transparency into the pharmaceutical
industry (46-50). The Legislator’s intention
was to force industrialists to make public
all the RCTs they were setting up with the
details of their main features, notably the
dates of initiation and termination,
including any discontinued RCT (46-50).
Importantly, by implementing New Clinical
Trial Regulations, the Health Authorities
implicitly admitted that previous drug
assessment procedures were not
satisfactory. As these New Regulations
were elaborated to provide more robust
scientific data and more protection for the
consumers, it could be hypothesized that
RCTs published after 2005/2006 are more
reliable than those published before 2005.
Coming back to statins, in case of a
significant discrepancy between the ancient
(before 2005/2006) and the more recent
(after 2005/2006) RCTs testing these drugs,
we would conclude that only the results of
the most recent RCTs should be retained.
However, the absence of discrepancy
between ancient and recent RCTs would be
very reassuring and allow physicians to keep
on prescribing statins as they did until now.
In order to provide more credible information
to physicians and help them make the right
decision regarding statin prescriptions, we
have conducted a careful analysis of
available company-sponsored statin RCTs
published after 2005/2006. We then
examined studies comparing statins to each
other and whether intense statin regimens
do protect high-risk patients better than
less-intense statin regimens. Finally, we
examined some safety issues including the
very important statin-diabetes issue.
Methods
Search strategy
We identified RCTs published after
2005/2006 and testing a statin against a
placebo via a MEDLINE search using the
following key words “statins,” “RCT,”
“placebo, “cardiovascular disease,”
“ischemic heart disease,” “stroke,”
“myocardial infarction,” and “mortality.” The
search was updated on March 2015 and
retained only randomized double-blinded
RCTs designed to examine the effects of a
statin on cardiovascular outcomes during a
period of at least 1 year. In addition, we
examined the reference lists and related links
of retrieved articles that met the inclusion
criteria and expert review and published
meta-analyses to detect all studies
potentially eligible for inclusion. Cross-
sectional, cohort, case-control, and meta-
analysis studies were not included. Studies
comprising secondary and/or subgroup
analyses were excluded because they were
performed “a posteriori after unblinding, a
major cause of bias. We also performed a
MEDLINE search to specifically identify
double-blinded RCTs testing a statin in
diabetic patients. Again studies comprising
secondary and subgroup analyses were
excluded. The selection was done by Michel
de Lorgeril and verified by Mikael Rabaeus;
and there was no discrepancy between them.
The excluded references are included as
supplementary file.
Because of major clinical heterogeneity of the
RCTs published after 2005/2006, a meta-
analysis was not feasible. Indeed, no meta-
analysis of those RCTs has been published
so far, the main reason simply being that it is
not methodologically acceptable. We cannot
put in the same database such very different
cohorts of patients, namely patients in
primary prevention (Justification for the Use
of Statins in Prevention: an Intervention Trial
Evaluating Rosuvastatin [JUPITER]), patients
in secondary prevention with various degrees
of cardiac dysfunction (Controlled
Rosuvastatin Multinational Trial in Heart
Failure [CORONA]), patients with heart
failure (Gruppo Italiano per lo Studio della
Sopravvivenza nell’Insufficienza cardiaca
[HF] [GISSI-HF]), or patients with chronic
renal failure (A Study to Evaluate the Use of
Rosuvastatin in Subjects on Regular
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 70
Hemodialysis: An Assessment of Survival
and Cardiovascular Events [AURORA]).
In addition, as discussed further in the
Results section, data of certain RCTs are
not correctly provided. For instance,
cardiovascular mortality in JUPITER is not
reported in the first published article. Then,
five different versions of cardiovascular
mortality were reported. Which one should
we consider? Moreover, regarding the overall
mortality in JUPITER, the data were not
validated by the statisticians of the FDA
because the trial was prematurely stopped.
We thus had to renounce to make any
meta-analysis in the present study.
Results
The statin efficacy data
The only statin that has been tested (against
placebo) after the implementation of the
New Regulations is rosuvastatin that was
tested in four RCTs (Figure 1 and Table 1):
The JUPITER trial, wherein the patients
were considered free from cardiovascular
disease and carrying a rather moderate
risk of cardiac death (51);
The CORONA trial, wherein patients
were all survivors of a prior acute
myocardial infarction (AMI) with
various degrees of cardiac dysfunction
and at high risk of AMI recurrence and
cardiac death (52);
The GISSI-HF trial, wherein all patients
had cardiac dysfunction 50%
following a previous AMI and 50% due
to other heart disease and a high risk
of cardiac death (53);
The AURORA trial, wherein patients
presented with severe renal failure,
with 50% having already suffered an
AMI or other ischemic complications.
Evidently, they had a major risk of
recurrent AMI and cardiac death (54).
Thus, a large proportion of the patients
recruited in these four rosuvastatin RCTs
were in the context of secondary prevention,
thereby testing what has become an
apparently indisputable statement: “beyond
any doubt, statins are effective in secondary
prevention” (55-58). A corollary statement
was also tested: the higher the risk of AMI,
the more the reduction of cholesterol levels by
means of a statin will be beneficial” (55-58).
The patients in AURORA with the highest
risk should get the greatest benefit and
those in JUPITER with the lowest risk
the least benefit. Let us start with the
patients whose risk was the lowest.
The JUPITER trial
The JUPITER trial was a primary
prevention trial (51). About 18,000
participants selected on the basis of a
moderately elevated C-reactive protein
(CRP) were distributed randomly into two
groups: one was treated with a placebo,
and the other with rosuvastatin. The
primary hypothesis was to test
rosuvastatin against placebo. An implicit
additional objective was to test whether
CRP levels could serve as indicators for the
prescription of a cholesterol-lowering drug,
even in patients with normal or even low
blood cholesterol levels. JUPITER was
therefore supposed to demonstrate that
rosuvastatin is indicated in a specific “new”
category of patients, i.e., those with slightly
raised CRP levels (59-61).
As the main investigator of JUPITER also
holds part of the license for the CRP assay
kit the other owner being a major Boston
hospital this additional objective implies
that very serious conflicts of interest were
present (51, 59).
What happened with JUPITER? The whole
story has been told in several articles and
book chapters (50, 51, 59-61). Briefly, by
the end of 2007, the investigators and the
sponsors announced highly favorable
results for rosuvastatin and that the trial
should be discontinued (50, 51). According
to them, it would have been unethical to
leave millions of potential patients without
treatment when they had already
demonstrated the highly significant
protective effect of rosuvastatin, notably on
cardiovascular mortality (59-61).
Accordingly, in March 2008, a press
release announced the discontinuation of
the JUPITER trial, with an average follow-
up of less than 2 years per patient (59-61).
The adequacy of this premature
discontinuation was strongly challenged
(59-61) but was ultimately confirmed by a
committee supposedly “independent from
the sponsor.”
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 71
Figure 1. Flow diagram of selection of statin RCTs published after 2005/2006.
In November 2008, the results of JUPITER
were published (51) and controversy grew
further as many realized that the mortality
data were not presented correctly. Criticisms
abounded, triggering numerous answers and
counterattacks from the investigators (59-
61). As the debate progressed, new data
(previously unreleased) were reported by the
investigators and/or the sponsor,
surprisingly accompanied by modifications of
the survival curves (59-61). This finally
resulted in at least five different versions of
cardiovascular mortality data being reported
(59-61), which obviously is just as
unacceptable as was the modification of the
survival curves.
Ultimately, cardiovascular mortality was
not judged different in the placebo and
rosuvastatin groups, and the small
difference in overall mortality (Table 2) was
not validated by the statisticians of the
FDA (59-61). As the raw clinical data,
detained by the sponsor, are not available
to independent experts and have not been
examined by the FDA experts, it remains
however impossible to make any definite
conclusion regarding the true effectiveness
of rosuvastatin in JUPITER. Admittedly,
the lack of effect on death rate and the
existence of mortality data misreporting do
not necessarily question the effectiveness
of rosuvastatin against nonlethal
388 Relevant citations were identified
and screened for retrieval
375 Articles were excluded on basis of title and/or
abstract review: not RCT, RCTs published before
2006, use of surrogate endpoints, analyses, reviews,
studies of mechanisms…
13 Articles were retrieved for more
detailed evaluation
8 Studies were excluded based on not fulfilling
inclusion criteria: not double-blinded (MEGA), open
RCT (Kojima et al), published before 2006
(ALLIANCE, ALERT), no placebo RCT (JART), no (or
very small numbers of) clinical cardiovascular
endpoint (METEOR, ASTRONOMER, Bone et al)
5 RCTs testing a statin (vs. placebo)
fulfilled criteria
One 2006 study in diabetics (ASPEN)
is analyzed in the section “statins in
diabetics”
4 appropriately conducted RCTs testing
rosuvastatin against placebo were retained
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 72
complications. An answer is however
indirectly given by the three other trials
testing rosuvastatin CORONA, GISSI-HF,
and AURORA that did not report any
effect on nonlethal complications (52-54).
Was the premature discontinuation of
JUPITER a deliberate form of misreporting?
The investigators must have been aware
that they would be criticized for this as
many scientists consider that when RCTs
are stopped early for benefit, they usually
show implausibly large treatment effects
(62, 63). So what could have been the true
reason motivating the decision for this
methodological flaw in JUPITER? The
answer might lie with the unexpected
significant increase of new cases of diabetes
in the rosuvastatin-treated patients.
The investigators tried to minimize this
finding in 2008 (51) and later, claiming that
the cardiovascular and mortality benefits of
statin therapy exceed the diabetes hazard
(64). They wrongly seem to support the idea
that the only consequence of diabetes is
cardiovascular complications, forgetting
that type 2 diabetes increases the risk of
many noncardiovascular diseases, such as
cancers, eye and kidney diseases, dementia
and cognitive decline, depression, and bone
damage among many others (65-70). This
statin-diabetes issue is further discussed
below in the Safety section.
The CORONA and GISSI-HF trials
In the CORONA trial, over 5,000 AMI
survivors aged 60 years or more were
randomized to receive either a placebo or
rosuvastatin (52). Despite a striking
reduction in blood cholesterol levels, patients
taking rosuvastatin had no clinical benefit
whatsoever, particularly in terms of survival
(Table 2). The occurrences of cardiac death,
AMI, and other nonlethal ischemic
complications were unambiguously not
different between the two groups.
CORONA came in complete opposition to
previous post hoc analyses of RCTs and
also meta-analyses (71-73), all claiming
that statins have beneficial effects on
several endpoints, including mortality and
nonlethal complications, in patients with
post-AMI cardiac dysfunction and chronic
heart failure with or without coronary
heart disease.
Table 1. List of the main RCTs discussed in this review in the order of appearance in the text
Tested hypothesis
Publication
year
Significant
difference
for CV
mortality
Reference
number
Rosu vs. placebo
2008
No
51
Rosu vs. placebo
2007
No
52
Rosu vs. placebo
2008
No
53
Rosu vs. placebo
2009
No
54
Simva vs. placebo
1994
Yes
74
Ator vs. placebo
2005
No
77
Simva + Eze vs. placebo
2011
No
80
Rosu vs. Ator
2011
NA*
82
Ator vs. placebo
2001
No
83
Simva vs. placebo
2002
Yes
88
Simva vs. Ator
2005
No
89
Simva 80 vs. Simva 20
2011
No
91
Ator vs. Prava
2004
No
92
Ator vs. placebo
2004
No
122
Ator vs. placebo
2006
No
123
NA, “not applicable;” Rosu, rosuvastatin; Simva, simvastatin; Ator, atorvastatin; Prava,
pravastatin; Eze, ezetimib.
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 73
Table 2. Summary of mortality data in the 4 rosuvastatin RCTs
RCT acronym
Placebo
Rosuvastatin
Cardiovascular mortality
JUPITER
12*
12*
CORONA
487
488
GISSI-HF
488
478
AURORA
324
324
Total
1311
1302
Overall mortality
JUPITER
247**
198**
CORONA
759
728
GISSI-HF
644
657
AURORA
660
636
Total
2310
2219
*Calculated by the authors as the numbers were not provided by the JUPITER investigators
(see text).
**Data not formerly validated by the FDA statisticians because of the premature
termination of the trial (see text).
Explaining discrepant scientific data is a
fundamental work of independent
scientists. So how can we explain the
discrepancy between CORONA and
previous RCTs testing a statin in secondary
prevention, such as the often-cited
Scandinavian Simvastatin Survival Study
(4S) trial (74) for instance?
Somewhat strangely, it has been said that
the failure of CORONA to show any benefit of
rosuvastatin was hardly surprising because
there was no reason for the statin to protect
“elderly heart-failure” patients. According to
these post hoc interpretations, a statin is
supposed to prevent ischemic heart attacks,
certainly not to extend the life of elderly
patients with ruined hearts by stopping the
progression of cardiac dysfunction.
The analysis of CORONA outcomes shows
that this argument is not valid: most deaths
occurred during a recurrent AMI and only a
minority because of progression of heart
failure (52). This is no surprise as previous
studies have shown that recurrent AMI is
the first cause of death following a prior AMI
with cardiac dysfunction (75). CORONA was
therefore clearly a study of the efficacy of a
statin in preventing a recurrent AMI, i.e., a
secondary prevention RCT (52).
Finally, when the authors analyzed their
results, there was no difference when
comparing patients according to age or
degree of cardiac dysfunction at baseline:
the youngest did not benefit any more than
the oldest, and those who suffered from
minor or no symptoms of heart dysfunction
were no more protected than the most
severe cases (52).
This was reinforced when Italian
investigators reported the results of the
GISSI-HF trial where approximately 50% of
the patients recruited had very similar
characteristics to the CORONA population
(except that they were younger) and where
again no benefit (Table 2) was demonstrated
in the rosuvastatin group (53).
It is pointless to discuss the GISSI-HF
results in detail, although it was a
remarkable piece of clinical research. All
one needs to say is that, like CORONA,
GISSI-HF failed to show any benefit of
cholesterol-lowering with a statin in
secondary prevention.
The AURORA trial in chronic kidney disease
In the AURORA trial, rosuvastatin was
tested against placebo in patients with
severe chronic kidney disease, some of
them with a previous AMI or other cardiac
ischemic syndromes, thus again in
secondary prevention [54].
Renal failure patients being at high risk of
AMI, the expected benefit from lowering
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 74
their cholesterol level has also been
considered as very high. Indeed, for years,
on the basis of meta-analyses using weak
data extracted from studies not designed to
primarily test the effectiveness of statins on
renal failure patients (76), these patients
(and their doctors) were misled into
believing that their cholesterol level should
be lowered as much as possible (50).
So what did AURORA show? The results
were the same as in CORONA: no clinical
benefit at all for both fatal and nonfatal
complications (Table 2) despite a striking
reduction in blood cholesterol (54).
AURORA put an end to the belief that
cholesterol-lowering by a statin is useful in
chronic renal failure. Actually, AURORA
confirmed the negative results of a previous
RCT named 4D (for the "German Diabetes
and Dialysis Study Investigators") (77),
which had tested the effects of atorvastatin
in similar kidney failure patients.
AURORA and 4D underline that we should
only trust results of individual studies that
do respect the strict methods of RCTs based
on a well-defined primary hypothesis (37, 38,
50). Evidently, the same goes for meta-
analyses (50, 55-58, 62, 63, 71-73, 76) in
which flawed studies are very often included.
And indeed, investigators still recently
published new meta-analyses mixing well-
conducted RCTs (such as AURORA and 4D)
with a myriad of commercial studies
reporting secondary endpoints or post hoc
data (78, 79), resulting in the curious claim
that statins might be useful in chronic renal
failure patients.
The inadequacy of such methods is
evidenced by the fact that the results
differed. One meta-analysis claimed that
statins reduce the risk of cardiovascular
complications in patients with chronic
kidney disease, including those receiving
dialysis (78), while another concluded that
there was no effect in patients on dialysis
(79). One meta-analysis showed no effect of
statins on stroke (78), while the other
concluded that statins did reduce stroke in
patients not on dialysis (79). Such meta-
analyses should be discarded.
Also discarded by physicians should be the
SHARP trial testing intense cholesterol-
lowering (with simvastatin plus ezetimibe) in
patients with chronic kidney disease and
published in 2011, after the implementation
of the New Regulations (80). In SHARP,
there was no significant effect on coronary
death, nonfatal AMI, any major coronary
event, and all-cause death. The significant
effect on the composite endpoint called
“total cardiovascular events” (619 events in
the placebo group vs. 526 in the simvastatin
plus ezetimibe group) was almost totally the
consequence of the between-group
difference in the revascularization
procedures (352 vs. 284) (80). As discussed
(42, 50, 60), revascularization is not a
complication but a medical decision easily
biased by unblinding (43) and awareness of
patient allocation and can at best only be
considered as a very soft endpoint. It cannot
serve to judge the efficacy of any medicine
to prevent cardiovascular disease. Finally,
the trial was also criticized because of a lack
of clarity in the statistical analysis plan (81).
Thus, physicians should conclude that
cholesterol-lowering with a statin or a
combination of a statin with ezetimibe
does not protect their patients with chronic
kidney disease.
Summary on recent (post-2005/2006) statin
RCTs
Data regarding cardiovascular and overall
mortality in the four rosuvastatin RCTs are
summarized in Table 2. The only
conclusion can be that, taken as a whole,
the four RCTs testing rosuvastatin all
conducted or published after the
implementation of the New Regulations
show that cholesterol-lowering with that
specific statin is not proven to be effective,
whether in primary or in secondary
prevention. This is in total contradiction
with the commercial RCTs published before
the New Regulations.
The next question is then obvious: if
rosuvastatin has not been proven effective,
what about the statins tested in those
“ancient” studies and that are allegedly
remarkably effective on clinical outcomes
while being less effective than rosuvastatin
in lowering cholesterol?
Alternately, for the physicians in charge of
fragile patients, the question is: “should I
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 75
prefer another statin to protect my patients
or, all the statins being equal, should I
forget all the statins?”
Are “ancient” statins better than
rosuvastatin?
Atorvastatin
A few studies comparing statins head to
head are available (Table 1).
The SATURN or "The Study of Coronary
Atheroma by Intravascular Ultrasound:
Effect of Rosuvastatin versus Atorvastatin"
trial, published in 2011 and thus supposedly
conducted according to the New Regulations,
compared the effects of rosuvastatin to those
of atorvastatin, unfortunately in the absence
of a control (placebo) group (82). The primary
endpoint was the progression of
atherosclerotic plaque, claiming that plaque
volume measured with sophisticated
imaging techniques is predictive of
cardiovascular complications. The number of
patients was relatively small (about one
thousand), and the duration of the follow-up
was quite short (2 years).
The results showed no significant difference
between the two statins regarding the
evolution of plaque volume during follow-
up, which was curiously interpreted as
showing that both statins were equally
effective in slowing down the plaque
evolution, when there was no control group
(82). In addition, there was no difference in
the number of major cardiovascular
complications: 49 on atorvastatin versus 52
on rosuvastatin (82). One could argue that
the trial was short and the number of
patients too low to expect any significant
difference to emerge between both the
groups. However, the total lack of difference
(not even a trend) after 2 years does not
raise hope that, even with many more
patients, atorvastatin would suddenly
recover the remarkable effects it had
boasted in the RCTs conducted and
reported before the New Regulations.
Thus, according to SATURN, atorvastatin is
not better than rosuvastatin and, as the
latter is ineffective (50-54, 59-61), this
raises serious doubts about atorvastatin
efficacy. However, one has to consider the
limitations of SATURN, in particular the
small sample size. We therefore chose to
re-evaluate the results of another RCT
testing atorvastatin against placebo in
secondary prevention: the Myocardial
Ischemia Reduction with Aggressive
Cholesterol Lowering (MIRACL) trial
published in 2001 and often presented as
an unambiguous demonstration that
atorvastatin is effective to prevent
cardiovascular complications (83, 84).
Why come back on MIRACL in 2015? The
MIRACL trial is quite typical of the
commercial RCTs undertaken long before
the 2005 New Regulations. MIRACL
compared atorvastatin (80 mg) to a placebo
in over 3,000 patients who had just
suffered an AMI, within 24 hours to 4 days
after their admission to hospital. The
investigators wished to demonstrate that
the protective effect of large doses of
atorvastatin was close to immediate.
Importantly, the trial was totally controlled
by the sponsor, to the point that even the
main statistician of the study was a
member of the sponsor staff (83).
The results were unambiguous: there were
68 deaths in the placebo group versus 64
in the atorvastatin group; 113 nonlethal
AMIs in the placebo group versus 101 in
the atorvastatin group; and 10 versus 8
cardiac arrests, respectively (83). The
hypothesis that atorvastatin may protect
from recurrence in secondary prevention
should therefore be rejected without any
hesitation, confirming our conclusions
made from SATURN. However, MIRACL
was (83, 84) and still today (85) is
presented as an unequivocal
demonstration that a statin in particular
atorvastatin should be imperatively
prescribed in secondary prevention.
How was this surprising conclusion
reached? The procedure was subtle. A new
clinical cardiac endpoint category was
added, in place of AMI or unstable angina.
In their own words, the new category was
recurrent symptomatic myocardial ischemia
with objective evidence requiring emergency
hospitalization (83). These patients were
not suffering from AMI or unstable angina
according to established criteria but of
something else, i.e., emergency
hospitalization an endpoint even softer
than the revascularization endpoint
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 76
(discussed above) which can in no way be
used to judge the efficacy of a drug in
scientific medicine. Moreover, the validation
of that endpoint totally depended on the
data collected by field investigators who
belonged to the sponsor’s staff. By
performing this curious validation-
classification of a “new” endpoint, at last
something appeared to be slightly different
in the two groups: they recorded 130 and 95
of these types of “cardiac events,”
respectively, in the placebo and atorvastatin
groups. No additional comment is needed.
The failure of statins to reduce the risk of
recurrence and death in the early high-risk
period following AMI or acute coronary
syndromes the worst phase in secondary
prevention has been confirmed since then
in various meta-analyses (86, 87), thereby
also confirming that MIRACL was a flawed
trial. The only conclusion for physicians
then is that evidence shows that neither
rosuvastatin nor atorvastatin (even at high
dose) is effective in secondary prevention.
Simvastatin
For years, millions of AMI survivors
worldwide have been treated with
simvastatin on the basis of one single trial,
the 4S trial. The findings were published in
1994 and showed significant effects with
the reduction of both cardiac death and
nonfatal complications (74).
The 4S trial is the one and only published
RCT assessing the effect of simvastatin in
the well-defined context of post-AMI
prevention (74). One should note, however,
that here again, the trial was conducted on
the field by the sponsor’s staff and that the
main statistician of the trial belonged to
the sponsor’s staff (74), which would today
be unacceptable.
One could argue that there is another RCT,
the Heart Protection Study (HPS), where
simvastatin was tested against placebo in
high-risk people, as about 40% of the
randomized patients reported a previous
(undated) AMI (88). Involving over 20,000
adults, HPS was designed to test two
distinct hypotheses. The first was to
determine whether simvastatin might
reduce cardiovascular complication and
mortality rates. The second tested whether
an antioxidant cocktail could have the
same effect. Four groups of over 5,000
patients each made up the HPS trial: group
1 took simvastatin + placebo; group 2,
simvastatin + antioxidants; group 3,
placebo + placebo; and group 4, a placebo
+ antioxidants. Only the comparison
between group 1 (statin only) and group 3
(placebo only) matters in the present review
as comparison with antioxidants is not
relevant here.
Combining the four groups in their
analyses, the Oxford CTSU claimed that
simvastatin reduced total mortality by 13%
(relative risk reduction) and any vascular
death by 17% (88). However, the results
were given comparing all patients taking
simvastatin, i.e., 50% of the cohort, with all
patients taking placebo, whether they were
also taking antioxidants or not.
In other words, we cannot determine from
the results given, what the effect of
simvastatin given alone was when
compared to placebo given alone. Half of
the patients were taking antioxidants with
either simvastatin or placebo. To exclude
any unplanned interaction, it is evident
that the results from all four groups must
be reported separately. This is a minimum
requirement and failing to do so is suspect.
All the more considering are the very large
sample sizes (n > 5000 in each group) and
the follow-up of 5 years. Not complying
with this requirement should raise
suspicion that the comparison of
simvastatin alone against placebo alone
was not conclusive.
In view of this uncertainty about the
efficacy of simvastatin, is there any
indication that it is better than
atorvastatin?
Simvastatin was compared to atorvastatin
in a trial called Incremental Decrease in
End Points Through Aggressive Lipid
Lowering (IDEAL), published in 2005 (89),
at a time when investigators and sponsors
began to be very prudent, 2005 being right
in the middle of the transition phase
between the ancient and New Regulations.
Briefly, in IDEAL, almost 9,000 patients
with coronary heart disease were treated
with either atorvastatin or simvastatin. The
low-density lipoprotein (LDL)-cholesterol
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 77
level was a bit lower in the high-dose
atorvastatin group, but the 11% reduction
in the primary endpoint (nonfatal AMI +
cardiac death) in this group was not
statistically significant (89). More
specifically, there was no difference
between groups in total death rates (374
vs. 366) or in cardiac deaths (178 vs. 175).
Thus, IDEAL shows that atorvastatin and
simvastatin are not different in terms of
clinical effectiveness over a period of nearly
5 years in secondary prevention (89). As
atorvastatin is apparently ineffective in
post-AMI patients as seen in MIRACL (83)
simvastatin should be considered as
ineffective too. It means that the 4S results
have never been confirmed.
As discussed in the Introduction section,
reproducibility of scientific data is the
cornerstone of their credibility (31, 32). As
long as we do not have access to the raw
clinical data of HPS and 4S and because
the methods used in both RCTs are
questionable (in particular, the lack of
independent statistical analyses in 4S) it
seems to the least prudent to consider HPS
and 4S as doubtful RCTs. The lack of effect
of simvastatin in secondary prevention has
been indirectly confirmed in the Study of
the Effectiveness of Additional Reductions
in Cholesterol and Homocysteine (SEARCH)
trial, comparing intensive simvastatin
regimen with a four-time lower simvastatin
dosage, as discussed in the next section.
Is intensive statin regimen more
effective?
It has been claimed that more-intense versus
less-intense statin regimen is more effective
to reduce cardiovascular complications (90).
Is there any difference between the “ancient”
and the recent RCTs in this respect?
Only one RCT investigating intensive
cholesterol-lowering with a statin alone has
been published after the 2005/2006
transition period; it is the SEARCH trial
comparing 80 mg versus 20 mg of
simvastatin in a huge (n = 12,064)
population of AMI survivors (91). Results
after a mean follow-up of almost 7 years are
by no way ambiguous: there was no
significant difference between groups for any
cardiovascular endpoint, including the very
soft composite endpoint (p = 0.10). More
specifically, intense simvastatin regimen did
not significantly reduce coronary death (447
vs. 439), major coronary events (1189 vs.
1225), stroke (255 vs. 279), or any death
rate (964 vs. 970) (91). Neither the sample
size nor the duration of follow-up could
explain the failure.
Curiously, the Oxford CTSU investigators
concluded that the SEARCH results were
consistent with previous RCTs
demonstrating that more intense statin
therapy safely produces extra benefits (91).
This is obviously wrong and raises major
concerns about the review process in some
medical journals, as well as about the
credibility of the Oxford CTSU studies.
Another interesting study (although
published in 2004), the Pravastatin or
Atorvastatin Evaluation and Infection
TherapyThrombolysis in Myocardial
Infarction 22 (PROVE IT-TIMI 22) trial, is
worthwhile to examine. The trial tested
whether aggressive lipid-lowering using
atorvastatin 80 mg/day provided greater
protection against death or major
cardiovascular events than did moderate
lipid-lowering using pravastatin 40 mg/day
[92]. More than 4,000 patients were
recruited a median of 7 days after AMI and
followed up for 2 years.
Importantly, the trial whose results were
published before the 2005/2006 New
Regulations tested several hypotheses (as in
HPS), with a second randomization to
allocate patients to groups receiving either an
antibiotic or a placebo. As discussed above,
testing two hypotheses in the same patients
is not a good procedure as interactions are
liable to contaminate each comparison.
The antibiotic part of PROVE IT-TIMI 22
was unfortunately reported in a separate
article (93). This is a situation where
providing the results of all 4 trial groups is
essential but was not done in PROVE IT-
TIMI 22, representing a source of bias.
LDL-cholesterol levels were decreased by
49% in the atorvastatin group and 21% in
the pravastatin group.
Curiously, all clinical data are only
expressed as percentages. We can however
make some calculations and obtain
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 78
approximate absolute numbers. The
authors announce a reduction of 28% for
total mortality and of 30% for cardiac
mortality, which seems quite impressive
but that are nonsignificant. Moreover, as
shown in Figure 4 of the article (92)
indicating the 2-year event rates (page
1501), the mean risks of dying were,
respectively, 2.2% and 3.2% and the risk of
cardiac death were 1.1% and 1.4%. In
other words and making the story short,
we can calculate that, in fact, there were
something like 18 versus 22 cardiac deaths
for 1,600 patients after 2 years, a
difference of four deaths. In other words, a
minute difference in absolute Figures was
disguised as a 30% reduction in the risk of
cardiac death” in PROVE IT-TIMI 22.
Using the same calculations, we found 55
nonfatal AMIs in the atorvastatin group
and 59 in the pravastatin group, an
obviously nonsignificant between-group
difference. No additional comment is
needed, and we can safely conclude that
pravastatin is not better than atorvastatin,
and vice versa.
Summary of the studies comparing
statin versus statin
In short, rosuvastatin (which is not
effective) is not different from atorvastatin,
which, itself, is not different from
simvastatin and pravastatin (see Table 1).
This leads to the conclusion based on the
comparison of statin versus statin that
the early statins (simvastatin, pravastatin,
and atorvastatin) are not different from the
most recent one (rosuvastatin). Thus,
cholesterol-lowering with any of these
medicines yields no detectable benefit
against cardiovascular complications, in
particular cardiac death and nonfatal AMI,
and no effect on the overall mortality.
This lack of difference between the early
and new statins as examined in face-to-
face RCTs was recently and indirectly
supported by a very large cohort study
based on the huge French national health
insurance database comparing the cardiac
and cerebrovascular prognosis of 106,941
patients prescribed rosuvastatin with
56,860 patients prescribed simvastatin, the
average follow-up being 36 months (94). No
difference between the two statins was
observed in this real-life study, suggesting
again that the lack of significant protective
effect of rosuvastatin may represent the
true effect of statins in general.
Finally, the observed discrepancy between
“historic” statin RCTs and post-2005/2006
statin RCTs not considering the studies
comparing statin versus statin implies
that mixing data from these two categories
of RCTs in meta-analyses should no longer
be accepted. On the contrary, to be
credible, any new meta-analysis should
separately analyze RCTs conducted before
and after the implementation of the 2005
New Regulations.
However, this analytical strategy is facing a
major problem: the clinical heterogeneity of
the patients included in the four
rosuvastatin RCTs published after
2005/2006. Clinical homogeneity is the
cornerstone of consistent and credible
meta-analysis as seen by medical doctors.
Mixing healthy people with AMI survivors
(and more or less severe cardiac
dysfunction), chronic heart failure patient,
and chronic kidney failure patient in the
same data set is scientific nonsense.
The statin safety issue
The statin safety issue is becoming a major
problem as according to the Oxford
CTSU, CTT consortium, and even the
Cochrane collaboration (5) experts did
not seriously examine (and report) statin
adverse effects in commercial RCTs and in
the meta-analyses, notably in those
combining data from up to 27 statin RCTs
(12-15). This raises trust issues: how can
we continue to trust experts who have so
long claimed that statin prescription
resulted in major benefits without any
evidence of emerging hazards?
To illustrate the point, we chose two
examples the thromboembolism and
diabetes issues because they are very
important for medical doctors who must
systematically evaluate the benefit/harm
balance of any treatment before
prescribing.
Statins and thromboembolisms
Do statins decrease thromboembolism risk?
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 79
This example brings us back to the
JUPITER trial (51). Despite the premature
termination of the trial and that
thromboembolism was not a primary
endpoint both facts considerably
increasing the possibility of a chance effect
and biased results JUPITER investigators
nonetheless claimed that rosuvastatin
significantly reduces the occurrence of
symptomatic venous thromboembolism
(95). One should note that the absolute
reduction was 0.14% (!) and that no
reduction in pulmonary embolism was
observed. This is already enough not to
attach any importance to the findings, as
confirmed by a subsequent meta-analysis
(96), which analyzed published and
unpublished results of statin RCTs
including JUPITER. It was found that
statins do not significantly reduce the risk
of venous thromboembolism: events
occurred in 0.9% of the participants who
were given statins and in 1% of the
participants who were given placebo. The
whole issue strongly indicates (as expected)
that JUPITER results about
thromboembolism happened by chance.
Until we get new and consistent data, the
theory that statins may have some
anticoagulant properties should be
rejected.
Statins and new-onset diabetes
Whether statins induce new-onset diabetes
is a major question because diabetes is a
serious disease with many cardiovascular
and noncardiovascular complications,
including kidney diseases, eye diseases,
and also cancers.
In fact, they do. Curiously, it is only with
the JUPITER trial in 2008 that the statin-
diabetes issue was revealed (51) and, as
discussed above, it might have been a
major reason to prematurely stop
JUPITER. It took 4 additional years before
the FDA sent out a warning (97).
This means that it took at least 30 statin
RCTs and 30 years during which the
statins were fully prescribed to bring to
light this toxic effect. The whole story
seems to be a remarkable illustration of
high bias in the reporting of harmful
outcomes within the company-sponsored
RCTs (98, 99). In fact, statins not only
increase the risk of de novo diabetes but
even more frequently increase insulin
resistance and metabolic syndrome,
probably through their toxic effect (at least
in part) on skeletal muscles (100).
Nevertheless, the investigators who had not
seen (or reported) anything until then,
immediately reacted by claiming that we
must not change anything in our way of
prescribing statins (101-103). Their
“reasoning” was (and still is) that as statins
are highly effective in preventing AMI and
stroke in diabetics, becoming a diabetic is
not a problem as the patient would
ultimately anyway be protected from
cardiovascular problems (101-103). Should
physicians trust such an advice?
While probably untrue in itself (104, 105),
this reasoning does in addition not take
into consideration the several
complications of diabetes that statins
cannot reduce or may even stimulate (50,
60, 65-70, 106-113). And physicians must
remember that the vast majority of patients
prescribed a statin are in fact at low risk of
AMI or stroke.
On one hand, even if statins were really
protective against AMI and stroke an
elusive theory as we have shown only a
very small proportion of the treated
patients would benefit (7, 9). On the other
hand, among the huge number of low-risk
patients treated with statins, a significant
proportion (see below) will become diabetic
or insulin-resistant and suffer
complications from this including
noncardiovascular complications. If we
then add to this the other deleterious side
effects of statins (106-117), which have
been systematically misreported or
underestimated, the whole issue is of major
importance.
Putting data from company-sponsored
RCTs aside, a crucial question for
physicians (and their patients) remains:
what is the true pro-diabetic effect of
statins? In a real-world setting, the risk of
new-onset diabetes has been reported to
increase with dose regimen and as
adherence with statin treatment increases;
the relative risk increase of new-onset
diabetes may reach 40 to 70% (118-121).
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 80
Do statins prevent cardiovascular
complications in diabetics?
This then becomes a major issue for the
treating physicians. Let us first cautiously
have a look at the existing data as some
statin experts are claiming that statins do
prevent cardiovascular complications in
diabetics (101-103), whereas others say the
opposite (104, 105).
To stay in line, only robust data should be
retained. For that reason, we have
conducted a MEDLINE search to
specifically identify double-blinded RCTs
testing a statin against placebo in diabetic
patients. Studies comprising secondary
and subgroup analyses were excluded
because a posteriori analysis based on
subgroups extracted from previous
unblinded trials is open to major bias.
Results of our MEDLINE search are
summarized in Figure 2 and Table 1.
How many RCTs have tested the effects of
statins in diabetics as a primary hypothesis?
There are three RCTs, namely Collaborative
Atorvastatin Diabetes Study (CARDS) (122),
Atorvastatin Study for Prevention of
Coronary Heart Disease Endpoints in non-
insulin-dependent diabetes mellitus (ASPEN)
(123), and 4D (77). Despite the fact that
these three RCTs did not show unambiguous
benefits of statins in diabetics, some statin
experts (124) claimed the opposite. So, let us
carefully examine the data.
Figure 2. Flow diagram of selection of statin RCTs testing a statin against placebo in diabetic
patients. This an extension of a systematic review published in 2012 (104). Inclusion and exclusion
criteria are the same as those used in our previous systematic review (104), with a special attention to
studies reporting secondary and subgroup analyses.
633 Relevant citations were identified
and screened for retrieval
613 Articles were excluded on basis of title and/or
abstract review: not RCT, use of surrogate
endpoints, analyses, reviews, commentaries,
studies of biological mechanisms…
20 Articles were retrieved for more
detailed evaluation
17 Studies were excluded based on not fulfilling
inclusion criteria: not double-blinded, open RCT,
secondary analysis, diabetics included as
nonrandomized subgroups
3 RCTs in diabetics testing a statin
(vs placebo) fulfilled criteria: 4D,
ASPEN and CARDS
One study (CARDS) was excluded because of
premature interruption without pertinent
justification and possible bias in the data set
Two well-conducted RCTs in
diabetics were selected: ASPEN
and 4D
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 81
In brief, 4D is a RCT testing atorvastatin
against placebo (median follow-up 4 years)
in 1,255 diabetics receiving maintenance
hemodialysis (77). There was no significant
difference between the two groups for the
primary endpoint (relative risk 0.92) and
for total mortality (relative risk 0.93). The
risk of fatal stroke was significantly
increased among patients receiving
atorvastatin (relative risk 2.03).
The only possible conclusion of 4D should
have been that the statin did not protect
diabetics (77). The investigators actually
concluded that initiation of statin therapy
in patients with diabetes who already have
end-stage renal disease may come too late
to translate into consistent improvement of
the cardiovascular outcome” (77).
Curiously, in a subsequent substudy of 4D
however reanalyzing the data set and
making an a posteriori subgroup analysis,
thereby drastically increasing a chance
effect they claimed that in patients with
type 2 diabetes mellitus undergoing
hemodialysis, atorvastatin significantly
reduces the risk of fatal and nonfatal
cardiac events and death from any cause if
pre-treatment LDL-cholesterol is >145
mg/dl (125). This is simply not
scientifically acceptable and, once again,
shows that subgroup and secondary
analyses contradicting the results of the
tested primary hypothesis should not be
retained.
The failure of 4D to show a protective effect
of atorvastatin in diabetics receiving
maintenance hemodialysis is supported by
the results of another RCT in patients with
hemodialysis, the AURORA trial (54)
discussed above, in which rosuvastatin
also failed to protect against cardiovascular
complications.
Nonetheless, the comment made by the 4D
investigators in their first original report
(77) lack of benefit because of too late
initiation of treatment might be relevant.
It has been examined in ASPEN, an RCT
where diabetics with severe renal
dysfunction were excluded (123).
The ASPEN trial investigated the
cardiovascular effects of atorvastatin in
diabetics, with or without documented
coronary heart disease (CHD) (123). The
trial was originally designed as a secondary
prevention trial but updates in treatment
guidelines for individuals with CHD
impaired recruitment. The protocol was
therefore amended to enroll subjects
without prior CHD (123).
Following the new statistical calculations,
the trial was powered to detect differences
between the statin and the placebo groups
but not to detect differences in the primary
or secondary prevention subgroups alone
(104). Subjects were followed up during 4
years.
There was no significant difference between
groups for the primary endpoint (166 and
180 events for the atorvastatin and the
placebo group, respectively), for
cardiovascular mortality (38 and 37 deaths),
and overall mortality (70 and 68 deaths).
Thus, the results of ASPEN were similar to
those of 4D but in the absence of severe
renal dysfunction. The extension of criteria
for enrollment was likely not an important
cause of bias because the statistical
protocol was amended accordingly.
The two trials complement each other: in
4D (diabetics with severe renal
dysfunction), patients were at very high
risk, while in ASPEN patients were at
rather low risk. In both RCTs, we see no
effect of cholesterol-lowering with
atorvastatin.
In CARDS, the third RCT testing
atorvastatin against placebo, 2,838
diabetic patients were included (122). In
contrast to ASPEN and 4D, significant
reduction of a composite primary endpoint
was reported (relative risk 0.63). However,
the numbers of primary endpoints in
CARDS were small (83 and 127 in the
statin and placebo group), despite the fact
that the investigators used a composite
primary endpoint mixing hard and soft
(such as revascularization) events. This
criticized strategy considerably increases
the probability of a chance effect (42).
Indeed, there was no statistically
significant difference for all-cause mortality
and coronary mortality in CARDS.
In this context, the decision of early
termination 2 years before the anticipated
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 82
end without a clear explanation was
unjustified. Also, the clinical
inconsistencies seen in CARDS suggest
that the validation and classification of the
endpoints were questionable. And finally
because, as written by the investigators,
site monitoring, data collection, and data
entry was done by sponsor’s staff (122)
the possibility of outcome misreporting in
CARDS must be considered. Clearly, it was
ethically and scientifically indicated to
continue the trial to definitely clarify the
effect on cardiac and total mortality.
The CARDS trial has to be suspected of
being biased until confirmed by other
trials. No such confirmation has occurred.
On the contrary, both 4D and ASPEN failed
to report any benefit (not even a trend
toward benefit) of atorvastatin in diabetics
(77, 123).
Taken together, the three RCTs testing a
statin in diabetics as a primary hypothesis
failed to show any benefit.
Summary of the statin-diabetes issue
Despite the absence of evidence, why do the
“official” recommendations still state that
most diabetics (if not all) should be treated
with cholesterol-lowering drug (126, 127)?
One explanation is that these
recommendations are usually based on
meta-analyses that are supposed to
objectively synthetize the whole scientific
knowledge about the issue. In fact, even
meta-analyses examining whether statins
may protect diabetics do not all show the
same results. For instance, Chang et al.
(105) concluded in 2013 that no significant
benefit of statin is found in primary (p =
0.24) as well as in secondary (p = 0.26)
prevention of cardiovascular complications in
diabetics whereas Collins, his Oxford CTSU
colleagues, and the CTT’s Collaborators
concluded that statins reduce the risk of AMI
in diabetics, even stating that statin should
be considered for all diabetics (124).
How can we explain such discordant
conclusions?
The CTT meta-analysis pooled in 2008 the
data from 14 statin RCTs but none of the
statin RCTs published after 2005 was
included thereby curiously excluding 4D
(77) and ASPEN (123). Moreover, among
the 14 included RCTs, only one CARDS
(122) for which we have exposed the major
methodological problems prospectively
randomized diabetic patients and thus
actually tested the effect of a statin in
diabetics as a primary hypothesis.
Data from the other 13 trials were from
nonrandomized subgroups of diabetics
representing between 1% and 35% of the
total of the patients enrolled in each trial
(124) and therefore open to major bias.
Even more surprisingly, 4D and ASPEN
although not included in the main analysis
were mentioned at the end of the
discussion section of the CTT report, the
authors writing that their conclusions are
not materially affected by the results of
ASPEN and 4D trials” (124).
On the contrary, true science imposes to only
consider statin RCTs where diabetics were
prospectively randomized namely CARDS,
4D, and ASPEN as Chang et al. (105) did,
rather than partial retrospective data from
nonrandomized subgroups of diabetics. The
CTT meta-analysis is therefore flawed by a
major selection bias (124).
Limitations of this analysis
The main limitation of the present study is
that we do not have free access to the raw
data of the many RCTs we are discussing.
The lack of transparency of commercial
RCTs i.e., the impossibility of verifying
the way the clinical data are collected, the
data sets are constituted, cleaned and
digitized, and the way statistical analyses
are conducted definitively limits our
ability to evaluate the accuracy of the
published data.
Even if we can suspect the existence of
problems in some RCTs JUPITER, HPS,
MIRACL, and many others not mentioned
in the present article raw data remain in
the darkness. This is a major problem for
medical doctors who must make a decision
(prescription or not) every day.
So despite advances in clinical research and
RCT transparency, there are still scientists
and regulators the EMA for instance (29)
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 83
saying that the present regulations are not
sufficient and should be reinforced (30).
Obviously, full access to raw RCT data (still
not possible) would allow independent
researchers to examine the risks and benefits
of medical drugs and thereby counterbalance
the industry’s power to assess its own
products in the “industry-sponsored” RCTs.
Clearly, legitimate interests in the
protection of private (industry) investments
must be weighed against other legitimate
interests, such as the benefit and the
protection of patients. The right balance
between these interests is an obvious duty
for all stakeholders involved, including
regulators. And truly, when industry
investments have been paid back, years
after publication of RCTs that justified the
marketing of a new medicine, there is no
reason remaining not to give free access to
RCT raw data unless, of course, there are
things that are not to be shown.
Conclusions
A careful examination of the most recent
statin RCTs (Table 2), followed by
comparing statins to each other, clearly
shows that contrary to what has been
claimed for decades, statins do not have a
significant effect in primary and secondary
prevention of cardiovascular disease. One of
the major lessons of the rosuvastatin RCTs
was to confirm that only RCTs testing
clearly defined primary hypotheses and
only a primary hypothesis (38, 50) can
provide a reliable evaluation of the efficacy
of any medical drug. As a consequence, the
well-spread theory, based on ancient RCTs,
that statins are unambiguously protective in
secondary prevention should be discussed
in the light of more robust data provided by
more recent and more credible RCTs.
Regarding the statin-diabetes issue, for
instance, the only possible interpretation
based on robust data is that statins do not
protect the diabetics, while there is no
question about their diabetogenic effect. It is
high time to re-assess the whole statins-
diabetes issue. In our opinion built on
evidence-based medicine and in
contradiction with official recommendations,
medical doctors should not prescribe statins
in diabetics and in patients with metabolic
syndromes.
As for statin safety, we are facing a major
problem after the official admission that we
lack the data (5). For medical doctors, this
is unacceptable as their prescriptions must
be based on a right evaluation of the
benefit/harm balance of any medical drug.
We must enter a new era of full access to
raw data from industry-sponsored RCTs
(20, 21). This is the only way to allow
transparency and to restore the credibility
of clinical research. It is time to require the
implementation of completely reliable
methods to conduct medical trials so as to
restore mutual confidence between all
participants in the patient’s care (22-24).
The 2005/2006 New Regulations definitely
represented a step in the right direction (46-
50), but it nevertheless remains that
investigators and industrials can still succeed
in finding a way around them. Indeed, since
2006, the media in various countries report
problems every week between the
pharmaceutical industry (and the experts
working with it) and the law courts (25-28).
This has led to the dogmas about statin
efficacy and safety, based on unrealistic
clinical reports and flawed meta-analyses,
resulting in biased recommendations about
statin use (16, 17, 126, 127) and ultimately
extravagant situations and claims (128, 129).
The obvious final conclusion for physicians
is that the present claims about the
efficacy and safety of statins are not
evidence-based.
Competing interests
None of the authors have any financial
links with the pharmaceutical industry;
Michel de Lorgeril discloses receiving
research grants (through the Grenoble
University School of Medicine) from the
European Community and from the Barilla
Inc.
References
1. Jefferson T, Jones MA, Doshi P, Del Mar
CB, Hama R, Thompson MJ, et al.
Neuraminidase inhibitors for preventing
and treating influenza in healthy adults
and children. Cochrane Database Syst Rev.
2014;4:CD008965.
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 84
http://dx.doi.org/10.1002/14651858.CD0
08965.pub4
2. Jefferson T, Doshi P. Multisystem
failure: the story of anti-influenza drugs.
BMJ. 2014;348:g2263.
3. Loder E, Tovey D, Godlee F. The Tamiflu
trials. BMJ. 2014;348:g2630.
4. Seife C. Is drug research trustworthy?
The pharmaceutical industry funnels
money to prominent scientists who are
doing research that affects its products
and nobody can stop it. Sci Am.
2012;307:56-63.
5. Statins expert calls for safety checks
over the drug.
http://www.express.co.uk/news/uk/5582
49/statins-expert-heart-drug-rory-collins
6. Collins R. “Not for publication” Letter
addressed to the BMJ Editors.
http://journals.bmj.com/site/bmj/statins
/SP17%20Letter%201%20from%20Rory%2
0Collins%20to%20FG%20dated%2031%20
March%20Not%20for%20Publication.pdf
7. Abramson JD, Rosenberg HG, Jewell N,
Wright JM. Should people at low risk of
cardiovascular disease take a statin? BMJ.
2013;347:f6123.
8. Sever P. The BMJ statins papers
misrepresent the facts. BMJ.
2014;348:g4030.
9. Godlee F. Adverse effects of statins.
BMJ. 2014;348:g3306.
10. Fahey T, Smith S. Retraction of statins
article is not in the public interest: better
characterisation of benefits and risks is
crucial. BMJ. 2014;348:g4028.
11. Goldacre B, Godlee F, Heneghan C,
Tovey D, Lehman R, Chalmers I, et al.
Open letter: European Medicines Agency
should remove barriers to access clinical
trial data. BMJ. 2014;348:g3768.
12. Armitage J. The safety of statins in
clinical practice. Lancet. 2007;370:
1781-90.
http://dx.doi.org/10.1016/S0140-
6736(07)60716-8.
13. Armitage J, Baigent C, Collins R.
Misrepresentation of statin safety evidence.
Lancet. 2014;384:1263-4.
http://dx.doi.org/10.1016/S0140-
6736(14)61765-7.
14. Collins R. Lack of adverse effect of
statin therapy on common muscle-related
adverse events. Eur J Prev Cardiol.
2015;22:1066.
http://dx.doi.org/10.1177/204748731454
1732
15. Cholesterol Treatment Trialists’ (CTT)
Collaborators, Mihaylova B, Emberson J,
Blackwell L, Keech A, Simes J, et al. The
effects of lowering LDL cholesterol with
statin therapy in people at low risk of
vascular disease: meta-analysis of
individual data from 27 randomised trials.
Lancet. 2012;380:581-90.
16. Stone NJ, Robinson JG, Lichtenstein AH,
Bairey Merz CN, Blum CB, Eckel RH, et al.;
American College of Cardiology/American
Heart Association Task Force on Practice
Guidelines. 2013 ACC/AHA guideline on the
treatment of blood cholesterol to reduce
atherosclerotic cardiovascular risk in adults:
a report of the American College of
Cardiology/American Heart Association Task
Force on Practice Guidelines. J Am Coll
Cardiol. 2014;63:2889-934.
http://dx.doi.org/10.1016/j.jacc.2013.11.
002.
17. National Institute for Health and Care
Excellence: NICE clinical guideline no. 181.
Lipid modification: cardiovascular risk
assessment and the modification of blood
lipids for the primary and secondary
prevention of cardiovascular disease. July
2014.
http://www.nice.org.uk/guidance/cg181/r
esources/guidance-lipid-modification-
cardiovascular-risk-assessment-and-the-
modification-of-blood-lipids-for-the-
primary-and-secondary-prevention-of-
cardiovascular-disease-pdf.
Accessed November 10, 2015.
18. Godlee F. Statins and The BMJ. BMJ.
2014;349:g5038.
19. Diamond DM, Ravnskov U. How
statistical deception created the appearance
that statins are safe and effective in primary
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 85
and secondary prevention of cardiovascular
disease. Expert Rev Clin Pharmacol.
2015;8:201-10.
http://dx.doi.org/10.1586/17512433.201
5.1012494
20. Doshi P, Goodman SN, Ioannidis JP.
Raw data from clinical trials: within reach?
Trends Pharmacol Sci. 2013;34:645-7.
http://dx.doi.org/10.1016/j.tips.2013.10.006
21. Strom BL, Buyse M, Hughes J,
Knoppers BM. Data sharing, year 1 - access
to data from industry-sponsored clinical
trials. N Engl J Med. 2014;371:2052-4.
http://dx.doi.org/10.1056/NEJMp1411794
22. Abbasi K. The missing data that cost
$20bn. BMJ. 2014;348:g2695.
23. Protecting citizens’ health:
transparency of clinical trial data on
medicines in the EU. Available at:
http://haieurope.org/wp-
content/uploads/2013/10/HAI_Protecting-
citizenshealth-transparency-of-clinical-
trial-data-on-medicines-in-the-EU.pdf.
Accessed November 20, 2015.
24. Protecting citizens’ health. Available at:
http://english.prescrire.org/en/79/207/4
6302/2612/2506/SubReportDetails.aspx.
Accessed November 20, 2015.
25. Jefferson T, Jones MA, Doshi P.
Neuraminidase inhibitors for preventing
and treating influenza in healthy adults
and children. Cochrane Database Syst Rev.
2012;1:CD008965.
26. Heneghan CJ, Onakpoya I, Thompson
M, Spencer EA, Jones M, Jefferson T.
Zanamivir for influenza in adults and
children: systematic review of clinical study
reports and summary of regulatory
comments. BMJ. 2014;348:g2547.
27. Nisen P, Rockhold F. Access to patient-
level data from GlaxoSmithKline clinical
trials. N Engl J Med. 2013;369:475-8.
http://dx.doi.org/10.1056/NEJMsr1302541
28. Jain A, Nundy S, Abbasi K. Corruption:
medicine's dirty open secret. BMJ.
2014;348:g4184.
29. Eichler HG, Pétavy F, Pignatti F, Rasi
G. Access to patient-level trial data - a
boon to drug developers. N Engl J Med.
2013;369:1577157-9.
http://dx.doi.org/10.1056/NEJMp1310771
30. Rabesandratana T. Drug watchdog
ponders how to open clinical trial data
vault. Science. 2013;339:1369-1370.
http://dx.doi.org/10.1126/science.339.61
26.1369
31. McNutt M. Reproducibility. Science.
2014;343:229.
http://dx.doi.org/10.1126/science.1250475
32. Collins FS, Tabak LA. Policy: NIH plans
to enhance reproducibility. Nature.
2014;505:612-3.
33. Dwan K, Altman DG, Clarke M, Gamble
C, Higgins JP, Sterne JA, et al. Evidence
for the selective reporting of analyses and
discrepancies in clinical trials: a systematic
review of cohort studies of clinical trials.
PLoS Med. 2014;11:e1001666.
http://dx.doi.org/10.1371/journal.pmed.1
001666
34. Ebrahim S, Sohani ZN, Montoya L,
Agarwal A, Thorlund K, Mills EJ, et al.
Reanalyses of randomized clinical trial
data. JAMA. 2014;312:1024-32.
http://dx.doi.org/10.1001/jama.2014.9646
35. Landewé RB. How publication bias may
harm treatment guidelines. Arthritis
Rheumatol. 2014;66:2661-3.
http://dx.doi.org/10.1002/art.38783
36. Wieseler B, Wolfram N, McGauran N,
Kerekes MF, Vervölgyi V, Kohlepp P, et al.
Completeness of reporting of patient-
relevant clinical trial outcomes:
comparison of unpublished clinical study
reports with publicly available data. PLoS
Med. 2013;10:e1001526.
http://dx.doi.org/10.1371/journal.pmed.1
001526
37. Ioannidis JP. Why most published
research findings are false. PLoS Med.
2005;2:e124.
http://dx.doi.org/10.1371/journal.pmed.0
020124
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 86
38. Ioannidis JP. How to make more
published research true. PLoS Med.
2014;11:e1001747.
http://dx.doi.org/10.1371/journal.pmed.1
001747
39. Karha J, Topol EJ. The sad story of
Vioxx, and what we should learn from it.
Cleve Clin J Med. 2004;71:933-4, 936,
938-9.
40. Alpert JS. The Vioxx debacle. Am J
Med. 2005;118:203-4.
http://dx.doi.org/10.1016/j.amjmed.2005.
01.020
41. Landefeld CS, Steinman MA. The
Neurontin legacy - marketing through
misinformation and manipulation. N Engl J
Med. 2009;360:103-6.
http://dx.doi.org/10.1056/NEJMp0808659
42. Cordoba G, Schwartz L, Woloshin S,
Bae H, Goetzsche PC. Definition, reporting
and interpretation of composite outcomes
in clinical trials: systematic review. BMJ.
2010;341:c3920.
43. Nguyen PV. Electronic health records
may threaten blinding in trials of statins.
BMJ. 2014;349:g5239.
44. Blendon RJ, Benson JM, Hero JO.
Public trust in physicians - U.S. medicine
in international perspective. N Engl J Med.
2014;371:1570-72.
http://dx.doi.org/10.1056/NEJMp1407373
45. Duncan Moore J. U.S. Physician Leaders
Suffer Loss of Public Trust. Available at:
http://www.medpagetoday.com/PublicHeal
thPolicy/GeneralProfessionalIssues/48402.
Accessed November 30, 2015.
46. New Clinical Trial Regulation. Available
at:
http://ec.europa.eu/health/files/eudralex
/vol-1/dir_2005_28/dir_2005_28_en.pdf.
Accessed November 30, 2015.
47. Commission Directive 2005/28/EC of 8
April 2005 laying down principles and
detailed guidelines for good clinical practice
as regards investigational medicinal
products for human use, as well as the
requirements for authorization of the
manufacturing or importation of such
products. Official Journal of the European
Communities L91: 1319. Available at:
http://ec.europa.eu/enterprise/pharmaceu
ticals/eudralex/vol-
1/dir_2005_28/dir_2005_28_en.pdf.
Accessed November 30, 2014.
48. Bollapragada SS, Norrie JD, Norman
JE. Review of new regulations for the
conduct of clinical trials of investigational
medicinal products. BJOG. 2007;114:917-
21.
http://dx.doi.org/10.1111/j.1471-
0528.2007.01415.x.
49. Hartmann M. Impact assessment of the
European Clinical Trials Directive: a
longitudinal, prospective, observational
study analyzing patterns and trends in
clinical drug trial applications submitted
since 2001 to regulatory agencies in six EU
countries. Trials. 2012;13:53.
http://dx.doi.org/10.1186/1745-6215-13-
53
50. de Lorgeril M. Cholesterol and statins.
Sham science and bad medicine. Vergèze,
France: Thierry Souccar Publishing, 2014.
51. Ridker PM, Danielson E, Fonseca FA,
Genest J, Gotto AM Jr, Kastelein JJ, et al.;
for the JUPITER Study Group.
Rosuvastatin to prevent vascular events in
men and women with elevated C-reactive
protein. N Engl J Med. 2008;359:2195-
207.
http://dx.doi.org/10.1056/NEJMoa0807646
52. Kjekshus J, Apetrei E, Barrios V, Böhm
M, Cleland JG, Cornel JH, et al.; CORONA
Group. Rosuvastatin in older patients with
systolic heart failure. N Engl J Med.
2007;357:2248-61.
http://dx.doi.org/10.1056/NEJMoa0706201
53. Gissi-HF Investigators, Tavazzi L,
Maggioni AP, Marchioli R, Barlera S,
Franzosi MG, Latini R, et al. Effect of
rosuvastatin in patients with chronic heart
failure (the GISSI-HF trial): a randomised,
double-blind, placebo-controlled trial.
Lancet. 2008;372:1231-9.
54. Fellström BC, Jardine AG, Schmieder
RE, Holdaas H, Bannister K, Beutler J, et
al. for the AURORA Study Group.
Rosuvastatin and cardiovascular events in
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 87
patients undergoing hemodialysis. N Engl J
Med. 2009;360:1395-407.
http://dx.doi.org/10.1056/NEJMoa0810177
55. Baigent C, Keech A, Kearney PM,
Blackwell L, Buck G, Pollicino C, et al;
Cholesterol Treatment Trialists' (CTT)
Collaborators. Efficacy and safety of
cholesterol-lowering treatment: prospective
meta-analysis of data from 90,056
participants in 14 randomised trials of
statins. Lancet. 2005;366:1267-78.
http://dx.doi.org/10.1016/S0140-
6736(05)67394-1
56. Ray KK, Seshasai SR, Erqou S, Sever P,
Jukema JW, Ford I, et al. Statins and all-
cause mortality in high-risk primary
prevention: a meta-analysis of 11 randomized
controlled trials involving 65,229 participants.
Arch Intern Med. 2010;170:1024-31.
http://dx.doi.org/10.1001/archinternmed.
2010.182
57. Taylor F, Ward K, Moore TH, Burke M,
Davey Smith G, Casas JP, et al. Statins for
the primary prevention of cardiovascular
disease. Cochrane Database Syst Rev.
2011;1:CD004816.
58. Abramson JD, Rosenberg HG, Jewell N,
Wright JM. Should people at low risk of
cardiovascular disease take a statin? BMJ.
2013;347:f6123.
59. de Lorgeril M, Salen P, Abramson J,
Dodin S, Hamazaki T, Kostucki W, et al.
Cholesterol lowering, cardiovascular
disease, and the rosuvastatin-JUPITER
controversy: a critical reappraisal. Arch
Intern Med. 2010;170:1032-6.
http://dx.doi.org/10.1001/archinternmed.
2010.184
60. de Lorgeril M, Salen P, Defaye P,
Rabaeus M. Recent findings on the health
effects of omega-3 fatty acids and statins,
and their interactions: do statins inhibit
omega-3? BMC Med. 2013;11:5.
http://dx.doi.org/10.1186/1741-7015-11-5
61. de Lorgeril M. The JUPITER and statin
controversy. American Heart Association,
Los Angeles 2012. Available at:
http://michel.delorgeril.info/conferences/
diapositives-congres-de-l-aha-a-los-
angeles.
Accessed November 10, 2015.
62. Montori VM, Devereaux PJ, Adhikari NK,
Burns KE, Eggert CH, Briel M, et al.
Randomized trials stopped early for benefit: a
systematic review. JAMA. 2005;294:2203-9.
http://dx.doi.org/10.1001/jama.294.17.2203
63. Bassler D, Briel M, Montori VM, Lane
M, Glasziou P, Zhou Q, et al. Stopping
randomized trials early for benefit and
estimation of treatment effects: systematic
review and meta-regression analysis.
JAMA. 2010;303:1180-7.
http://dx.doi.org/10.1001/jama.2010.310
64. Ridker PM, Pradhan A, MacFadyen JG,
Libby P, Glynn RJ. Cardiovascular benefits
and diabetes risks of statin therapy in
primary prevention: an analysis from the
JUPITER trial. Lancet. 2012;380:565-71.
http://dx.doi.org/10.1016/S0140-
6736(12)61190-8
65. Halimi S. Do not forget that type 2
diabetes does not only expose to
cardiovascular complications. Diabetes
Metab. 2014;40:167-8.
http://dx.doi.org/10.1016/j.diabet.2014.0
3.005
66. Cowey S, Hardy RW. The metabolic
syndrome: a high-risk state for cancer? Am
J Pathol. 2006;169:1505-22.
http://dx.doi.org/10.2353/ajpath.2006.05
1090
67. Sieri S, Muti P, Claudia A, Berrino F,
Berrino F, Pala V, Grioni S, et al.
Prospective study on the role of glucose
metabolism in breast cancer occurrence.
Int J Cancer. 2012;130:921-9.
http://dx.doi.org/10.1002/ijc.26071
68. Bordier L, Doucet J, Boudet J,
Bauduceau B. Update on cognitive decline
and dementia in elderly patients with
diabetes. Diabetes Metab. 2014;40:331-7.
http://dx.doi.org/10.1016/j.diabet.2014.0
2.002
69. Carnevale V, Romagnoli E, D'Erasmo L,
D'Erasmo E. Bone damage in type 2
diabetes mellitus. Nutr Metab Cardiovasc
Dis. 2014;27:1151-7.
http://dx.doi.org/10.1016/j.numecd.2014.
06.013
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 88
70. Pan A, Lucas M, Sun Q, van Dam RM,
Franco OH, Manson JE, et al: Bidirectional
association between depression and type 2
diabetes mellitus in women. Arch Intern
Med. 2010;170:1884-91.
http://dx.doi.org/10.1001/archinternmed.
2010.356
71. Horwich TB, MacLellan WR, Fonarow
GC. Statin therapy is associated with
improved survival in ischemic and non-
ischemic heart failure. J Am Coll Cardiol.
2004;43:642-8.
http://dx.doi.org/10.1016/j.jacc.2003.07.
049
72. Mozaffarian D, Nye R, Levy WC. Statin
therapy is associated with lower mortality
among patients with severe heart failure.
Am J Cardiol. 2004;93:1124-9.
http://dx.doi.org/10.1016/j.amjcard.2004.
01.039
73. Go AS, Lee WY, Yang J, Lo JC, Gurwitz
JH. Statin therapy and risks for death and
hospitalization in chronic heart failure.
JAMA. 2006;296:2105-11.
http://dx.doi.org/10.1001/jama.296.17.21
05
74. Scandinavian Simvastatin Survival
Study Group. Randomised trial of
cholesterol lowering in 4444 patients with
coronary heart disease: the Scandinavian
Simvastatin Survival Study (4S). Lancet.
1994;344:1383-9.
75. Orn S, Cleland JG, Romo M, Kjekshus
J, Dickstein K. Recurrent infarction causes
the most deaths following myocardial
infarction with left ventricular dysfunction.
Am J Med. 2005;118:752-8.
http://dx.doi.org/10.1016/j.amjmed.2005.
02.010
76. Strippoli GF, Navaneethan SD, Johnson
DW, Perkovic V, Pellegrini F, Nicolucci A, et
al. Effects of statins in patients with chronic
kidney disease: meta-analysis and meta-
regression of randomised controlled trials.
BMJ. 2008;336:645-51.
http://dx.doi.org/10.1136/bmj.39472.580
984.AE
77. Wanner C, Krane V, März W, Olschewski
M, Mann JF, Ruf G, et al.; for the German
Diabetes and Dialysis Study Investigators.
Atorvastatin in patients with type 2 diabetes
mellitus undergoing hemodialysis. N Engl J
Med. 2005;353:238-48.
http://dx.doi.org/10.1056/NEJMoa043545
78. Hou W, Lv J, Perkovic V, Yang L, Zhao
N, Jardine MJ, et al. Effect of statin
therapy on cardiovascular and renal
outcomes in patients with chronic kidney
disease: a systematic review and meta-
analysis. Eur Heart J. 2013;34:1807-17.
http://dx.doi.org/10.1093/eurheartj/eht0
65
79. Palmer SC, Craig JC, Navaneethan SD,
Tonelli M, Pellegrini F, Strippoli GF.
Benefits and harms of statin therapy for
persons with chronic kidney disease: a
systematic review and meta-analysis. Ann
Intern Med. 2012;157:263-75.
http://dx.doi.org/10.7326/0003-4819-
157-4-201208210-00007
80. Baigent C, Landray MJ, Reith C,
Emberson J, Wheeler DC, Tomson C, et al.;
SHARP Investigators. The effects of
lowering LDL cholesterol with simvastatin
plus ezetimibe in patients with chronic
kidney disease (Study of Heart and Renal
Protection): a randomised placebo-
controlled trial. Lancet. 2011;377:2181-92.
http://dx.doi.org/10.1016/S0140-
6736(11)60739-3
81. Trial-Results Center. SHARP trial,
description and results. Available at:
http://www.trialresultscenter.org/study80
81-SHARP.htm.
Accessed November 15, 2015.
82. Nicholls SJ, Ballantyne CM, Barter PJ,
Chapman MJ, Erbel RM, Libby P, et al.
Effect of two intensive statin regimens on
progression of coronary disease. N Engl J
Med. 2011;365:2078-87.
http://dx.doi.org/10.1056/NEJMoa11108
74
83. Schwartz GG1, Olsson AG, Ezekowitz
MD, Ganz P, Oliver MF, Waters D, et al.;
for the Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering (MIRACL)
Study Investigators: Effects of atorvastatin
on early recurrent ischemic events in acute
coronary syndromes: the MIRACL study: a
randomized controlled trial. JAMA.
2001;285:1711-8.
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 89
84. Waters D, Schwartz GG, Olsson AG.
The Myocardial Ischemia Reduction with
Acute Cholesterol Lowering (MIRACL) trial:
a new frontier for statins? Curr Control
Trials Cardiovasc Med. 2001;2:111-4.
85. National Clinical Guideline Centre (UK).
Lipid Modification: Cardiovascular Risk
Assessment and the Modification of Blood
Lipids for the Primary and Secondary
Prevention of Cardiovascular Disease.
London: National Institute for Health and
Care Excellence (UK), 2014.
86. Briel M, Schwartz GG, Thompson PL,
de Lemos JA, Blazing MA, van Es GA, et al.
Effects of early treatment with statins on
short-term clinical outcomes in acute
coronary syndromes: a meta-analysis of
randomized controlled trials. JAMA.
2006;295:2046-56.
http://dx.doi.org/10.1001/jama.295.17.20
46
87. Vale N, Nordmann AJ, Schwartz GG, de
Lemos J, Colivicchi F, den Hartog F, et al.
Statins for acute coronary syndrome.
Cochrane Database Syst Rev.
2014;9:CD006870.
88. Heart Protection Study Collaborative
Group. MRC/BHF Heart Protection Study of
cholesterol lowering with simvastatin in
20,536 high-risk individuals: a randomised
placebo-controlled trial. Lancet. 2002;360:
7-22.
89. Pedersen TR, Faergeman O, Kastelein
JJ, Olsson AG, Tikkanen MJ, Holme I, et
al.; for the Incremental Decrease in End
Points Through Aggressive Lipid Lowering
(IDEAL) Study Group: High-dose
atorvastatin vs usual-dose simvastatin for
secondary prevention after myocardial
infarction: the IDEAL study: a randomized
controlled trial. JAMA. 2005;294:2437-45.
http://dx.doi.org/10.1001/jama.294.19.24
37
90. Cholesterol Treatment Trialists’ (CTT)
Collaboration, Baigent C, Blackwell L,
Emberson J, Holland LE, Reith C, Bhala N,
et al. Efficacy and safety of more intensive
lowering of LDL cholesterol: a meta-
analysis of data from 170,000 participants
in 26 randomized trials. Lancet.
2010;376:1670-81.
91. Study of the Effectiveness of Additional
Reductions in Cholesterol and
Homocysteine (SEARCH) Collaborative
Group, Armitage J, Bowman L,
Wallendszus K, Bulbulia R, Rahimi K,
Haynes R, et al. Intensive lowering of LDL
cholesterol with 80 mg versus 20 mg
simvastatin daily in 12,064 survivors of
myocardial infarction: a double-blind
randomised trial. Lancet. 2010;376:1658-
69 Erratum in: Lancet. 2011;377:126.
92. Cannon CP, Braunwald E, McCabe CH,
Rader DJ, Rouleau JL, Belder R, et al.; for
the Pravastatin or Atorvastatin Evaluation
and Infection Therapy-Thrombolysis in
Myocardial Infarction 22 Investigators:
intensive versus moderate lipid lowering
with statins after acute coronary
syndromes. N Engl J Med. 2004;350:1495-
504. Erratum in: N Engl J Med.
2006;354:778.
93. Cannon CP, Braunwald E, McCabe CH,
Grayston JT, Muhlestein B, Giugliano RP,
et al.; for the Pravastatin or Atorvastatin
Evaluation and Infection Therapy-
Thrombolysis in Myocardial Infarction 22
Investigators. Antibiotic treatment of
Chlamydia pneumoniae after acute
coronary syndrome. N Engl J Med.
2005;352:1646-54.
http://dx.doi.org/10.1056/NEJMoa043528
94. Neumann A, Maura G, Weill A,
Ricordeau P, Alla F, Allemand H.
Comparative effectiveness of rosuvastatin
versus simvastatin in primary prevention
among new users: a cohort study in the
French national health insurance
database. Pharmacoepidemiol Drug Saf.
2014;23:240-245.
http://dx.doi.org/10.1002/pds.3544
95. Glynn RJ, Danielson E, Fonseca FA,
Genest J, Gotto AM Jr, Kastelein JJ, et al.
A randomized trial of rosuvastatin in the
prevention of venous thromboembolism. N
Engl J Med. 2009;360:1851-61.
http://dx.doi.org/10.1056/NEJMoa09002
41
96. Rahimi K, Bhala N, Kamphuisen P,
Emberson J, Biere-Rafi S, Krane V, et al:
Effect of statins on venous thromboembolic
events: a meta-analysis of published and
unpublished evidence from randomised
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 90
controlled trials. PLoS Med.
2012;9:e1001310.
http://dx.doi.org/10.1371/journal.pmed.1
001310
97. FDA announces safety changes in
labeling for some cholesterol-lowering
drugs. Available at:
http://www.fda.gov/NewsEvents/Newsr
oom/PressAnnouncements/ucm293623.
htm.
Accessed October 10, 2015.
98. Saini P, Loke YK, Gamble C, Altman
DG, Williamson PR, Kirkham JJ. Selective
reporting bias of harm outcomes within
studies: findings from a cohort of
systematic reviews. BMJ. 2014;349:g6501.
99. Bero LA. Why the Cochrane risk of bias
tool should include funding source as a
standard item. Cochrane Database of
System Rev. 2013;12:ED000075.
100. Muscogiuri G, Sarno G, Gastaldelli A,
Savastano S, Ascione A, Colao A, et al. The
good and bad effects of statins on insulin
sensitivity and secretion. Endocr Res.
2014;39:137-43.
http://dx.doi.org/10.3109/07435800.201
4.952018
101. Jukema JW, Cannon CP, de Craen
AJ, Westendorp RG, Trompet S. The
controversies of statin therapy: weighing
the evidence. J Am Coll Cardiol.
2012;60:875-81.
http://dx.doi.org/10.1016/j.jacc.2012.07.
007
102. Sattar N, Preiss D, Murray HM, Welsh
P, Buckley BM, de Craen AJ, et al. Statins
and risk of incident diabetes: a
collaborative meta-analysis of randomised
statin trials. Lancet. 2010;375:735-42.
http://dx.doi.org/10.1016/S0140-
6736(09)61965-6
103. Ridker PM, Pradhan A, MacFadyen
JG, Libby P, Glynn RJ. Cardiovascular
benefits and diabetes risks of statin
therapy in primary prevention: an analysis
from the JUPITER trial. Lancet.
2012;380:565-71.
http://dx.doi.org/10.1016/S0140-
6736(12)61190-8
104. de Lorgeril M, Hamazaki T, Kostucki
W, Okuyama H, Pavy B, McGill AT, et al. Is
the use of cholesterol-lowering drugs for
the prevention of cardiovascular
complications in type 2 diabetics evidence-
based? A systematic review. Rev Recent
Clin Trials. 2012;7:150-7.
105. Chang YH, Hsieh MC, Wang CY, Lin
KC, Lee YJ. Reassessing the benefits of
statins in the prevention of cardiovascular
disease in diabetic patients - a systematic
review and meta-analysis. Rev Diabet Stud.
2013;10:157-70.
http://dx.doi.org/10.1900/RDS.2013.10.157
106. Hung SH, Lin HC, Chung SD. Statin
use and thyroid cancer: a population-based
case-control study. Clin Endocrinol (Oxf).
2015;83:111116.
http://dx.doi.org/10.1111/cen.12570
107. Vinogradova Y, Coupland C, Hippisley-
Cox J. Exposure to statins and risk of
common cancers: a series of nested case-
control studies. BMC Cancer. 2011;11:409.
http://dx.doi.org/10.1186/1471-2407-11-
409
108. de Lorgeril M, Salen P. Do statins
increase and Mediterranean diet decrease
the risk of breast cancer? BMC Med.
2014;12:94.
http://dx.doi.org/10.1186/1741-7015-12-94
109. Hoffman KB, Kraus C, Dimbil M,
Golomb BA. A survey of the FDA's AERS
database regarding muscle and tendon
adverse events linked to the statin drug
class. PLoS One. 2012;7:e42866.
http://dx.doi.org/10.1371/journal.pone.0
042866
110. Golomb BA, Evans MA, Dimsdale JE,
White HL. Effects of statins on energy and
fatigue with exertion: results from a
randomized controlled trial. Arch Intern
Med. 2012;172:1180-2.
http://dx.doi.org/10.1001/archinternmed.
2012.2171
111. Cham S, Evans MA, Denenberg JO,
Golomb BA. Statin-associated muscle-related
adverse effects: a case series of 354 patients.
Pharmacotherapy. 2010;30:541-53.
http://dx.doi.org/10.1592/phco.30.6.541
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 91
112. Ravnskov U, McCully KS, Rosch PJ.
The statin - low cholesterol - cancer
conundrum. QJM. 2012;105:383-8.
http://dx.doi.org/10.1093/qjmed/hcr243
113. You H, Lu W, Zhao S, Hu Z, Zhang J.
The relationship between statins and
depression: a review of the literature.
Expert Opin Pharmacother. 2013;14:
1467-76.
http://dx.doi.org/10.1517/14656566.201
3.803067
114. Gøtzsche PC. Muscular adverse effects
are common with statins. BMJ.
2014;348:g3724.
115. Redberg RF, Katz MH. Reassessing
benefits and risks of statins. N Engl J Med.
2012;367:776.
http://dx.doi.org/10.1056/NEJMc120707
9#SA1
116. Abramson JD, Rosenberg HG, Jewell
N, Wright JM. Should people at low risk of
cardiovascular disease take a statin? BMJ.
2013;347:f6123.
117. Sun GH: Statins: The Good, the Bad,
and the Unknown. Available at:
http://www.medscape.com/viewarticle/8
32841?src=wnl_int_edit_tp10&uac=78143
HG.
Accessed December 1, 2015.
118. Culver AL, Ockene IS,
Balasubramanian R, Olendzki BC,
Sepavich DM, Wactawski-Wende J, et al.
Statin use and risk of diabetes mellitus in
postmenopausal women in the Women's
Health Initiative. Arch Intern Med.
2012;172:144-52.
http://dx.doi.org/10.1001/archinternmed.
2011.625
119. Corrao G, Ibrahim B, Nicotra F,
Soranna D, Merlino L, Catapano AL, et al:
Statins and the risk of diabetes: evidence
from a large population-based cohort
study. Diabetes Care. 2014;37:2225-32.
http://dx.doi.org/10.2337/dc13-2215
120. Zaharan NL, Williams D, Bennett K.
Statins and risk of treated incident
diabetes in a primary care population. Br J
Clin Pharmacol. 2013;75:1118-24.
http://dx.doi.org/10.1111/j.1365-
2125.2012.04403.x
121. Cederberg H, Stančáková A, Yaluri N,
Modi S, Kuusisto J, Laakso M. Increased
risk of diabetes with statin treatment is
associated with impaired insulin sensitivity
and insulin secretion: a 6 year follow-up
study of the METSIM cohort. Diabetologia.
2015;58:1109-1117.
122. Colhoun HM, Betteridge DJ,
Durrington PN, Hitman GA, Neil HA,
Livingstone SJ, et al.; for the CARDS
Investigators. Primary prevention of
cardiovascular disease with atorvastatin in
type 2 diabetes in the Collaborative
Atorvastatin Diabetes Study (CARDS): a
multicentre randomised placebo-controlled
trial. Lancet. 2004;364:685-96.
http://dx.doi.org/10.1016/S0140-
6736(04)16895-5
123. Knopp RH, d'Emden M, Smilde JG,
Pocock SJ. Efficacy and safety of
atorvastatin in the prevention of
cardiovascular end points in subjects with
type 2 diabetes: the Atorvastatin Study for
Prevention of Coronary Heart Disease
Endpoints in non-insulin-dependent
diabetes mellitus (ASPEN). Diabetes Care.
2006;29:1478-85.
http://dx.doi.org/10.2337/dc05-2415
124. Kearney PM, Blackwell L, Collins R,
Keech A, Simes J, Peto R, et al., for the
Cholesterol Treatment Trialists' (CTT)
Collaborators. Efficacy of cholesterol-
lowering therapy in 18,686 people with
diabetes in 14 randomised trials of statins:
a meta-analysis. Lancet. 2008;371:117-
125.
125. März W, Genser B, Drechsler C, Krane
V, Grammer TB, Ritz E, et al.; German
Diabetes and Dialysis Study Investigators:
Atorvastatin and low-density lipoprotein
cholesterol in type 2 diabetes mellitus
patients on hemodialysis. Clin J Am Soc
Nephrol. 2011;6:1316-25.
http://dx.doi.org/10.2215/CJN.09121010
126. American Diabetes Association.
Standards of medical care in diabetes
2011. Diabetes Care. 2011;34 (Suppl
1):S11-61.
de Lorgeril and Rabaeus Efficacy and safety of cholesterol-lowering with statins
Journal of Controversies in Biomedical Research 2015; 1(1):67-92. 92
127. American Heart Association.
Cardiovascular disease and diabetes:
Available:
http://www.heart.org/HEARTORG/
Conditions/Diabetes/WhyDiabetes
Matters/Cardiovascular-Disease-
Diabetes_UCM_313865_Article.
jsp.
Accessed November 12, 2015.
128. Gøtzsche PC. Big pharma often
commits corporate crime, and this must be
stopped. BMJ. 2012;345:e8462.
129. Ioannidis JP. More than a billion
people taking statins? Potential
implications of the new cardiovascular
guidelines. JAMA. 2014;311:463-4.
http://dx.doi.org/10.1001/jama.2013.284657
... Indeed, as shown in previous reports (1,2), statins are likely not effective for cardiovascular-disease prevention and for prolonging life. One should note that the studies published before 2005/2006 (and the Vioxx tragedy) were probably flawed, and this concerned in particular the efficacy issue (1,2). ...
... Indeed, as shown in previous reports (1,2), statins are likely not effective for cardiovascular-disease prevention and for prolonging life. One should note that the studies published before 2005/2006 (and the Vioxx tragedy) were probably flawed, and this concerned in particular the efficacy issue (1,2). This is supported by the fact that it is quite common to notice serious discrepancies in analyses done by industry-sponsored authors and independent authors (3)(4)(5)(6)(7)(8). ...
... In particular, whether statins improve survival in randomized clinical trials (RCTs) is a critical issue as mortality remains the major endpoint to be considered in RCTs testing any cardiovascular medication. The way the commercial RCTs are conducted and the ways the clinical endpoints are recorded, validated, and analyzed are open to major biases (1,2). In the absence of open access to the raw data for independent scientists, it is clear that the mortality endpoint should be the main criterion to test efficacy. ...
Article
Full-text available
There is an ongoing intense controversy around cholesterol lowering using statins, questioning the reality of the benefits and the safety of this treatment. Going even further, this has led to a growing questioning of the robustness of the well-established cholesterol-heart theory, stating that high cholesterol levels ineluctably and strongly increase the risk of coronary artery obstruction and acute myocardial infarction. In the same way, many scientists no longer agree with the theory that high cholesterol increases the risk of ischemic stroke. To test the cholesterol-heart theory, the present systematic review aimed at examining whether the most recent clinical trials testing powerful cholesterol-lowering interventions (such as anti-CETP and anti-PCSK9) report effective reduction of fatal cardiovascular complications and improved survival. Because of high heterogeneity between studies, a meta-analysis was not feasible. The review did show that neither anti-CETP nor anti-PCSK9 treatment can significantly reduce the risk of cardiovascular death, thereby giving credit to the questioning of the cholesterol-heart theory. Our review also shows that the quality of the included trials is generally poor with suspicion of inefficient blinding. This undermines the validity of the reported nonfatal events and thereby increases the importance of comparing fatal endpoints in both groups to test the cholesterol-heart theory.
... In 2004-2005 health authorities in Europe and the US introduced New Clinical Trial Regulations, which specified that all trial data had to be made public. Since 2005, claims of benefit from statin trials have virtually disappeared [72]; see figures 4 and 5. ...
... For decades, a decrease of CVD mortality has been observed in many countries, and the presumed reason for the decrease is the increasing use of statin treatment. However, this interpretation is highly questionable [72]. In a Swedish study including 289 of the 290 municipalities, no association was found between statin use and the change in mortality from acute myocardial infarction (AMI) [102]. ...
Article
Full-text available
Introduction For half a century, a high level of total cholesterol (TC) or low-density-lipoprotein cholesterol (LDL-C) has been considered to be the major cause of atherosclerosis and cardiovascular disease (CVD), and statin treatment has been widely promoted for cardiovascular prevention. However, there is an increasing understanding that the mechanisms are more complicated, and that statin treatment, in particular when used as primary prevention, is of doubtful benefit. Areas covered The authors of three large reviews recently published by statin advocates have attempted to validate the current dogma. This paper delineates the serious errors in these three reviews as well as other obvious falsifications of the cholesterol hypothesis. Expert commentary Our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality, and that the conclusions of the authors of the three reviews are based on misleading statistics, exclusion of unsuccessful trials and by ignoring numerous contradictory observations.
... The chapter is also seriously wrong on one very important point: in welcoming, as an example of desirable non-government-influenced medical innovation, the introduction of statin drugs (p. 168), which in reality cause demonstrable harm by weakening the body's energy-producing mechanisms (e.g., Langsjoen & Langsjoen, 2008;Langsjoen et al., 2008;Hansen et al., 2005;Anonymous, 2010;de Lorgeril & Rabaeus, 2015;Rabaeus et al., 2017) and whose supposed benefit is based on the mistaken view (Ravnskov, 2000;Kendrick, 2008Kendrick, , 2014) that high cholesterol levels in the blood constitute cardiovascular disease. The building up of plaque in the arteries is initiated by inflammation or physical damage, and some of the occasional benefit attributed to statins can be explained by their somewhat anti-inflammatory properties. ...
... The chapter is also seriously wrong on one very important point: in welcoming, as an example of desirable non-government-influenced medical innovation, the introduction of statin drugs (p. 168), which in reality cause demonstrable harm by weakening the body's energy-producing mechanisms (e.g., Hansen et al., 2005;Anonymous, 2010;de Lorgeril & Rabaeus, 2015;Rabaeus et al., 2017) and whose supposed benefit is based on the mistaken view (Ravnskov, 2000;Kendrick, 2008Kendrick, , 2014) that high cholesterol levels in the blood constitute cardiovascular disease. The building up of plaque in the arteries is initiated by inflammation or physical damage, and some of the occasional benefit attributed to statins can be explained by their somewhat anti-inflammatory properties. ...
Article
Full-text available
The Introduction is spot on: “”Science can be a force for good, and it has enhanced our lives in countless ways, but even a cursory look at the 20th century shows that what passes for science can be detrimental” (p. 1).
... 14 Several SRs investigating the use of statins for the primary prevention of CVD have been published reaching varying conclusions. [15][16][17][18][19][20] strengths and limitations of this study ► Overview of systematic reviews that reviewed exclusively primary prevention data on statins. ► Transparent search strategy, published protocol and validated instruments to assess the methodological quality of included reviews. ...
Article
Full-text available
Objective To synthesise evidence from exclusively primary prevention data on the effectiveness of statins for prevention of cardiovascular disease (CVD), including stroke, and outcomes stratified by baseline risk and gender. Design Overview of systematic reviews (SRs) using Revised-AMSTAR approach to assess quality. Data sources Cochrane Database of Systematic Reviews, MEDLINE, Embase, PubMed, Scopus and PROSPERO to June 2017. Eligibility criteria for selecting studies SRs of randomised control trials (RCTs) or individual patient data (IPD) from RCTs, examining the effectiveness of statins versus placebo or no treatment on all-cause mortality, coronary heart disease, CVD (including stroke) and composite endpoints, with stratification by baseline risk and gender. Data extraction and synthesis Two independent reviewers extracted data and assessed methodological quality. A narrative synthesis was conducted. Results Three SRs were included. Quality of included SRs was mixed, and none reported on the risk of bias of included trials. We found trends towards reduced all-cause mortality in all SRs (RR 0.91 [95% CI 0.85 to 0.97]), (RR 0.91 [95% CI 0.83 to 1.01]) and (RR 0.78 [95% CI 0.53 to 1.15]) though it was not statistically significant in two SRs. When stratified by baseline risk, the effect on all-cause mortality was no longer statistically significant except in one medium risk category. One review reported significant reductions (RR 0.85 [95% CI 0.77 to 0.95]) in vascular deaths and non-significant reductions in non-vascular deaths (RR 0.97 [95% CI 0.88 to 1.07]). There were significant reductions in composite outcomes overall, but mixed results were reported in these when stratified by baseline risk. These reviews included studies with participants considered risk equivalent to those with established CVD. Conclusions There is limited evidence on the effectiveness of statins for primary prevention with mixed findings from studies including participants with widely ranging baseline risks. Decision making for the use of statins should consider individual baseline risk, absolute risk reduction and whether risk reduction justifies potential harms and taking a daily medicine for life. Trial registration number CRD42017064761.
... However, despite its lack of effect in rats, compactin was, by chance, found to lower circulating levels of cholesterol in chickens and, subsequently, in other animal species; and the race to develop the ultimate statin was on. Although statins' effectiveness in saving lives is now controversial (de Lorgeril and Rabaeus, 2015), there is no doubt of their effectiveness in lowering cholesterol in humans. It is hard to imagine a world without antibiotics, the most life-saving class of drugs ever discovered. ...
... 21 Recently, celluar biochemistry research creates another massive strike to the lipid hypothesis. In recent publication in the journal of cellular biochemistry by ShuanShian Huang and colleagues, 22 opened new era of respectful scientific understanding about the true mechanism of the plaque formation. The authors were activated by the new epidemiological evidence documenting absence of support of the claimed relationship between dietary cholesterol and/or blood cholesterol and atherosclerosis. ...
... Questions asked about statins include which subgroups of people with raised cholesterol levels will gain a significant benefit from taking a statin [45] and how to deal with patients who cannot tolerate statins-for example, because of the common side effect of muscle aches [46]. However, the prevailing debate in the medical literature concerns the interpretation of evidence on whether the benefits and harms of statin therapy have been overor underestimated [47][48][49]. Some scholars argue that almost everyone should take a statin as it may prolong their life, and side effects are rare; others for whom side effects are much commoner than the results of RCTs suggest and people with minimally raised cholesterol and no other risk factors would be better to avoid these drugs. ...
Article
Full-text available
Background: As a response to the criticisms evidence-based practice currently faces, groups of health care researchers and guideline makers have started to call for the appraisal and inclusion of different kinds of knowledge in guideline production (other than randomized controlled trials [RCTs]) to better link with the informal knowledge used in clinical practice. In an ethnographic study, Gabbay and Le May showed that clinicians in everyday practice situations do not explicitly or consciously use guidelines. Instead, they use mindlines: collectively shared, mostly tacit knowledge that is shaped by many sources, including accumulated personal experiences, education (formal and informal), guidance, and the narratives about patients that are shared among colleagues. In this study on informal knowledge, we consider virtual networks of clinicians as representative of the mindlines in the wider medical community, as holders of knowledge, as well as catalysts of knowing. Objective: The aim of this study was to explore how informal knowledge and its creation in communities of clinicians can be characterized as opposed to the more structured knowledge produced in guideline development. Methods: This study included a qualitative study of postings on three large virtual networks for physicians in the United Kingdom, the Netherlands, and Norway, taking the topic of statins as a case study and covering more than 1400 posts. Data were analyzed thematically with reference to theories of collaborative knowledge construction and communities of practice. Results: The dataset showed very few postings referring to, or seeking to adhere to, explicit guidance and recommendations. Participants presented many instances of individual case narratives that highlighted quantitative test results and clinical examination findings. There was an emphasis on outliers and the material, regulatory, and practical constraints on knowledge use by clinicians. Participants conveyed not-so-explicit knowledge as tacit and practical knowledge and used a prevailing style of pragmatic reasoning focusing on what was likely to work in a particular case. Throughout the discussions, a collective conceptualization of statins was generated and reinforced in many contexts through stories, jokes, and imagery. Conclusions: Informal knowledge and knowing in clinical communities entail an inherently collective dynamic practice that includes explicit and nonexplicit components. It can be characterized as knowledge-in-context in practice, with a strong focus on casuistry. Validity of knowledge appears not to be based on criteria of consensus, coherence, or correspondence but on a more polyphonic understanding of truth. We contend that our findings give enough ground for further research on how exploring mindlines of clinicians online could help improve guideline development processes.
Article
Over the past decades, lipid-lowering therapy, which is essentially limited today to the prescription of statins, has become extremely popular in cardiology for the primary and secondary prevention of cardiovascular diseases of atherosclerotic nature. Prescription of statins to cardiac patients is a mandatory element of comprehensive treatment. However, one must admit that treatment with statins is characterized by many unresolved problems: the feasibility of primary prevention with statins has not been proven in particular in young people; no data regarding the true frequency of side effects were obtained especially for the long-term follow-up; the principles of control during treatment were not identified; the target levels of low-density lipoprotein cholesterol (LDL-C) that physician should strive to achieve are also questionable; and most importantly, the question of the true effectiveness of lipid-lowering therapy itself remains open since there are no clear signs of causal associations between serum cholesterol levels and cardiovascular events. The purpose of the review is to draw attention of researchers to this issue and to show that the mechanisms of atherogenesis are more complex, and that only cholesterol-lowering therapy with statins does not completely solve the problem.
Article
Ancel Keys, whose life spanned over 100 years (1904–2004), made a wealth of seminal scientific and public health contributions. As a physiologist, nutritionist, and public health scientist, he has left his mark on the 20th century by exploring different areas of physiology and nutrition, as well as by contributing to the understanding of basic public health issues. Among his major achievements one can mention in chronological order: studying adaptation to very high altitude, developing the K ration to enable the US military to survive with light but dense food, dissecting the physiology of starvation and nutritional rehabilitation to optimize recovery of functions, uncovering the link between serum cholesterol and heart disease, coordinating the first multi‐country epidemiological longitudinal study in nutrition and health, coining the word “body mass index” (BMI), which he showed to be the best body weight index to predict body fat, and promoting the Mediterranean diet for a healthy life style. This review examines the historical events and scientific intrigues that have surrounded Ancel Keys's major classical studies that have ensured him a central place in the history of medical science.
Article
Full-text available
BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. OBJECTIVE: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. METHODS Search methods: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. Selection criteria: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. Data collection and analysis: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported. Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children. Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not oseltamivir. Bronchitis, sinusitis and otitis media. Zanamivir significantly reduced the risk of bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not oseltamivir. Neither NI significantly reduced the risk of otitis media and sinusitis in both adults and children. Harms of treatment. Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I2 statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I2 = 0%). Prophylaxis. In prophylaxis trials, oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33); zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like illness could not be assessed due to data not being fully reported. In oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population. Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116). AUTHORS' CONCLUSIONS: Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.
Article
Full-text available
We have provided a critical assessment of research on the reduction of cholesterol levels by statin treatment to reduce cardiovascular disease. Our opinion is that although statins are effective at reducing cholesterol levels, they have failed to substantially improve cardiovascular outcomes. We have described the deceptive approach statin advocates have deployed to create the appearance that cholesterol reduction results in an impressive reduction in cardiovascular disease outcomes through their use of a statistical tool called relative risk reduction (RRR), a method which amplifies the trivial beneficial effects of statins. We have also described how the directors of the clinical trials have succeeded in minimizing the significance of the numerous adverse effects of statin treatment.