Am J Cardiovasc Drugs

DOI 10.1007/s40256-015-0139-y

CURRENT OPINION

Meta-Analyses of Statin Therapy for Primary Prevention Do Not

Answer Key Questions: An Empirical Appraisal of 5 Years
of Statin Meta-Analyses
Chetan Huded1 • Vinay Prasad2

Ó Springer International Publishing Switzerland (outside the USA) 2015

Abstract Although meta-analyses of statins in primary
prevention are designed to provide doctors and patients
with better evidence about the risks and potential benefits
of treatment, they may ignore important patient-centered
outcomes and concerns. We examined all meta-analyses of
statins for primary prevention over the last 5 years. We
assessed whether each meta-analysis addressed five key
points: whether authors examined endpoints based on the
use of statin therapy, and not stratified by low-density
lipoprotein reduction; whether authors included only
studies of statin versus placebo, and not varying doses or
brands of statin; whether authors considered commonly
cited harms; whether secondary prevention patients were
excluded; and, whether overall mortality was examined.
We examined 189 articles to identify 24 meta-analyses of
statins that made claims regarding primary prevention. Six
studies (25 %) reported outcomes as a function of reduc-
tion in serum lipid levels rather than treatment received.
Seven studies (29 %) included trials of high-dose versus
low-dose statin in their analysis. Five studies (21 %) did
not examine all-cause mortality. The majority of studies
(n = 21, 88 %) failed to exclude patients with known
cardiovascular disease, and 22 (92 %) studies failed to
assess two of three common safety concerns. Nevertheless,
most (n = 20, 83 %) meta-analyses supported the use of
statins in primary prevention. Based on our findings, we
conclude that most recent meta-analyses of statins for
primary prevention do not adequately address the question
they seek to answer.
Key Points
Whether or not healthy people should take statin
medications as primary prevention has become a
controversial topic, and is frequently debated.
Meta-analyses often claim to adjudicate the debate
by providing a summary estimate of statins’ benefits
and harms.
In an empirical analysis, we found that few meta-
analyses properly frame the primary prevention
question. Specifically, they do not always report
outcomes in terms of taking a statin or not, exclude
randomized controlled trials of a high- versus low-
dose or two different statins, exclude patients with
established cardiovascular disease, report all-cause
mortality, and assess at least two of three safety
concerns.

1 Introduction
& Vinay Prasad
vinayak.prasad@nih.gov The benefits of statin therapy in secondary prevention are
1 well known. Evidence supports their use in patients after
Department of Medicine, Northwestern University, Chicago,
IL, USA myocardial infarction (MI) [1], post stroke [2], in patients
2 with angina and elevated cholesterol [3], and even in
Medical Oncology Branch, National Cancer Institute,
National Institutes of Health, 10 Center Dr. 10/12N226, patients with peripheral arterial disease (PAD) [4]. For
Bethesda, MD 20892, USA patients with known coronary heart disease (CHD),

improvements have been shown not only for future car-
diovascular events, but also for all-cause mortality [1, 5].
However, there are patient populations known to not ben-
efit from statins. Statins have failed to improve outcomes in
patients with heart failure [6, 7], and for patients on
hemodialysis [8, 9]. Debate continues regarding their use in
primary prevention [10].
Whether or not statins should be recommended to
healthy patients, including those with risk factors but no
history of cardiovascular disease (CVD), has emerged as a
contentious topic in medicine [11–13]. Pooled analysis of
randomized controlled trials (RCTs) of statins for this
purpose have yielded mixed results [10]. While some RCTs
have shown benefit in reducing cardiovascular events, the
absolute risk reduction has been small [14–16]. Harms
related to statin therapy have been inconsistently docu-
mented, and improvements in all-cause mortality have not
been well established.
Meta-analyses of statins in primary prevention attempt
to resolve the dispute. In 2012, the Cholesterol Trialists’
Group (CTT) published their findings in The Lancet [17].
The group analyzed pooled data from 27 RCTs and
134,537 participants. They found that, for every 18 mg/dl
that statins lowered cholesterol, patients benefitted from a
21 % reduction in vascular events. However, the CTT’s
analysis has several limitations. First, the authors weighed
trials based on change in lipid levels, meaning that end-
points were given more importance in trials where levels of
low-density lipoprotein (LDL) fell the most. However, this
analysis does not reflect the real-world decision to take a
statin or not, realizing that a priori we cannot know how
much LDL reduction a patient may experience. Addition-
ally, weighing outcomes based on response is a flawed
analytic technique that places undue weight on patients
who respond to a therapy [18, 19]. Second, the analysis did
not exclude trials comparing two different statins (or dif-
ferent doses). Such trials may confound the results, as both
groups may experience most of the harms of the medica-
tion, but only one may experience disproportionate bene-
fits. Third, the article did not consider potential harms,
including common patient concerns such as incident dia-
betes, cancer, or cognitive dysfunction related to long-term
statin therapy. Two other common points of contention in
most meta-analyses on this topic are a failure to examine
overall mortality and failure to exclude secondary pre-
vention patients. However, the CTT did meet these metrics.
An updated analysis in 2015 by the same group continues
to be subject to the same criticism [20].
These five criteria are key preconditions for a meta-
analysis to adequately address whether a patient should
take a statin for primary prevention. Using them, we set out
C. Huded, V. Prasad
to assess all meta-analyses of statins in primary prevention
over the last 5 years.
2 Meta-Analysis Selection Strategy
We performed a systematic review of statin meta-analyses.
Meta-analyses of statin therapy in primary prevention were
obtained via a search of the MEDLINE database using the
following terms: statin(s) primary prevention, meta-analysis
statin(s), pooled analysis of statin(s), statin(s) benefits,
statin(s) cardiovascular prevention, and HMG CoA reduc-
tase inhibitor(s) meta-analysis. The search was filtered to
include only meta-analyses published after 1 December
2007 and before 18 September 2012, the date of our search.
A total of 189 articles were retrieved and read in full
(Fig. 1). Articles were excluded if the authors did not
attempt to analyze whether statins were beneficial in pri-
mary prevention. Articles regarding novel therapeutic uses
of statins, such as the prevention of aortic stenosis, atrial
fibrillation, infection, renal impairment, and malignancy,
were excluded, as were those that studied whether statins
confer peri-procedural benefits. Articles assessing statins’
impact on surrogate endpoints only, including vascular
imaging (computed tomography [CT] angiogram, intravas-
cular ultrasound [IVUS], carotid intima-media thickness
[IMT]) or serum lipid measurements, were excluded.
Studies limited to secondary prevention, or those pertaining
to specific subpopulations (i.e. end-stage renal disease and
familial hypercholesterolemia) were also excluded. All
other articles were included. Our study was conducted
between 18 September 2012 and 1 February 2013.
2.1 Design Choices that Statin Meta-Analyses
Should Embrace to Address the Primary
Prevention Question
The following five points were examined in each article:
(1) outcomes should be reported in terms of taking a statin
or not, and not based on changes in serum lipid concen-
trations; (2) analyses should exclude RCTs of statin versus
statin (high vs. low dose or two different statins); (3)
patients with established CVD, for whom statin therapy is
indicated for secondary prevention, should be excluded; (4)
all-cause mortality should be reported rather than only
disease-specific mortality; (5) at least two of the following
safety endpoints should be reported: cognitive dysfunction,
new-onset diabetes or worsening glycemic control in prior
diabetics, new-onset malignancy or malignancy-related
death. These five criteria were pre-specified and chosen
because they more precisely identify the question in
5 Years of Statins’ Meta-analyses

189 arcles idenfied through database search and

reviewed by hand

165 arcles were excluded

82 tested stan therapy for indicaons not related to CV outcomes
34 did not pertain to risks/benefits of stan therapy
13 were commentary or review arcles
9 tested secondary prevenon only
7 compared stans to non-stan lipid lowering therapy rather than placebo
5 studied familial hypercholesterolemia
5 reported effect of stans on lab surrogates (CV risk markers or lipid levels)
4 compared stan regimens (either type or dose of stan)
3 studied ESRD or renal transplant paents
3 reported effect of stans on vascular imaging surrogates (CT, IVUS, CIMT)

24 arcles were included in the analysis

Fig. 1 A search of the MEDLINE database resulted in 189 articles. excluded. CIMT carotid intima-media thickness, CT computed
The articles were reviewed manually, and only meta-analyses relating tomography, CV cardiovascular, ESRD end-stage renal disease, IVUS
to the risks and benefits of statin therapy for the primary prevention of intravascular ultrasound
cardiovascular endpoints were included. In total, 165 articles were

primary prevention: does taking a statin (not knowing how
much LDL will fall) improve survival in patients who do
not otherwise have an indication for statins, and if it does,
does it do so without significant toxicity or harms [10].
Primary RCTs included in each meta-analysis were
reviewed when questions could not be answered by review
of the meta-analysis alone. All meta-analyses were
reviewed by one reviewer (CH).
2.2 Meta-Analysts’ Opinion of Statins
The authors’ commentary on the use of statin therapy in
primary prevention was classified into one of three groups:
(1) positive—the authors support the use of statins in pri-
mary prevention; (2) equivocal—the authors make no
definitive claims regarding the use or avoidance of statins
in primary prevention; or (3) negative—the authors suggest
caution regarding the use of statins in primary prevention.
3 The Results of Our Analysis
Our search strategy yielded 189 articles, which were
reviewed in full; 24 assessed the effect of statins in primary
prevention and were included in this study [17, 21–43]
(Table 1). Six studies (25 %) reported outcomes as a
function of reduction in serum lipid levels rather than based
simply on whether patients were assigned to statin therapy.
Seven studies (29 %) included trials of high-dose versus
low-dose statins, or two different statin medications, in
their analysis. The majority of studies (88 %, n = 21)
included at least some patients with known CVD, defined
as established CHD, peripheral arterial disease, or cere-
brovascular disease, including prior transient ischemic
attack (TIA) or stroke (Table 2).
A recent study by the CTT [17] included both primary
prevention and secondary prevention populations, although
all-cause mortality was reported separately in the popula-
tion without established vascular disease. A study by Ray
et al. [28] included RCTs that enrolled secondary preven-
tion patients, but the authors obtained the primary datasets
for those RCTs and meticulously excluded patients with
known CVD. A study assessing primary prevention in
women by Mora et al. [31] relied exclusively on three RCTs
that excluded all patients with established CVD (AFCAPS/
TexCAPS [Airforce/Texas Coronary Atherosclerosis
Prevention Study] [15], MEGA [primary prevention of
cardiovascular disease with pravastatin in Japan] [44], and
JUPITER [Rosuvastatin to prevent vascular events in men
and women with elevated C-Reactive Protein] [16]).
Among these three trials that rigorously excluded patients
with known CVD, only the CTT study reported a benefit on
all-cause mortality [per 1.0 mmol/l reduction in LDL, rel-
ative risk 0.91; 95 % confidence interval (CI) 0.85–0.97;
p = 0.007). However, as noted, that study was one of six
that reported endpoints based on reduction in LDL levels
rather than by treatment arm. All-cause mortality was
reported in all but five studies (21 %) (Table 2).
 C. Huded, V. Prasad

Table 1 Each meta-analysis was assessed for achievement of the five benchmarks described above
Article Reports outcomes Excludes trials comparing Excludes patients Reports Reports at least Study
based on taking a two different statins or taking statin all-cause two of three conclusions
statin or not a statin at two different doses for secondary mortality common safety
prevention concernsa

Mihaylova et al. [17] Y Y Y ?

Kostis et al. [21] Y Y ?
Chen et al. [22] Y Y Y ?
Tonelli et al. [23] Y Y Y Y ?
Chan et al. [24] Y ?
Mills et al. [25] Y Y Y Y ?
Taylor et al. [26] Y Y Y ?
Baigent et al. [27] Y ?
Ray et al. [28] Y Y Y Y -
Kizer et al. [29] Y ?
Bukkapatnam et al. [30] Y Y Y ?/-
Mora et al. [31] Y Y Y Y ?
Petretta et al. [32] Y Y Y -
Sheng et al. [33] Y ?
Brugts et al. [34] Y Y Y ?
Amarenco and Labreuche Y ?
[35]
Navaneethan et al. [36] Y Y ?
Delahoy et al. [37] ?
Mills et al. [38] Y Y Y ?
Strippoli et al. [39] Y Y Y ?/-
Messerli et al. [40] Y Y Y ?
Kearney et al. [41] Y Y ?
O’Regan et al. [42] Y Y Y ?
Henyan et al. [43] Y Y ?
a
Three common safety concerns include incident diabetes or glycemic dysfunction, cognitive dysfunction, and incident or fatal malignancy
Y indicates the designated benchmark was achieved, ? indicates the authors support the use of statins in primary prevention, - indicates the
authors suggest caution regarding the use of statins in primary prevention, ?/- indicates the authors make no definitive claims regarding the use
or avoidance of statins in primary prevention

Table 2 The percentage of meta-analyses not achieving each of the proposed benchmarks is shown
Benchmark Not achieveda

The article reports outcomes based on taking a statin or not taking a statin 6 (25)
The article excludes trials comparing two different statins or a statin at two different doses 7 (29)
The article excludes patients who are using a statin for secondary prevention 21 (88)
The article reports all-cause mortality 5 (21)
The article reports at least two out of three common safety concerns (diabetes, cognitive dysfunction, malignancy) 22 (92)
a
Data are presented as n (%)

Commonly purported adverse effects of statin therapy
were generally under-reported by these 24 articles. Of the
24 studies, 22 (92 %) did not meet our prespecified criteria
of reporting outcomes on at least two of the three safety
endpoints defined above (diabetes, cognitive dysfunction,
malignancy-related events). None of the 24 studies
reported the effects of statin therapy on cognitive function,
and only two studies (8 %) reported incident diabetes. Nine
studies (38 %) reported effects of statins on malignancy-
related death or incident malignancy (Table 3).
None of the meta-analyses achieved all of the five
benchmarks. Four studies (17 %) achieved four benchmarks,
5 Years of Statins’ Meta-analyses

Table 3 Each meta-analysis was assessed for the monitoring and reporting of three commonly reported risks of statin therapy
Article Reports on incident diabetes Reports on cognitive Reports on incident
or glycemic dysfunction dysfunction or fatal malignancy

Mihaylova et al. [17] Y

Kostis et al. [21]
Chen et al. [22]
Tonelli et al. [23] Y Y
Chan et al. [24] Y
Mills et al. [25] Y Y
Taylor et al. [26] Y
Baigent et al. [27] Y
Ray et al. [28]
Kizer et al. [29]
Bukkapatnam et al. [30] Y
Mora et al. [31]
Petretta et al. [32]
Sheng et al. [33]
Brugts et al. [34] Y
Amarenco and Labreuche [35]
Navaneethan et al. [36]
Delahoy et al. [37]
Mills et al. [38] Y
Strippoli et al. [39]
Messerli et al. [40]
Kearney et al. [41]
O’Regan et al. [42]
Henyan et al. [43]
Y indicates the designated harm was assessed and reported in the manuscript

ten (42 %) achieved three benchmarks, four (17 %) achieved
two benchmarks, five (21 %) achieved one benchmark, and
one study (4 %) achieved none of the benchmarks. Despite
these findings, the overwhelming majority (n = 20, 83 %)
of trials supported the use of statins in primary prevention. Of
the four other trials, two (8 %) reported negative findings and
two (8 %) reached equivocal findings.
4 Making Sense of the Statins Meta-Analysis
Literature
Our results provide evidence for why the use of statin
therapy in patients without established CVD is a con-
tentious issue in preventive medicine. Patients are
increasingly exposed to the idea that taking statins to treat
CVD before the manifestation of overt symptoms offers
significant benefits [45]. However, clinical trials on this
topic have yielded mixed results—many trials have shown
improvements in cardiovascular event rates, but the effect
on all-cause mortality has not been reliably replicated [10,
14, 16, 44]. Pooled data in meta-analyses should prove
useful to clarify these discrepancies. Our findings highlight
limitations in our most recent pooled datasets intended to
address the topic of statin therapy in primary prevention.
Remarkably, 88 % of the meta-analyses on this topic in
the past 5 years have included patients with established
CVD. Three primary trials—the HPS (Heart Protection
Study) [46, 47], the ASCOT-LLA (Anglo-Scandinavian
Cardiac Outcomes Trial) [47], the ALLHAT-LLT (Anti-
hypertensive and Lipid-Lowering to Prevent Heart Attack
Trial) [48]—were commonly included in primary preven-
tion meta-analyses although these studies included patients
with established vascular disease. The ALLHAT cohorts
included up to 17 % of patients with established CHD,
while the ASCOT population included 10 % with known
symptomatic cerebrovascular disease, 5 % with PAD, and
over 3 % with ‘‘other’’ CVD at baseline. The HPS trial was
a mixed primary and secondary prevention population,
with known CHD in over 20 % of the study population.
Inclusion of patients with established CVD introduces
considerable bias in favor of statin therapy given that the
benefits of statin therapy in such patients are well docu-
mented. The inclusion of secondary prevention patients is

not a necessary consequence of pooled analyses, as some
authors did perform a review of the individual patient-level
data for trials with mixed populations and meticulously
excluded patients with known CVD in their analysis [28].
Although the updated meta-analysis by the Cochrane col-
laboration on this topic fell outside our study dates, it also
includes secondary prevention patients, as long as these
patients accounted for \10 % of the total in a given trial
[49]. We acknowledge that including these patients is
neither inherently wrong nor incorrect but, rather, shifts the
question away from the primary prevention question.
Over one-fifth (21 %) of the meta-analyses analyzed did
not report the effect of statin therapy in primary prevention
on all-cause mortality. All of these five studies ultimately
concluded that statin therapy is beneficial in this setting
despite the omission of overall mortality data.
Instituting statin therapy in primary prevention should
include a process of shared decision making with patients
based on the risks and benefits. Our study illustrates that
the reporting of risks has been limited. Although serum
markers of liver and muscle dysfunction have been closely
monitored in the primary trial literature, there is little
evidence on other safety concerns. The JUPITER [16] trial,
published in 2008, demonstrated a 0.6 % absolute risk
increase in the development of diabetes (p = 0.01) in the
rosuvastatin group compared with placebo. This effect
correlates with a new diagnosis of diabetes in one out of
every 167 patients treated with rosuvastatin [50]. In our
investigation, only two studies (8 %) reported on the risk of
incident diabetes. However, in 2012, the US FDA expan-
ded the safety label on statins to include the risk of new-
onset diabetes as well as the risk of cognitive dysfunction
[51]. Although no durable association between statin
therapy and cognitive dysfunction has been demonstrated
in limited studies [52], the monitoring and reporting of
cognitive outcomes should be performed meticulously in
studies of statin therapy. The risk of incident malignancy in
patients treated with statins has also not been reliably
demonstrated [53, 54]. However, despite commonly cited
concerns regarding neoplastic effects of statins, malig-
nancy-related outcomes have been reported by less than
half of the studies analyzed here (38 %, n = 9).
Some may contend that we are holding meta-analysts to
an unfair standard. The FDA did not mandate warnings that
statins may be linked to incident diabetes or cognitive
dysfunction until February 2012 [55], therefore it is
unreasonable to ask whether older analyses examined these
concerns. Yet, we granted credit to studies that addressed
two of three of these concerns, and two studies did, and the
harms we queried (cancer/incident diabetes/cognitive dys-
function) have been widely known and discussed for years.
Concerns that statins may be linked to higher rates of
C. Huded, V. Prasad
cancer have been voiced since at least the 1990s [56, 57].
Links to incident diabetes gained prominence in 2008,
largely with the dissemination of results from the JUPITER
study (only five meta-analyses we included were published
prior) [16], and concern that statin use could precipitate
cognitive dysfunction have been present for over a decade
[58]. Of course, we agree with others that simply being
linked to diabetes mellitus should not invalidate statins for
all their uses [59]; instead, we merely asked whether meta-
analysts quantified potential benefits and harms.
4.1 Important Caveats
Our study has several limitations. We did not extract
information regarding reported conflicts of interest among
authors of meta-analyses or sources of funding, and whether
these are associated with the conclusions of meta-analysts.
Other groups have shown that industry-supported meta-
analyses are more likely to reach favorable conclusions, are
less transparent, and appreciate fewer methodological
reservations than corresponding Cochrane reviews [60].
However, when it comes to the use of statins, nearly all
meta-analyses support the use of these drugs. In our study,
only two meta-analyses reached negative conclusions, and
two were equivocal. The vast majority 20 (83 %) reached
favorable conclusions. Thus, studying any association
between funding source and conclusion would be under-
powered to draw firm conclusions. Other groups have
examined the conclusions of articles assessing the cost
effectiveness of statins [61]. Indeed, they found that
industry sponsorship was strongly associated with favorable
cost-effectiveness conclusions for statins in primary pre-
vention. Specifically, the percent of studies with negative or
neutral conclusions was 0 % for industry-sponsored inves-
tigations and 57.9 % for non-conflicted studies (p \ 0.001).
Additionally, we did not examine outcomes by sex.
Prior meta-analyses have reached divergent conclusions
about whether the risk benefit profile for statins in men is
comparable to that profile in women [5, 21]. Women have
historically been under-represented in statin trials, and their
outcomes may be different than those for men. We believe
this topic is of immense importance, but did not pre-specify
it prior to our data collection. Future researchers may
consider specifically examining this question, using the
framework we outline.
5 Conclusions
Whether or not patients without established CVD should
use statins for primary prevention remains a topic of
intense debate. Many authors have advocated widespread
5 Years of Statins’ Meta-analyses
adoption of statin therapy for prevention purposes, while
others endorse a more cautious approach. We analyzed five
design choices that a meta-analysis should embrace in
order to provide sufficient evidence for the use of statins in
primary prevention—choices that more accurately define
the primary prevention question. Our investigation is the
first study to systematically appraise meta-analyses for
statins in primary prevention based on key questions that
face providers and patients. Future meta-analyses, partic-
ularly those that promote the use of statins in primary
prevention, should aim to address the concerns raised here.
Compliance with Ethical Standards This article was fully com-
pliant with all ethical standards.
Conflicts of interest The views and opinions of Dr. Prasad do not
necessarily reflect those of the National Cancer Institute or the
National Institutes of Health. Chetan Huded and Vinay Prasad report
no disclosures or conflicts of interest in preparing this manuscript.
Neither Chetan Huded or Vinay Prasad received any funding for the
present manuscript.
Author contributions Chetan Huded and Vinay Prasad contributed
to the data analysis and writing of the manuscript.
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