CLINICAL REVIEW Peer-reviewed

Statins and their effect on cognition:

Let’s clear up the confusion
Jérémie M. Gauthier, BScPharm; Anne Massicotte, BPharm, MSc

We received a question Introduction spectrum, some research evaluated the potential

in the drug information Lipid-lowering drugs, such as statins, rank in the use of statins in the prevention and treatment of
centre about statins top 5 most frequently used prescription drugs Alzheimer disease (AD).4 This article focuses on
possibly inducing in Canada. In fact, between 2007 and 2011, the effects of statins on cognition and the use of
confusion in a patient. more than 2.9 million Canadians were taking a statins for the prevention and treatment of AD.
This clinical request lipid-lowering drug.1 With a plethora of robust
prompted us to review evidence for secondary prevention of cardio- Search strategy and findings
the evidence on this topic. vascular disease, coupled with a well-tolerated For this review, searches of the following data-
We retrieved articles adverse effect profile, it is no wonder that statins bases were initially carried out on July 4, 2014,
discussing the impact are prescribed quite often. In the past decade, and then subsequently on January 30, 2015:
of statins on cognition however, some case reports have suggested a MEDLINE, PubMed and the Cochrane Library.
but also found research possible increase in the risk of cognitive adverse Search terms in MEDLINE included hydroxy-
investigating statins to events, such as memory loss, forgetfulness or methylglutaryl-CoA reductase inhibitors, cogni-
prevent or treat cognitive feeling “fuzzy,” associated with their use.2 tion, dementia, cognition disorders, mild cognitive
impairment. In 2005, Health Canada released a statement impairment, Alzheimer disease, memory and
in the Canadian Adverse Reaction Newsletter sug- memory disorders. In PubMed and Cochrane
Une question a été soumise
gesting a possible association between statins and Library, search terms included atorvastatin, rosu-
au Centre d’information
memory loss.3 The onset of these adverse events vastatin, fluvastatin, pravastatin, simvastatin, lov-
sur les médicaments
described in the case reports varied, but most astatin, statin*, cogniti*, dement*, and memory.
concernant la possibilité
occurred within 1 year of statin initiation. Most Searches were limited to systematic reviews and
que les statines entraînent
of the cases (11/19) reported an improvement in meta-analyses only and restricted to English
un état de confusion chez
cognitive symptoms once the statin was stopped language and humans. A total of 71 potentially
un patient. La demande
or the dose reduced. In 2012, the Food and Drug relevant articles were identified. After removal
de données cliniques
Administration (FDA) issued a safety announce- of duplicates and irrelevant and older systematic
nous a incités à examiner
ment to health care professionals, warning them reviews, which contained trials that were ana-
les données probantes
about the potential risk of cognitive impairment lyzed in more recent systematic reviews, a total
à ce sujet. Nous avons
(memory loss, forgetfulness, amnesia, memory of 5 articles were considered the best available
trouvé des articles qui
impairment, confusion) with the use of statins evidence. Based on the Evidence Updates from
investiguaient un lien
for a period of 1 day to years.2 Review of these BMJ News Alerts, another recently published
entre les statines et les
cases did not reveal an association between cog- meta-analysis, which was not identified with our
troubles cognitifs ainsi que
nitive impairment and a specific statin, dose or search strategy due to its recent publication, was
des projets de recherche
age of patient. These cases were generally revers- also examined.
portant sur l’utilisation des
statines pour prévenir ou ible, with symptoms disappearing approximately
traiter les troubles cognitifs. 3 weeks after statin discontinuation. The FDA Statins and their effect on cognition
also enforced a change in the monograph of Broadly speaking, cognition may be subdivided
statin products to warn health care profession- under 4 domains: executive function, memory,
als about this rare, but possible, adverse event. language and visuospatial ability. Cognitive
This change in monograph has not been man- impairment can therefore be defined as a decline
© The Author(s) 2015 dated in Canada. On the opposite end of the from baseline in any of the 4 domains, sometimes
DOI: 10.1177/1715163515578692

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overlapping one another.4 For an overview of

some validated tests used to examine cognition, KNOWLEDGE INTO PRACTICE
refer to Table 1.5-8
In 2013, Richardson et al.9 conducted a sys- •• Despite some case reports of statin-induced memory loss and
tematic review of observational and randomized confusion, statins do not appear to be associated with an increased
trials looking at the effects of statins on cognition. risk of cognitive impairment.
Except for 2, all trials in this systematic review •• If cognitive impairment is suspected in a patient taking a statin, look
were designed to look at cognitive function. A for other medications that may be contributing.
meta-analysis of 4 cohort trials (n > 4019) dem- •• It is important to highlight the cardiovascular benefits of statins in
onstrated a lower risk for mild cognitive impair- patients concerned about cognitive impairment effects.
ment associated with statin use in patients with •• With the current level of evidence, especially from the analyses of
intact cognition at baseline (relative risk [RR], randomized controlled trials, statins cannot be recommended for the
0.66; 95% confidence interval [CI], 0.51-0.86). prevention or treatment of dementia.
On the other hand, one large randomized con-
trolled trial (RCT) (n = 20,536) from the system-
atic review revealed no difference in incidence trend towards improvement in DSST scores in
of cognitive impairment between statin and pla- patients taking statins vs those taking placebo
cebo use (RR, 0.98; 95% CI, 0.93 to 1.03). The (mean difference, 1.65; 95% CI, –0.03 to 3.32).
authors also looked at Mini-Mental State Exami- This increase of 1.65 in score means that par-
nation (MMSE, Table 1) scores in their sys- ticipants exposed to statins were able to match
tematic review. When analyzing these scores in almost 2 pairs more within the time limit com-
patients with intact cognition at baseline, the tri- pared to patients not exposed to statins. The
als demonstrated no difference in MMSE scores clinical significance of this increase in score has
between placebo and statin use on global cogni- not been determined. Despite a small sample
tive performance. With regards to declarative size used to perform the meta-analysis, there was
memory (learning, representation, recalling facts little heterogeneity (I2 = 2%), and all studies had
and events) (n = 6434), processing speed (time low risk of bias based on the Cochrane Risk of
required to process set amount of information) Bias Assessment Tool.10
(n = 6975), and visuoperception (perception and In 2014, Macedo and colleagues13 conducted
interpretation of visual signs) (n = 556), sev- a meta-analysis of observational trials looking at
eral RCTs demonstrated no difference between the unintended effects of statins, including cog-
statins and placebo. The authors assessed most of nitive impairment, in the general population.
the larger trials to be at low risk of bias, based on They identified 2 trials looking at specific cog-
the Cochrane Risk of Bias Assessment Tool and nitive scores, a modified MMSE (3MS, Table 1)
the Newcastle-Ottawa Scales, which suggests a and the Community Screening Interview for
greater validity and applicability of the results.10,11 Dementia (CSI-D), which together demon-
One limitation of this systematic review is that strated an effect size of 0.18 (95% CI, 0.09-0.27).
results from different trials could not be pooled This means that 57% of individuals in the control
together for analysis due to nonstandardized group had lower scores than the average indi-
methods of assessment for the various cognitive vidual in the statin group, suggesting a greater
components. incidence of cognitive impairment in the control
Swiger et al.12 examined the effects of statins group.14 These 2 trials had almost 5000 patients
on short-term cognition, defined as “impairment when combined, but they were observational in
in mental faculty of knowing, including perceiv- nature, and therefore results must be interpreted
ing, recognizing, conceiving, judging, reasoning carefully. No heterogeneity was reported, but 2
and imagining within 1 year of drug initiation,” different cognitive tests were used in each indi-
by conducting a systematic review of trials that vidual trial, which suggests high heterogeneity
examined validated tests of cognitive impair- and thus limits the applicability of the pooled
ment. They conducted a meta-analysis of 3 RCTs result.
(n = 296), which used the Digit Symbol Substi- The most recent meta-analysis published in
tution Test (DSST, Table 1) scores, as this was 2015 by Ott et al.15 evaluated the risk of cogni-
the most prominent cognitive assessment in the tive impairment from statins vs placebo, analyz-
trials. The meta-analysis found a nonsignificant ing exclusively RCTs. Three RCTs (n = 38,360)

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TABLE 1 Cognition tests5-8

MMSE 3MS Test ADAS-Cog DSST

Goal To evaluate orientation (time, place), registration, attention and To evaluate attention, short-term
calculation, recall, language, ability to follow commands memory, processing speed

Description 11 questions 24 questions (15-min test) 11 blocks of different Consists of 9 digits and symbols
(10-min test) tasks to do (30- to to pair. Under each digit,
As the MMSE but more
45-min test). More the subject writes down the
comprehensive with
in-depth test corresponding symbol, pairing
different levels of difficulties
as many as possible in 90 s.

Score range 0-30 0-100 0-70 0-76* (number of correct pairs of

symbols/digits)

Threshold for ≥26: no or <79 suggests cognitive Score ≥18 suggests A low score indicates cognitive
diagnosis questionable impairment greater cognitive impairment but no specific
impairment impairment. threshold defined.
<48 suggests severe
21-25: mild impairment A 4-point change
in 6 months is a
11-20: moderate
clinically significant
0-10: severe difference.

ADAS-Cog, Alzheimer’s Disease Assessment Scale–Cognition; DSST, Digital Symbol Substitution Test; MMSE, Mini Mental State Examination; 3MS
Test, Modified Mini-Mental State Test.
*In theory, the maximum score is 90; in practice, the maximum is set at 76.

in patients with normal cognition at baseline Statin Cognitive Safety Task Force (SCSTF)
reported the incidence of dementia, confusion recommends a series of steps, based on expert
and other cognitive adverse events. This analy- opinion, to perform should a patient report cog-
sis did not find a significant difference between nitive impairment after initiation of therapy.4 It
the statins and placebo groups for the develop- recommends cognitive testing, looking at other
ment of these events. When looking at cognitive potential contributors such as anticholinergic
test outcomes (measuring attention, executive medications (e.g., diphenhydramine, tricyclic
function, memory, processing speed), data from antidepressants, some antipsychotics) and per-
16 RCTs (n = 27,693) did not find a difference forming a risk assessment of stopping or decreas-
across all cognitive domains between the 2 ing the dose vs continuing the statin. Statins have
groups. Heterogeneity was low between the stud- robust evidence supporting their use in second-
ies, and most RCTs in this meta-analysis were at ary prevention of cardiovascular events. It is
low risk of bias. With a large sample size, includ- therefore of utmost importance to discuss with
ing patients from a wide range of ages (20-86 the patient the risks of stopping (increased risk of
years), and good-quality evidence, this meta- cardiovascular events) or continuing (cognitive
analysis demonstrates that the risk of cognitive impairment) the statin. If it is suspected that the
impairment with statins is not substantiated in statin is contributing to the symptoms, a drug-
cognitively normal patients. free period of 1 to 2 months is recommended
prior to a rechallenge. Expert opinion suggests a
Bottom Line: Observational data and RCTs switch to a less lipophilic statin, such as rosuvas-
do not support a decrease in cognition with tatin or pravastatin, to limit drug entry into the
statin use. central nervous system and diminish the effects
on cognition.

Managing cognitive impairment as

a side effect Statins and dementia
Despite most of the data showing no impair- In 2012, 747,000 Canadians were living with AD
ment in cognition associated with statins, the and other dementias. This number is expected

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to increase to over 1.4 million by 2031.16 It is

therefore not unexpected that a lot of effort and MISE EN PRATIQUE DES CONNAISSANCES
resources are going into dementia prevention
and treatment research. Pathological hallmarks •• Malgré le fait que certains rapports recensent des cas de pertes
of AD include senile neuritic plaques and neuro- de mémoire et de confusion imputables à la prise de statines, ces
fibrillary tangles, which are potentially related to dernières ne semblent pas être associées à un risque accru de trouble
high levels of brain cholesterol and some degree cognitif.
of inflammation.17 Due to the beneficial effects •• En cas d’apparition de troubles cognitifs chez un patient qui prend
of statins on lipids, as well as their pleiotropic une statine, déterminez si d’autres médicaments peuvent contribuer
effects, this class of medication has been the sub- aux symptômes.
ject of much research for the prevention as well •• Il importe d’insister sur les avantages des statines sur la santé
as the treatment of dementia. Some recent meta- cardiovasculaire auprès des patients préoccupés par les effets associés
analyses have examined the use of statins in this aux troubles cognitifs.
off-label setting. •• Compte tenu des données probantes disponibles à ce jour,
particulièrement celles issues d’essais contrôlés randomisés, les
Prevention of dementia statines ne peuvent faire l’objet d’une recommandation pour prévenir
A meta-analysis of observational studies con- ou traiter la démence.
ducted by Macedo et al.13 looked at the associa-
tion between development of all-type dementia
and exposure to statins. A pooled analysis of 13 causes of vascular dementia, and since this type
trials (n = 2,762,899) demonstrated an odds ratio of dementia was included in the definition of all-
of 0.70 (95% CI, 0.59-0.83) for the development type dementia, statins may overestimate this ben-
of all-type dementia and cognitive impairment efit on dementia prevention.18 Heterogeneity was
without dementia in patients exposed to statins, not significant for this analysis.
suggesting a protective effect from their use. A Richardson et al.9 also looked at prevention
similar odds ratio of 0.74 (95% CI, 0.62-0.87) of dementia in statin users. The meta-analysis
was calculated when low-quality studies were of cohort trials (n = 4,360,137) found that statin
excluded from the analysis. Looking at partici- use was associated with a relative risk reduction
pants who developed AD specifically, exposure of 13% (RR, 0.87; 95% CI, 0.82-0.92) and 21%
to statins was associated with an odds ratio of (RR, 0.79; 95% CI, 0.63-0.99) for all-type demen-
0.61 (95% CI, 0.50-0.75). These results signify tia and AD, respectively. Pooling the results of
a 39% reduction in odds of developing AD in case-control trials demonstrated similar results,
patients taking statins compared with control but these trials had a much smaller sample size.
patients. Although this meta-analysis comprised Once again, these results, although interesting,
a large amount of participants, all these trials come from observational trials and therefore are
were observational, and the pooled analysis had of low quality of evidence.
significant heterogeneity. A Cochrane review conducted in 2009 exam-
In 2013, Swiger and colleagues12 published a ined the potential use of statins for the preven-
meta-analysis examining the use of statins for the tion of dementia by retrieving RCTs addressing
prevention of dementia. Following exclusion of this topic.19 The review identified only 2 RCTs,
trials with a high risk of bias, the pooled results for a total of 26,340 patients. The first and also the
of the remaining 8 trials (n = 23,443), in which largest RCT is the Heart Protection Study (HPS)
patients had a mean statin exposure time of 3 (n = 20,536)—the only RCT in this systematic
to 24.9 years, demonstrated a favourable hazard review to include dementia as an outcome. How-
ratio (0.71; 95% CI, 0.61-0.82) for statin users in ever, as dementia was not a primary outcome, no
the prevention of all-type dementia. Five trials in baseline cognitive test was performed. Despite
this meta-analysis provided sufficient informa- this potential source of bias, 31 participants in
tion and follow-up time for the authors to calcu- each group developed dementia by the end of
late an absolute risk reduction of 2%. This means the trial, suggesting no role for statins in the pre-
that for every 50 patients treated with a statin for vention of dementia. The second RCT included
6.2 years, 1 case of dementia will be prevented 5804 patients at a reasonable risk of developing
compared with patients who were not treated dementia over the 3.2 years of follow-up. Cogni-
with a statin. Strokes are one of the most common tive decline was similar in the statin group and

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the placebo group. This Cochrane review thus when examining the ADAS-Cog score changes
reinforces that statins have no effect on the pre- (mean difference, –0.26; 95% CI, –1.05 to 0.52;
vention of dementia. p = 0.50) or the MMSE score changes (mean dif-
ference, –0.32; 95% CI, –0.71 to 0.06; p = 0.10).
Treatment of dementia Both analyses of ADAS-Cog and MMSE scores
On top of examining dementia prevention, Rich- had an I2 score of 62% and 81%, respectively, sug-
ardson et al.9 also conducted a meta-analysis gesting high heterogeneity between trials. This
looking at the potential benefits of statins on cog- meta-analysis does not support the use of statins
nitive scores in patients already living with AD. in the treatment of dementia.
Four RCTs were identified, comprising a total of
1127 patients, all with probable to possible AD of
Bottom Line: Although meta-analyses of
mild to moderate severity. Of the 4 RCTs, 3 of the
observational trials are suggestive of some
trials were pooled (n = 1064) using the ADAS-
benefit from statins in the prevention of AD,
Cog score (Table 1) and revealed no significant
the review of RCTs found no effect of statins
difference in score between statin and placebo
in the prevention of dementia. When looking
users (difference in score, 0.11; 95% CI, –1.76 to
at statins for the treatment of dementia,
1.97). The MMSE scores were also examined but,
2 meta-analyses of RCTs at low risk of bias
due to high heterogeneity, could not be pooled
concluded that statins have neither positive
together. Each of the 3 largest trials (n = 1083)
nor negative effects on cognition in this
showed no significant difference in MMSE score,
population of patients.
while the smallest one (n = 44) found a signifi-
cant difference favouring the statins. The authors
determined that the 2 largest trials in this meta- Conclusion
analysis had a low risk of bias. With these results, Despite case reports suggesting a risk of impair-
it appears that statins do not improve cogni- ment in cognitive function with the use of
tion in patients with dementia, but on the other statins, several large meta-analyses seem to
hand, they are not associated with a worsening suggest no increase in risk. If cognitive impair-
of cognition. ment is suspected in a patient taking a statin,
Another Cochrane review published in 2014 it would be important to look at other causes,
included 4 RCTs (n = 1154) examining the role such as those suggested by the SCSTF, before
of statins in the treatment of dementia.20 All tri- attributing it to the statin. The well-established
als compared statins with placebo, had a low risk cardiovascular benefits of statins, including
of bias and assessed a change in ADAS-Cog and stroke reduction, should always be highlighted
MMSE from baseline, although these were sec- to the patient.
ondary endpoints in 1 and 3 of the trials, respec- With the current level of evidence, especially
tively. Duration of trials varied from 6 to 18 from the analyses of RCTs, statins cannot be rec-
months. After combining the results, there was no ommended for the prevention or treatment of
difference between the placebo and statin groups dementia. ■

From the Pharmacy Department of The Ottawa Hospital, General campus (Gauthier) and Civic campus
(Massicotte), Ottawa, Ontario. Contact jergauthier@toh.on.ca.
Acknowledgments: The authors thank Dina MacLeod, Drug Information Pharmacist at The Ottawa
Valley Regional Drug Information Service, for her valuable comments during the preparation of the
manuscript.
Author Contributions: J. Gauthier initiated the project, searched the literature, wrote the initial drafts
and made revisions to the final manuscript prior to submission. A. Massicotte initiated the project;
reviewed the search literature, initial drafts and references used; and revised the final manuscript prior
to submission.
Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect
to the research, authorship and/or publication of this article.

154  C P J / R P C • M AY / J U N E 2 0 1 5 • V O L 1 4 8 , N O 3
 CLINICAL REVIEW

Funding: The authors received no financial support for the research, authorship and/or publication of
this article.

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