Systematic review/Meta-analysis

Sleep changes following statin therapy: a systematic

review and meta-analysis of randomized
placebo-controlled polysomnographic trials

Marlena Broncel1, Paulina Gorzelak-Pabiś1, Amirhossein Sahebkar2,3, Katarzyna Serejko1,

Sorin Ursoniu4, Jacek Rysz5, Maria Corina Serban6,7, Monika Możdżan1, Maciej Banach8;
Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

1
Department of Internal Diseases and Clinical Pharmacology, Medical University Corresponding author:
of Lodz, Lodz, Poland Prof. Maciej Banach MD, PhD,
2
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran FNLA, FAHA, FESC, FASA
3
Metabolic Research Centre, Royal Perth Hospital, School of Medicine Department of Hypertension
and Pharmacology, University of Western Australia, Perth, Australia WAM University Hospital
4
Department of Functional Sciences, Discipline of Public Health, “Victor Babes” Medical University of Lodz
University of Medicine and Pharmacy, Timisoara, Romania 113 Zeromskiego St
5
Department of Nephrology, Hypertension and Family Medicine, Chair of Nephrology 90-549 Lodz, Poland
and Hypertension, Medical University of Lodz, Lodz, Poland Phone: +48 42 639 37 71
6
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Fax: +48 42 639 37 71
AL, USA E-mail:
7
Department of Functional Sciences, Discipline of Pathophysiology, “Victor Babes” [email protected]
University of Medicine and Pharmacy, Timisoara, Romania
Department of Hypertension, Chair of Nephrology and Hypertension,
8

Medical University of Lodz, Lodz, Poland

Submitted: 27 August 2015

Accepted: 27 August 2015

Arch Med Sci 2015; 11, 5: 915–926

DOI: 10.5114/aoms.2015.54841
Copyright © 2015 Termedia & Banach

Abstract
Introduction: Statin use might be associated with an increased risk of sleep
disturbances including insomnia, but the evidence regarding sleep changes
following statin therapy has not been conclusive. Therefore we assessed the
impact of statin therapy on sleep changes through a systematic review and
meta-analysis of available randomized controlled trials (RCTs).
Material and methods: We searched MEDLINE and SCOPUS up to October 1,
2014 to identify placebo-controlled RCTs investigating the effect of statin
therapy on sleep changes. A meta-analysis was performed using either a fixed-ef-
fects or a random-effect model according to the I2 statistic. Effect size was ex-
pressed as weighted mean difference (WMD) and 95% confidence interval (CI).
Results: Overall, the impact of statin therapy on polysomnography (PSG)
indices of sleep was reported in 5 trials comprising 9 treatment arms. Over-
all, statin therapy had no significant effect on total sleep duration (WMD:
–7.75 min, 95% CI: –18.98, 3.48, p = 0.176), sleep efficiency (WMD: 0.09%,
95% CI: –2.27, 2.46, p = 0.940), entries to stage I (WMD: 0.36, 95% CI: –0.91,
1.63, p = 0.580), or latency to stage I (WMD: –1.92 min, 95% CI: –4.74, 0.89,
p = 0.181). In contrast, statin therapy significantly reduced wake time (WMD:
–4.43 min, 95% CI: –7.77, –0.88, p = 0.014) and number of awakenings (WMD:
–0.40, 95% CI: –0.46, –0.33, p < 0.001). Meta-regression did not suggest any
correlation between changes in wake time and awakening episodes with
duration of treatment and LDL-lowering effect of statins.
Conclusions: The results indicated that statins have no significant adverse
effect on sleep duration and efficiency, entry to stage I, or latency to stage I
sleep, but significantly reduce wake time and number of awakenings.

Key words: statins, stain therapy, sleep, polysomnography, meta-analysis.

M. Broncel, P. Gorzelak-Pabiś, A. Sahebkar, K. Serejko, S. Ursoniu, J. Rysz, M.C. Serban, M. Możdżan, M. Banach;
Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

Introduction a prospective cohort of 149 patients followed for

6 months; self-reported sleep disturbances were
Statin therapy is the cornerstone for primary
not significantly different between the simvasta-
and secondary prevention of cardiovascular dis-
tin, lovastatin, and placebo groups [17].
eases (CVD) and is generally safe and well tolerat-
In the majority, data examining statins and
ed [1]. Most adverse effects associated with these
sleep by using the most objective method, which
drugs are muscle symptoms (weakness, myalgia,
is PSG, are limited and mixed [12, 18–21]; therefore
myopathies and rhabdomyolysis), gastrointesti-
there is still very limited knowledge on the effects
nal discomfort and liver enzyme elevations [2, 3].
of statins on sleep quality. The electroencephalo-
Diabetes mellitus, alopecia, hemorrhagic stroke,
gram (EEG), electrooculogram (EOG), and skeletal
and cataract are rarely observed, and the causal-
muscle electromyogram (EMG) provide measures
ity has not always been confirmed [4]. Some re-
characterizing the states of sleep and wakeful-
ports have noted other side effects, which might
ness [20]. Polysomnography can be summarized
reduce patients’ quality of life and might result in
according to specific scoring criteria such as stag-
statin discontinuation [5–7]. Accumulating data-
es (1 to 4) of non-rapid eye movement (NREM),
bases from the US Food and Drug Administration
and REM sleep [20]. Using PSG, the following sleep
Adverse Event Reporting System (FAERS) suggest
parameters can be evaluated: number of awaken-
that statin use is associated with an increased
ings, latency to stage I sleep, sleep efficiency, en-
risk of sleep disturbances including insomnia [8].
tries to stage I, wake time during steep, total wake
In other studies hallucinations and nightmares
and total sleep time [20].
during statin therapy were also observed [6, 7].
The data on the risk of sleep disturbances as-
There are few clinical trials evaluating the effect
sociated with statin use might be very important
of statins on sleep as a primary outcome. Three of
in clinical practice, especially with regard to the
them suggested an essential effect of statins on
elderly population, in which sleep disorders are
sleep quality [9–11], while two others presented
a common problem. Taking into account the di-
no impact of statin treatment on sleep [12, 13].
vergent data, we performed a meta-analysis to
It has been suggested that statins with a high
investigate the effect of statin therapy on sleep
degree of lipophilicity (lovastatin, simvastatin)
parameters using the polysomnography method.
might be associated with a higher rate of cen-
tral nervous system disturbances in comparison
Material and methods
with hydrophilic statins (pravastatin) [9, 10, 14,
15]. Tobert et al. reported that 17% of subjects Search strategy
taking lovastatin complained of shortening sleep
This study was designed according to the guide-
duration (by 1 to 3 h) compared to no reports
lines of the 2009 Preferred Reporting Items for
from patients treated with pravastatin [15].
Systematic Reviews and Meta-Analysis (PRISMA)
Vgontzas et al. [9] noted that lovastatin therapy
statement [21]. SCOPUS (http://www.scopus.
in comparison to pravastatin was associated with
com) and MEDLINE (http://www.ncbi.nlm.nih.gov/
increased time in stage 1, wake time and number
pubmed) databases were searched using the fol-
of weakness. These results based on polysom-
lowing search terms in titles and abstracts (also
nography (PSG) were not significantly correlated
in combination with MESH terms): (atorvastatin
with the post-sleep questionnaire completed by
OR simvastatin OR rosuvastatin OR fluvastatin
patients [7]. Males with coronary artery disease
OR pravastatin OR pitavastatin OR lovastatin OR
(CAD) during 12-month observation slept less and
cerivastatin OR “statin therapy” OR statins OR sta-
had greater sleep disturbances due to simvastatin
tin) AND (polysomnography OR sleep OR “statin
therapy compared to those using pravastatin [11].
disturbances” OR “sleep changes” OR insomnia
However, no conclusive evidence exists that
OR parasomnia). The wild-card term “*” was used
a particular statin is more likely to be associated
to increase the sensitivity of the search strategy.
with sleep disturbances over others, and wheth-
No language restriction was used in the literature
er statin therapy itself indeed influences sleep
search. The search was limited to studies in hu-
changes. Most of the studies were short-term
man. The literature was searched from inception
observations, incorporated small cohorts, or did
to October 1, 2014.
not have placebo control groups [7, 9, 10, 13]. In
the Justification for the Use of Statins in Primary
Study selection
Prevention: An Intervention Trial Evaluating Ro-
suvastatin (JUPITER) trial, rates of adverse sleep Original studies were included if they met the
events were similar in the placebo and rosuvas- following inclusion criteria: (1) being a randomized
tatin groups, and in subjects with and without controlled trial (RCT) with either parallel or cross-
low-density lipoprotein cholesterol (LDL-C) below over design, (2) using polysomnographic recording
50 mg/dl [16]. Similar results were obtained in to assess at least one of the following measures:

916 Arch Med Sci 5, October / 2015

 Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebo-controlled polysomnographic trials

total sleep time, sleep efficiency, latency to stage I, od described by Hozo et al. [24]. Where only the
entries to stage I, number of awakenings and total standard error of the mean (SEM) was reported,
wake time, (3) statin therapy duration of at least the SD was estimated using the following formu-
2 weeks, (4) presentation of sufficient information la: SD = SEM × sqrt (n), where n is the number of
on PSG indices at baseline and at the end of fol- subjects.
low-up in each group or providing the net change A fixed-effects or random-effects model (using
values. the DerSimonian-Laird method) was applied when
Exclusion criteria were (1) non-randomized the heterogeneity (I2) value was < 50% and ≥ 50%,
trials, (2) lack of a control group in the study de- respectively. Heterogeneity was quantitatively
sign, (3) case reports or observational studies with assessed using the I2 index. Effect sizes were ex-
case-control, cross-sectional or cohort design, (4) pressed as the weighted mean difference (WMD)
employing subjective measures of sleep instead of and 95% confidence interval (CI). In order to eval-
PSG findings, and (5) lack of sufficient information uate the influence of each study on the overall ef-
on baseline or follow-up PSG indices. fect size, sensitivity analysis was conducted using
the leave-one-out method, i.e. removing one study
Data extraction each time and repeating the analysis.
Eligible studies were reviewed and the follow-
ing data were abstracted: 1) first author’s name; Meta-regression
2) year of publication; 3) study location; 4) study
Random-effects meta-regression was performed
design; 5) number of participants in the statin and
to evaluate the association between calculated
control (in the case of randomized design) groups;
WMD and potential confounders including duration
6) age of study participants; 7) type and duration
of statin therapy; and 8) baseline and follow-up of treatment with statins and changes in plasma
values of PSG indices. LDL-C concentrations following treatment.

Quality assessment Publication bias

A systematic assessment of bias in the includ- Potential publication bias was explored using
ed studies was performed using the Cochrane visual inspection of Begg’s funnel plot asymme-
criteria [22]. The items used for the assessment try, Begg’s rank correlation, and Egger’s weighted
of each study were as follows: adequacy of se- regression. Duval and Tweedie “trim and fill” was
quence generation, allocation concealment, used to adjust the analysis for the effects of pub-
blinding, reporting of dropouts (incomplete out- lication bias [25].
come data), selective outcome reporting, and
other potential sources of bias. According to the Results
recommendations of the Cochrane Handbook,
Flow and characteristics of included studies
a judgment of “yes” indicated low risk of bias,
while “no” indicated high risk of bias. Labeling Initial screening for potential relevance exclud-
an item as “unclear” indicated an unclear or un- ed articles whose titles or abstracts were clearly
known risk of bias. irrelevant. After assessment, 5 eligible studies
equivalent to 9 treatment arms were selected for
Quantitative data synthesis the final meta-analysis [12, 18–21].
Among 231 participants in the selected studies,
The meta-analysis was conducted using Com-
prehensive Meta-Analysis (CMA) V2 software 152 were allocated to statin intervention groups,
(Biostat, NJ) [23]. Net changes in measurements and 79 to the control group. All participants were
(change scores) were calculated as follows: mea- male. Three studies are focused on patients with
sure at end of follow-up – measure at baseline. primary hypercholesterolemia [12, 19, 20], 2 in-
For single-arm cross-over trials, the net change in cluded healthy young people [18, 21], and 4 com-
PSG parameters was calculated by subtracting the pare two different statins [12, 18–20]. Included
value after control intervention from that report- studies were published between 1992 and 1994,
ed after treatment. Standard deviations (SDs) of and were conducted in the USA (2 studies), Swe-
the mean difference were calculated using the fol- den, Finland and Japan. The following statin doses
lowing formula: SD = square root [(SDpre-treatment)2 + were administered in the included trials: 20 mg
(SDpost-treatment)2 – (2R × SDpre-treatment × SDpost-treatment)], to 40  mg/day pravastatin, 40 mg/day lovastatin
assuming a correlation coefficient of R  = 0.5. If and 20 mg/day simvastatin. Duration of statin in-
the outcome measures were reported as the me- tervention ranged between 16 days and 6 weeks.
dian and inter-quartile range, mean and stan- One study had a parallel group design, 2 studies
dard SD values were estimated using the meth- had a two-period crossover trial design (i.e. each

Arch Med Sci 5, October / 2015 917

M. Broncel, P. Gorzelak-Pabiś, A. Sahebkar, K. Serejko, S. Ursoniu, J. Rysz, M.C. Serban, M. Możdżan, M. Banach;
Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

Identification ings (WMD: –0.40, 95% CI: –0.46, –0.33, p < 0.001)
Published studies
identified through (Figure 7). These effect sizes were not sensitive
database search to any single trial, apart from the sensitivity of
(n = 1540)
pooled effect size for the wake time to the study
by Kamei et al. (WMD: –1.77, 95% CI: –9.81, 6.28,
p = 0.667) (Figures 6 and 7).
Screening

Records screened
(n = 33)
Not meeting the inclusion
criteria (n = 12)
Meta-regression
Full text articles Meta-regression did not suggest any associa-
Eligibility

assessed for
eligibility (n = 21)
tion between changes in wake time and awaken-
Non-random design (n = 1)
Non-original study (n = 2) ing episodes following statin therapy with dura-
Non-interventional study (n = 2) tion of treatment (slope: 1.99; 95% CI: –3.94, 7.93;
Not assessing statin’s effect
p = 0.510 (wake time); slope: –0.16; 95% CI: –0.78,
Inclusion

Studies included
in the systematic on sleep (n = 6)
review and meta- Not assessing polysomnographic 0.47; p = 0.628 (awakening episodes)). Likewise,
sleep indices (n = 5)
analysis (n = 5) there was no association of either of the param-
Figure 1. Flow chart of the number of studies iden- eters with LDL-lowering effect of statins (slope:
tified and included in the meta-analysis 0.08; 95% CI: –1.41, 1.57; p = 0.914 (wake time);
slope: –0.00004; 95% CI: –0.02, 0.02; p = 0.996
(awakening episodes)) (Figure 8).
patient received two of the three possible treat-
ments) and 2 studies were crossover studies. Publication bias
A summary of the study selection process is
The funnel plots of the study standard error by
shown in Figure 1 and the characteristics of stud-
effect size (mean difference) were slightly asym-
ies in Table I.
metrical for the meta-analyses of statins’ effects
on wake time and awakening episodes (Figure 9).
Risk of bias assessment Using Duval and Tweedie’s “trim and fill” method,
A systematic assessment of bias in the includ- these asymmetries were addressed by imputing
ed studies was carried out using the Cochrane cri- 1 (for the meta-analysis of awakening episodes)
teria [22]. The items used for the assessment of and 2 (for the meta-analysis of wake time) po-
each study were as follows: adequacy of sequence tentially missing studies. Corrected effect sizes
generation, allocation concealment, blinding, ad- were –0.40 min (95% CI: –0.46, –0.34) (for the
dressing of dropouts (incomplete outcome data), meta-analysis of awakening episodes) and –4.65
selective outcome reporting, and other potential (95% CI: –8.03, –1.27) (for the meta-analysis of
sources of bias. According to the recommenda- wake time). There was no evidence of publica-
tions of the Cochrane Handbook, a judgment of tion bias according to the results of Begg’s rank
“yes” indicated low risk of bias, while “no” indi- correlation (Kendall’s Tau with continuity correc-
cated high risk of bias. Labeling an item as “un- tion = 0, z = 0, two-tailed p-value = 1.000 (for the
clear” indicated an unclear or unknown risk of meta-analysis of awakening episodes); Kendall’s
bias (Table II). Tau with continuity correction = 0.24, z = 0.75,
two-tailed p-value = 0.453 (for the meta-analysis
Effect of statin therapy on of wake time)) and Egger’s linear regression (in-
polysomnography findings tercept = 0.39, standard error = 0.028; 95% CI =
–0.34, 1.12, t = 1.37, df = 5, two-tailed p = 0.229
The impact of statin therapy on PSG indices of
(for the meta-analysis of awakening episodes); in-
sleep was reported in 9 treatment arms. Overall,
tercept = 0.31, standard error = 0.36; 95% CI =
statin therapy had no significant effect on total
–0.61, 1.23, t = 0.86, df = 5, two-tailed p = 0.431
sleep duration (WMD: –7.75 min, 95% CI: –18.98,
(for the meta-analysis of wake time)) tests for ei-
3.48, p = 0.176) (Figure 2), sleep efficiency (WMD:
ther awakening episodes or wake time.
0.09%, 95% CI: –2.27, 2.46, p = 0.940) (Figure 3),
entries to stage I (WMD: 0.36, 95% CI: –0.91, 1.63,
Discussion
p = 0.580) (Figure 4) or latency to stage I (WMD:
–1.92 min, 95% CI: –4.74, 0.89, p = 0.181) (Figure 5). The first reports about the effect of statins on
These effect sizes were robust, and iteratively re- sleep quality come from the 1990s [9–11, 15, 16].
moving each study from the meta-analysis did Mainly they were case reports or small, retrospec-
not change the significance of the results (Figures tive, uncontrolled studies. The design, statistical
2–5). In contrast, statin therapy significantly re- methods and interpretation of results have been
duced wake time (WMD: –4.43 min, 95% CI: –7.77, questioned [26]. Previous studies were performed
–0.88, p = 0.014) (Figure 6) and number of awaken- on young normal volunteers rather than on hy-

918 Arch Med Sci 5, October / 2015

 Table I. Demographic characteristics and baseline parameters of the included studies

Parameter Study
Kostis et al. Eckernas et al. Roth et al. Partinen et al. Kamei et al.
Year 1994 1993 1992 1994 1993
Location USA Sweden USA Finland Japan
Design Randomized double-blind Randomized double-blind Randomized double-blind Randomized double-blind Double-blind placebo-
placebo-controlled placebo-controlled two-period placebo-controlled parallel placebo-controlled two-period controlled crossover trial
crossover trial crossover trial (i.e. each patient trial crossover trial (i.e. each

Arch Med Sci 5, October / 2015

received two of the three patient received two of the
possible treatments) three possible treatments)
Duration of therapy 6 weeks 4 weeks 3 weeks 4 weeks 16 days
Inclusion criteria Male patients aged 36 to Male patients with primary, Healthy men within 20% Male patients with primary Healthy male adults
65 years with a diagnosis moderate hypercholesterolemia of ideal body weight hypercholesterolemia
of hypercholesterolemia as characterized by an LDL (low-density lipoprotein
cholesterol level of 4–7 mmol/l 4 to 7 mmol/l, and
and triglycerides – 3.9 mmol/l triglycerides ~3.8 mmol/l)
Statin form Lovastatin Simvastatin Lovastatin Lovastatin Pravastatin
Pravastatin Pravastatin Pravastatin Pravastatin
Statin intervention 40 mg/day 20 mg/day 40 mg/day 40 mg/day 20 mg/day

40 mg/day 40 mg/day 40 mg/day 40 mg/day

Participants Case 22 16 20 16 5
22 16 19 16
Control 22 16 20 16 5
Age [years] Case 36–65* 52.9 25.8 ±0.6** 55 (34–70)## 36.4 (29–49)##
Control
Total sleep duration Case 366.4# 404.5 ±30.6 436 ±6** 402 ±26 392.6 ±9.6**
[min]
361.9# 402.1 ±30.6 434 ±6** 391 ±26
#
Control 361.9 389.5 ±30.6 429 ±5** 400 ±26 406.3 ±19.3**
Sleep efficiency (%) Case NS 88.2 ±5.9 NS 90 ±8 NS
NS 90.1 ±5.9 NS 84 ±8
Control NS 87.5 ±5.9 NS 87 ±8 NS

919
Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebo-controlled polysomnographic trials
 M. Broncel, P. Gorzelak-Pabiś, A. Sahebkar, K. Serejko, S. Ursoniu, J. Rysz, M.C. Serban, M. Możdżan, M. Banach;
Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

percholesterolemic [10, 11] or high cardiovascu-

lar (CV) risk patients with indications for statin
therapy. Harrison and Ashton [10] using the Leeds

28.3 ±13.5**

19.7 ±15.6**
Kamei et al.

Sleep Questionnaire claimed that simvastatin in

14.6 ±3.7**
5.9 ±3.3**

2.2 ±2.0**
1 ±0.5**
healthy young people (n = 25) may cause different
NS
NS

difficulties in getting to sleep versus pravastatin,

but not in comparison to the placebo group. Barth
et al. [11] noted that 4 of 15 males with CAD com-

Values are expressed as mean ± SD; *only range; #only mean; **values are expressed as mean ± SEM; ##mean (range). SD – standard deviation, SEM – standard error of the mean, NS – not stated.
plained of shorter sleep duration (approximately
by 1  h) during a one-year period of simvastatin
treatment (20 mg daily), and such effects were not
observed in patients taking colestipol or a bile acid
sequestrant [11]. In contrast to the above stud-
Partinen et al.

15.7 ±32.8
46.6 ±32.8
39.5 ±32.8
ies, Carlsson et al. found no impact of 6-month
22.6 ±5.7
20.8 ±5.7
23.7 ±5.7

22.0 ±11

2.9 ±0.1
2.9 ±0.1
2.5 ±0.1
8.7 ±6
9.6 ±6

pravastatin treatment on sleep [13]. Black et al.

used a questionnaire in 409 hyperlipidemic pa-
tients receiving a diet intervention, lovastatin,
simvastatin, pravastatin, or other lipid-lowering
drugs in a cross-sectional approach [27]. They
found no significant differences in the prevalence
of sleep disturbances between the groups [27].
It is, however, worth underlining that the above
observations were based only on the patients’ sub-
0.9 ±0.17**
Roth et al.

0.9 ±0.2**
0.9 ±0.2**
18 ±4**
16 ±4**
26 ±4**
24 ±5**
23 ±5**
22 ±4**

jective evaluation. The results are mixed, and no

Study

NS
NS
NS

conclusive evidence exists that statin therapy is as-

sociated with sleep disturbances, and there is not
enough data to confirm the causality of statin ther-
apy on sleep disturbances [2, 3]. Insomnia might
be due to the underlying diseases, rather than the
drug alone; however, the effect of hypercholesterol-
emia on sleep quality remains unclear [21].
There are only a few studies which have ob-
Eckernas et al.

jectively evaluated the effect of statin therapy

58.6 ±105.3
39.0 ±68.3

11.4 ±20.3
26.1 ±18.5
27.4 ±19.3
26.5 ±18.7
4.8 ±2.4
2.2 ±1.9

4.4 ±2.2
4.7 ±2.4
4.5 ±3.8
2.1 ±1.8

on sleep parameters using PSG [12, 18–21]. Due

to the time-consuming nature and high costs of
PSG, the cohorts of patients involved in the study
were usually small (n = 5–59), with the duration
of observation from 2 weeks to 6 months. Our
meta-analysis represents the first attempt to sys-
tematically evaluate the effects of statin therapy
versus placebo on sleep parameters estimated by
PSG. Surprisingly, taking into account previous
reports, our results indicate that statins have no
Kostis et al.

significant adverse effect on sleep duration and

NS
NS

NS
NS
NS
NS
NS
NS
NS

NS
NS

NS

efficiency, entry to stage I sleep, or latency to

stage I. What is more, they might even have some
beneficial effects, significantly reducing wake time
and number of awakenings. Meta-regression did
not suggest any correlation between changes in
wake time and awakening episodes with duration
Control

Control

Control

Control
Case

Case
Case
Case

of treatment and LDL-lowering effect of statins.

Kamei et al. [21] aimed to evaluate the ef-
fect of pravastatin on sleep in 5 healthy adults
Wake time during
Latency to stage I

treated for 16 days. In comparison to placebo

Entries to stage I
Table I. Cont.

they found no significant differences in total

awakenings
sleep [min]

Number of
Parameter

sleep, arousal after sleep and sleep latency be-

tween the baseline night values and the acute
[min]

or chronic phase values. The authors supposed

that the cause of these results depended on the

920 Arch Med Sci 5, October / 2015

 Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebo-controlled polysomnographic trials

Table II. Assessment of risk of bias in the included studies using Cochrane criteria

Study Sequence Allocation Blinding Blinding Incomplete Selective Other

genera- conce- of partici- of outcome outcome outcome potential
tion alment pants asses- data reporting threats
and personnel sment to validity
Kostis et al. 1994 U U L L L L L

Eckernäs et al. L L L L L L L
1993

Roth et al. 1992 U U L L L L L

Partinen et al. L L L L L L L
1994
Kamei et al. 1993 U U L L L L L
L – Low risk of bias, H – high risk of bias, U – unclear risk of bias.

Study name Statistics for each study Difference in means and 95% CI
Difference Standard Variance Lower Upper Z-value Value
in means error limit limit of p
Kostis et al., 1994a –34.300 7.971 63.529 –49.922 –18.678 –4.303 < 0.001
Kostis et al., 1994b –19.200 8.121 65.946 –35.116 –3.284 –2.364 0.018
Eckernäs et al., 1993a –15.000 13.250 175.568 –40.970 10.970 –1.132 0.258
Eckernäs et al., 1993b –12.600 13.250 175.568 –38.570 13.370 –0.951 0.342
Roth et al., 1992a 2.000 9.072 82.299 –15.781 19.781 0.220 0.826
Roth et al., 1992b 2.000 9.237 85.322 –16.104 20.104 0.217 0.829
Partinen et al., 1994a –2.000 11.782 138.821 –25.093 21.093 –0.170 0.865
Partinen et al., 1994b 9.000 11.782 138.821 –14.093 32.093 0.764 0.445
Kamei et al., 1993 27.900 23.829 567.807 –18.803 74.603 1.171 0.242
–7.750 5.730 32.837 –18.981 3.481 –1.352 0.176
–65.00 –32.50 0.00 32.50 65.00
Favours placebo Favours statin

Study name Statistics with study removed Difference in means (95% CI)
Point Standard Variance Lower Upper Z-value Value with study removed
error limit limit of p
Kostis et al., 1994a –4.155 4.360 19.006 –12.700 4.389 –0.953 0.341
Kostis et al., 1994b –5.676 6.531 42.660 –18.478 7.125 –0.869 0.385
Eckernäs et al., 1993a –6.769 6.340 40.190 –19.194 5.656 –1.068 0.286
Eckernäs et al., 1993b –7.019 6.357 40.406 –19.477 5.440 –1.104 0.270
Roth et al., 1992a –9.119 6.310 39.816 –21.487 3.248 –1.445 0.148
Roth et al., 1992b –9.097 6.309 39.802 –21.462 3.268 –1.442 0.149
Partinen et al., 1994a –8.264 6.361 40.459 –20.731 4.203 –1.299 0.194
Partinen et al., 1994b –9.842 5.951 35.414 –21.506 1.822 –1.654 0.098
Kamei et al., 1993 –9.479 5.656 31.985 –20.564 1.605 –1.676 0.094
–7.750 5.730 32.837 –18.981 3.481 –1.352 0.176
–65.00 –32.50 0.00 32.50 65.00
Favours placebo Favours statin
Figure 2. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of statin
therapy on total sleep duration. Lower plot shows leave-one-out sensitivity analysis

hydrophilic properties of pravastatin [21]. Due [30]. In fact, the majority of available reports
to not crossing the blood-brain barrier, pravas- have referred to lipophilic statins, namely sim-
tatin probably does not inhibit prostaglandin D2 vastatin and lovastatin [18, 31, 32]. However, no
(PGD2) synthase, a sleep-inducing substance. An conclusive evidence exists that a particular sta-
animal study reported that the intraventricular tin is more likely to be associated with sleep dis-
infusion of PGD2 increases the total sleep time turbances over others [26, 33–35]. Roth et al. in
and slows wave sleep [28]. There is also a hy- a randomized, double-blind, placebo-controlled
pothesis that sleep disorders during statin treat- study showed that neither pravastatin nor lo-
ment may depend on their degree of lipophilicity vastatin significantly affected nocturnal sleep
[21, 28]. It is known that lipophilic drugs, such or daytime sleepiness in healthy young men
as b-blockers, penetrate the blood-brain barrier (n = 59), but lovastatin significantly affected day-
and may affect central nervous system function time performance [18]. Two measures of perfor-
[29]. Thus, it is hypothesized that statins with mance – divided attention (p < 0.05) and vigi-
a high degree of lipophilicity might be associated lance (p < 0.001) – worsened significantly from
with a higher rate of central nervous system dis- baseline, as did global performance (p < 0.001).
turbances in comparison with hydrophilic statins The mechanism of these lovastatin effects is not

Arch Med Sci 5, October / 2015 921

M. Broncel, P. Gorzelak-Pabiś, A. Sahebkar, K. Serejko, S. Ursoniu, J. Rysz, M.C. Serban, M. Możdżan, M. Banach;
Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

Study name Statistics for each study Difference in means and 95% CI
Difference Standard Variance Lower Upper Z-value Value
in means error limit limit of p
Kostis et al., 1994a –2.200 2.978 8.866 –8.036 3.636 –0.739 0.460
Kostis et al., 1994b –1.700 2.954 8.727 –7.490 4.090 –0.575 0.565
Eckernäs et al., 1993a 0.700 2.555 6.527 –4.307 5.707 0.274 0.784
Eckernäs et al., 1993b 2.600 2.555 6.527 –2.407 7.607 1.018 0.309
Partinen et al., 1994a 3.000 3.625 13.143 –4.105 10.105 0.828 0.408
Partinen et al., 1994b –3.000 3.625 13.143 –10.105 4.105 –0.828 0.408
0.091 1.207 1.458 –2.275 2.458 0.076 0.940
–20.00 –10.00 0.00 10.00 20.00
Favours placebo Favours statin

Study name Statistics with study removed Difference in means (95% CI)
Point Standard Variance Lower Upper Z-value Value with study removed
error limit limit of p
Kostis et al., 1994a 0.542 1.321 1.745 –2.047 3.131 0.411 0.681
Kostis et al., 1994b 0.451 1.323 1.750 –2.142 3.043 0.341 0.733
Eckernäs et al., 1993a –0.084 1.370 1.877 –2.769 2.602 –0.061 0.951
Eckernäs et al., 1993b –0.630 1.370 1.877 –3.315 2.055 –0.460 0.646
Partinen et al., 1994a –0.272 1.280 1.640 –2.781 2.238 –0.212 0.832
Partinen et al., 1994b 0.477 1.280 1.640 –2.033 2.987 0.373 0.710
0.091 1.207 1.458 –2.275 2.458 0.076 0.940
–20.00 –10.00 0.00 10.00 20.00
Favours placebo Favours statin

Figure 3. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of statin
therapy on sleep efficiency. Lower plot shows leave-one-out sensitivity analysis

Study name Statistics for each study Difference in means and 95% CI
Difference Standard Variance Lower Upper Z-value Value
in means error limit limit of p
Eckernäs et al., 1993a 2.300 1.436 2.061 –0.514 5.114 1.602 0.109
Eckernäs et al., 1993b –0.100 0.793 0.630 –1.655 1.455 –0.126 0.900
Partinen et al., 1994a –1.800 2.583 6.672 –6.863 3.263 –0.697 0.486
Partinen et al., 1994b 1.100 2.583 6.672 –3.963 6.163 0.426 0.670
0.359 0.649 0.421 –0.913 1.631 0.553 0.580
–8.00 –4.00 0.00 4.00 8.00
Favours placebo Favours statin

Study name Statistics with study removed Difference in means (95% CI)
Point Standard Variance Lower Upper Z-value Value with study removed
error limit limit of p
Eckernäs et al., 1993a –0.140 0.728 0.530 –1.566 1.287 –0.192 0.848
Eckernäs et al., 1993b 1.288 1.129 1.274 –0.924 3.500 1.141 0.254
Partinen et al., 1994a 0.505 0.671 0.450 –0.810 1.819 0.752 0.452
Partinen et al., 1994b 0.309 0.671 0.450 –1.005 1.623 0.461 0.645
0.359 0.649 0.421 –0.913 1.631 0.553 0580
–8.00 –4.00 0.00 4.00 8.00
Favours placebo Favours statin
Figure 4. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of statin
therapy on entries to stage I sleep. Lower plot shows leave-one-out sensitivity analysis

clear. The authors eliminated the possibility that the differences between these statins, reported
the performance effects resulted from changes based on PSG, were probably not clinically rele-
in lipids since both lovastatin and pravastatin vant [20]. Kostis et al. reported that lovastatin
decreased LDL-C equivalently [18]. Partinen et al. and pravastatin did not have significant effects
reported significant differences between lovasta- on sleep or daytime performance measures in
tin and pravastatin treatment in sleep efficiency, patients (n = 22, all men) with hypercholesterol-
total wake time, wake time during sleep, entries emia [19]. They supposed that the patients with
to wake and percentage of REM stage sleep in unstable sleep architecture may have been pre-
men with primary hypercholesterolemia [20]. All disposed to disruptive effects on sleep, but such
changes in PSG parameters indicated improved patients were not included in this study. Simi-
sleep with lovastatin compared with pravastatin. lar conclusions were observed in another study
But neither lovastatin nor pravastatin had any ef- comparing simvastatin, pravastatin and placebo
fect on subjective, qualitative sleep ratings. Thus, in patients with hypercholesterolemia [12]. Anal-

922 Arch Med Sci 5, October / 2015

 Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebo-controlled polysomnographic trials

Study name Statistics for each study Difference in means and 95% CI
Difference Standard Variance Lower Upper Z-value Value
in means error limit limit of p
Kostis et al., 1994a 5.200 7.345 53.944 –9.195 19.595 0.708 0.479
Kostis et al., 1994b 2.700 7.964 63.427 –12.909 18.309 0.339 0.735
Eckernäs et al., 1993a 27.600 24.919 620.949 –21.240 76.440 1.108 0.268
Eckernäs et al., 1993b 47.200 40.664 1653.583 –32.501 126.901 1.161 0.246
Roth et al., 1992a 0.000 7.709 59.436 –15.110 15.110 0.000 1.000
Roth et al., 1992b –1.000 8.351 69.746 –17.368 15.368 –0.120 0.905
Partinen et al., 1994a –3.000 2.719 7.393 –8.329 2.329 –1.103 0.270
Partinen et al., 1994b –2.100 2.719 7.393 –7.429 3.229 –0.772 0.440
Kamei et al., 1993 –3.000 2.616 6.845 –8.128 2.128 –1.147 0.252
–1.921 1.437 2.065 –4.738 0.895 –1.337 0.181
–80.00 –40.00 0.00 40.00 80.00
Favours statin Favours placebo

Study name Statistics with study removed Difference in means (95% CI)
Point Standard Variance Lower Upper Z-value Value with study removed
error limit limit of p
Kostis et al., 1994a –2.205 1.465 2.147 –5.077 0.667 –1.505 0.132
Kostis et al., 1994b –2.077 1.461 2.134 –4.940 0.786 –1.422 0.155
Eckernäs et al., 1993a –2.020 1.439 2.072 –4.841 0.801 –1.403 0.161
Eckernäs et al., 1993b –1.983 1.438 2.067 –4.801 0.835 –1.379 0.168
Roth et al., 1992a –1.991 1.463 2.139 –4.857 0.876 –1.361 0.174
Roth et al., 1992b –1.949 1.459 2.128 –4.808 0.910 –1.336 0.181
Partinen et al., 1994a –1.503 1.693 2.865 –4.821 1.814 –0.888 0.374
Partinen et al., 1994b –1.852 1.693 2.865 –5.170 1.465 –1.094 0.274
Kamei et al., 1993 –1.455 1.720 2.957 –4.826 1.915 –0.846 0.397
–1.921 1.437 2.065 –4.738 0.895 –1.337 0.181
–8.00 –4.00 0.00 4.00 8.00
Favours statin Favours placebo
Figure 5. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of statin
therapy on latency to stage I sleep. Lower plot shows leave-one-out sensitivity analysis

Study name Statistics for each study Difference in means and 95% CI
Difference Standard Variance Lower Upper Z-value Value
in means error limit limit of p
Eckernäs et al., 1993a 1.500 11.279 127.220 –20.607 23.607 0.133 0.894
Eckernäs et al., 1993b –1.500 10.778 116.158 –22.624 19.624 –0.139 0.889
Roth et al., 1992a –3.000 7.845 61.545 –18.376 12.376 –0.382 0.702
Roth et al., 1992b –1.000 7.157 51.217 –15.027 13.027 –0.140 0.889
Partinen et al., 1994a –21.000 16.767 281.134 –53.863 11.863 –1.252 0.210
Partinen et al., 1994b –11.000 16.767 281.134 –21.863 43.863 0.656 0.512
Kamei et al., 1993 –4.900 1.943 3.774 –8.707 –1.093 –2.522 0.012
–4.327 1.756 3.083 –7.768 –0.885 –2.464 0.014
–75.00 –37.50 0.00 37.50 75.00
Favours statin Favours placebo

Study name Statistics with study removed Difference in means (95% CI)
Point Standard Variance Lower Upper Z-value Value with study removed
error limit limit of p
Eckernäs et al., 1993a –4.472 1.778 3.160 –7.956 –0.988 –2.516 0.012
Eckernäs et al., 1993b –4.404 1.780 3.167 –7.892 –0.916 –2.475 0.013
Roth et al., 1992a –4.397 1.802 3.246 –7.928 –0.866 –2.441 0.015
Roth et al., 1992b –4.540 1.811 3.281 –8.090 –0.990 –2.507 0.012
Partinen et al., 1994a –4.142 1.766 3.117 –7.602 –0.682 –2.346 0.019
Partinen et al., 1994b –4.497 1.766 3.117 –7.957 –1.036 –2.547 0.011
Kamei et al., 1993 –1.768 4.105 16.847 –9.813 6.276 –0.431 0.667
–4.327 1.756 3.083 –7.768 –0.885 –2.464 0.014
–50.00 –25.00 0.00 25.00 50.00
Favours statin Favours placebo
Figure 6. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of statin
therapy on total wake time. Lower plot shows leave-one-out sensitivity analysis

ysis of sleep EEG measures relevant to insomnia greater after simvastatin treatment than after ei-
provided no evidence of significant differences ther pravastatin or placebo (p < 0.05). The laten-
between these three treatments, except for en- cy to stage I sleep was significantly prolonged by
tries and latency to stage I sleep [12]. The num- pravastatin [12]. Eckernäs et al. [12], like Partinen
ber of entries to stage I sleep was significantly et al. [20], found that subjective ratings of sleep

Arch Med Sci 5, October / 2015 923

 M. Broncel, P. Gorzelak-Pabiś, A. Sahebkar, K. Serejko, S. Ursoniu, J. Rysz, M.C. Serban, M. Możdżan, M. Banach;
Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

Study name Statistics for each study Difference in means and 95% CI
Difference Standard Variance Lower Upper Z-value Value
in means error limit limit of p
Eckernäs et al., 1993a –0.100 1.039 1.080 –2.137 1.937 –0.096 0.923
Eckernäs et al., 1993b 0.300 0.981 0.962 –1.623 2.223 0.306 0.760
Roth et al., 1992a –0.100 0.509 0.259 –1.097 0.897 –0.197 0.844
Roth et al., 1992b 0.200 0.601 0.361 –0.978 1.378 0.333 0.739
Partinen et al., 1994a –0.400 0.045 0.002 –0.489 –0.311 –8.827 < 0.001
Partinen et al., 1994b –0.400 0.045 0.002 –0.489 –0.311 –8.827 < 0.001
Kamei et al., 1993 –1.200 1.118 1.251 –3.392 0.992 –1.073 0.283
–0.397 0.032 0.001 –0.459 –0.334 –12.442 < 0.001
–4.00 –2.00 0.00 2.00 4.00
Favours statin Favours placebo

Study name Statistics with study removed Difference in means (95% CI)
Point Standard Variance Lower Upper Z-value Value with study removed
error limit limit of p
Eckernäs et al., 1993a –0.397 0.032 0.001 –0.460 –0.335 –12.444 < 0.001
Eckernäs et al., 1993b –0.397 0.032 0.001 –0.460 –0.335 –12.458 < 0.001
Roth et al., 1992a –0.398 0.032 0.001 –0.461 –0.335 –12.454 < 0.001
Roth et al., 1992b –0.398 0.032 0.001 –0.461 –0.336 –12.477 < 0.001
Partinen et al., 1994a –0.394 0.045 0.002 –0.482 –0.306 –8.769 < 0.001
Partinen et al., 1994b –0.394 0.045 0.002 –0.482 –0.306 –8.769 < 0.001
Kamei et al., 1993 –0.396 0.032 0.001 –0.459 –0.334 –12.416 < 0.001
–0.397 0.032 0.001 –0.459 –0.334 –12.442 < 0.001
–4.00 –2.00 0.00 2.00 4.00
Favours statin Favours placebo
Figure 7. Forest plot detailing weighted mean difference and 95% confidence intervals for the impact of statin
therapy on number of awakenings. Lower plot shows leave-one-out sensitivity analysis

A 0.40
B 0.40
0.16 0.32
Difference in means

Difference in means

–0.08 0.24
–0.32 0.16
–0.56 0.08
–0.80 0.00
–1.04 –0.08
–1.28 –0.16
–1.52 –0.24
–1.76 –0.32
–2.00 –0.40
1.80

2.04

2.28

2.52

2.76

3.00

3.24

3.48

3.72

4.20
3.96

– 39.15 

– 35.84 

– 34.19 

– 32.54 

– 30.88 

– 29.23 

– 27.58 

– 25.93 

– 24.28 

– 22.62 
– 37.49

Treatment duration

LDL-C change (%)

C 11.00
D
11.00
7.80 7.80
Difference in means

Difference in means

4.60 4.60
1.40 1.40
–1.80 –1.80
–5.00 –5.00
–8.20 –8.20
–11.40 –11.40
–14.60 –14.60
–17.80 –17.80
–21.00 –21.00
1.80

2.04

2.28

2.52

2.76

3.00

3.24

3.48

3.72

4.20
3.96

– 39.15 

– 35.84 

– 34.19 

– 32.54 

– 30.88 

– 29.23 

– 27.58 

– 25.93 

– 24.28 

– 22.62 
– 37.49

Treatment duration
LDL-C change (%)
Figure 8. Meta-regression plots of the association between mean changes in the number of awakenings (A, B) and
wake time (C, D) with duration of statin therapy and magnitude of LDL-C reduction

initiation and maintenance during and after ther- with an increased risk for sleep disturbances in-
apy were not significantly different between the cluding insomnia. They examined the correlation
groups. In summary, the studies have shown that between various statins and sleep disturbances
both simvastatin and lovastatin, despite the li- using the US Food and Drug Administration (FDA)
pophilic properties, do not cause clinically signif- Adverse Event Reporting System (FAERS) and da-
icant sleep disorders. However, in 2014 Takada tabase vendor from Japan (Japan Medical Infor-
et al. [8] suggested that statin use is associated mation Research Institute, Inc. Japan [JMIRI]) [8].

924 Arch Med Sci 5, October / 2015

 Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebo-controlled polysomnographic trials

A 0.0 B 0

0.5 5
Standard error

Standard error
1.0 10

1.5 15

2.0 20
–2.0 –1.5 –1.0 –0.5 0.0 0.5 1.0 1.5 2.0 –50 –40 –30 –20 –10 0 10 20 30 40 50
Difference in means Difference in means
Figure 9. Funnel plots detailing publication bias in the meta-analyses of statins’ effects on the number of awak-
enings (A) and wake time (B)

In this observational cohort study, significant ized studies using validated outcome measures
evidence for disturbances in initiating and main- to finally confirm (or not) the causality between
taining sleep was found for the whole class of sleep disturbances and statin therapy.
statins in the analysis of the FAERS database,
and a significant association was found between Acknowledgments
statin use and hypnotic drug use in the analysis
Drs Broncel and Banach contributed equally to
of the JMIRI prescription database. However, in
this meta-analysis.
the analysis of individual statins, significant dis-
turbances of sleep were found for simvastatin,
Conflict of interest
rosuvastatin and lovastatin, but not for atorvas-
tatin, fluvastatin, and pitavastatin. Additionally, The authors declare no conflict of interest.
it has been reported that switching to a different
statin was able to resolve symptoms in some
cases, but in other cases, switching to a different References
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