http://archinte.jamanetwork.com/article.aspx?doi=10.1001/archinternmed.2012.2171
Although
many observational reports have cited fatigue and exertional fatigue
with statin use, to our knowledge, no randomized trials have addressed
this issue to date. Energy and exertional fatigue were measured as
tertiary and/or exploratory outcomes in the University of California,
San Diego (UCSD) Statin Study, which aimed to examine a range of
noncardiac outcomes.3
We capitalized on these data to evaluate whether moderate-dose statins
affected energy and exertional fatigue in a broadly sampled primary
prevention population.
Methods
A
total of 1016 subjects (692 men 20 years or older and 324
nonprocreative women, with screening low-density lipoprotein cholesterol
levels 115-190 mg/dL [to convert to millimoles per liter, multiply by
0.0259] and no cardiovascular disease or diabetes) were randomized
equally to 20-mg simvastatin (lipophilic statin), 40-mg pravastatin
(hydrophilic statin), or microcrystalline-cellulose placebo, to be taken
at bedtime in identical blinding capsules for 6 months.
Methods
The
off-site study pharmacist matched sequentially numbered bottles to
sequential computer-generated randomization assignment stratified by sex
(block size, 20; designed by statistician [H.L.W.]). Bottles were
transferred to the study site and given to successive eligible subjects
by staff blinded to the randomization schedule.4
Methods
The
protocol was approved by the UCSD Human Subjects Protection Program.
All subjects (seen exclusively at UCSD) gave written informed consent.
The data and safety monitoring board provided independent study
oversight.
Methods
Outcome
Single-item
self-ratings of change from baseline in “energy” and “fatigue with
exertion” were used, assessed on 6-month follow-up, and rated (5-point
scale) from “much less”(−2) to “much more”(+2) vs baseline.
Outcome
Energy
and fatigue with exertion were rated at baseline from 0 (none) to 10
(maximum possible). All subjects rated energy; the final 397 subjects (a
randomized subset) rated baseline fatigue with exertion (omitted
initially to limit subject burden, restored for the final 40% of
subjects). Missing values of baseline and change score were imputed
using the Stata “impute” command (StataCorp). “EnergyFatigEx” values
were generated by summing ratings for the energy and fatigue with
exertion measures, aligning signs with lower values worse (ie, recoding
such that for both variables lower values signified worse status), for
baseline and on-treatment, yielding a single outcome (on-treatment score
range, −4 to +4).
Methods
Statistical Analysis
We
assessed the correlation of EnergyFatigEx with actual exercise
(baseline assessment: episodes per week of vigorous exercise
>20minutes). The unpaired t test was used to examine the
difference in mean on-treatment EnergyFatigEx in all subjects and women
separately. Ordinal logistic regression with robust (“White”) standard
errors5
adjusted for baseline values of the combined variable, addressing
baseline disparities and regression to the mean (a source of
power-eroding variance). The χ2 test was used to examine
whether statins shifted, relative to placebo, the proportion reporting
changes of subjectively large magnitude (“much worse” or “much better”
vs placebo on both outcomes; the same principle that guides sign tests).
Analyses used Stata statistical software versions 8.0 and 11.0
(StataCorp). A 2-sided α level of .05 designated significance.
Results
For CONSORT (Consolidated Standards for Reporting of Trials) and study baseline characteristics, see eFigure and eTable.
Energy and predictors of exertional fatigue were comparable at
baseline; however, in the subsample with measured baseline exertional
fatigue, pravastatin values differed from other arms and influenced
imputed baseline values (Table). There was a significant relation between measured baseline EnergyFatigEx and actual exercise (r = 0.20; P < .001).
The drop in low-density lipoprotein cholesterol level with 20-mg
simvastatin (49 mg/dL) exceeded that with 40-mg pravastatin (40 mg/dL) (P < .001).
Results
Results of t
tests of difference in mean on-treatment change in EnergyFatigEx were
significant for combined statins vs placebo. Each statin contributed
(effects separately significant for simvastatin) (Table).
Women were disproportionately affected. The 0.4 mean difference
observed for women receiving simvastatin vs placebo would arise if 4 in
10 treated women cited worsening in either energy or exertional fatigue;
2 in 10 characterized both as “worse” or either as “much worse”; 1 in
10 characterized both components as “much worse”; or combinations of
these conditions, with the fractions of subjects for which each
statement holds, summing to 1. Adjusted for baseline EnergyFatigEx (via
ordinal logit), effects on EnergyFatigEx were significantly unfavorable
for combined statins and each statin separately.
Results
The
balance of those reporting maximal worsening vs maximal improvement
(“much worse” vs baseline on each component vs “much better” on each)
was adversely shifted for statins vs placebo (P = .002) and for each statin separately (simvastatin, P = .03; pravastatin, P = .01). These are based on small numbers, and findings are provisional.
Comment
To
our knowledge, this is the first randomized evidence affirming
unfavorable statin effects on energy and exertional fatigue. Effects
were seen in a generally healthy sample given modest statin doses, and
both simvastatin and pravastatin contributed to the significant adverse
effect of statins on energy and fatigue with exertion. Particularly for
women, these unfavorable effects were not uncommon. Findings support
case reports citing adverse effects to these outcomes and are buttressed
by literature rationale.1 ,6 These findings are important, given the central relevance of energy and functional status to well-being.
Comment
These
effects, germane to quality of life, merit consideration when
prescribing or contemplating use of statins, particularly in groups
without expected net morbidity/mortality benefit, extending to
“high-risk” primary prevention and women and elderly persons (including
those with coronary artery disease).7 - 9
There was a significant relation between EnergyFatigEx and actual
activity: reduced activity and exertional tolerance (irrespective of
activity) in turn predict hard adverse outcomes. Effects may take time
to manifest, as may benefits of statin use. Thus, long-term trials are
important, if statin use is to be recommended in younger individuals.
Meanwhile, physicians should be alert to patients' reports of exertional
fatigue or diminished energy during statin use.
A news report on it.
http://www.msnbc.msn.com/id/47772793/ns/health/#.T9bdzsVPGxM
A blogger writing about it.
http://www.medrants.com/archives/6864
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