Journal of the American College of Cardiology

2013 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 62, No. 8, 2013

ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2013.03.030

FOCUS ISSUE: CARDIOMETABOLIC RISK

Editorial Comment

Statins, Exercise, and Exercise Training*

Paul D. Thompson, MD,y Beth Parker, PHDz
Hartford, Connecticut
Statins are life-saving medications and so effective that some
have suggested they be added to the drinking water to
uorinate the vascular bed against atherosclerotic disease.
But statins, both in research models and clinically, can have
deleterious effects on skeletal muscle. The most serious side
effects are myositis and rhabdomyolysis manifested by
marked elevations in creatine kinase and associated, in
several studies, with variants in the hepatic organic anion
transporter protein SLCO1B1 (1). These variations result in
reduced statin hepatic uptake and expose more of the
periphery and skeletal muscle to the drug. Rhabdomyolysis is
extremely rare in the absence of concomitant medications
such as gembrozil, cyclosporine, human immunodeciency
virus protease inhibitors, azole antifungals, and macrolide
antibiotics that increase statin blood and muscle levels (2).
See page 709

Statins have also been associated with a rare inammatory

myositis that does not resolve with drug cessation, often
requires immunosuppressive therapy, and has antibodies
against hydroxy-methyl-glutaryl-CoA reductase (3). Much
more common, however, are milder muscle complaints
including myalgia, muscle cramps, and weakness.
The incidence of these milder muscle complaints was
10.5% in the French PRIMO (PRedIction of Muscular risk
in Observational conditions) study of 7,924 hyperlipidemic
patients treated with high-dose statins for at least 3 months
(4). We observed a similar incidence (11.3%) of muscle
complaints among 203 statin-naive subjects treated for 6

*Editorials published in the Journal of the American College of Cardiology reect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the yCardiology Division, Hartford Hospital, Hartford, Connecticut; and the
zDepartment of Health Sciences, University of Hartford, Hartford, Connecticut.
Funded in part by National Institutes of Health grants #R01HL081893,
#1RO1HL098085, and #RC1 AT005836. Dr. Thompson has received grant and
research support from GlaxoSmithKline, Genoma, Novartis, Roche, sano-aventis,
Regeneron, Esperion, and Amarin; has served as a consultant for AstraZeneca,
Amgen, Regeneron, Merck & Co., Inc., Roche, Genoma, Abbott, Lupin, Runners
World, Genzyme, sano-aventis, GlaxoSmithKline, and Esperion; has received
speaking honoraria from Merck, Abbott, AstraZeneca, GlaxoSmithKline, and Kowa;
owns stock in General Electric, JA Wiley Publishing, Johnson & Johnson, and
Abbott; and has served as a legal consultant on cases involving cardiac complications of
exercise and statin myopathy. Dr. Parker has reported that she has no relationships
relevant to the contents of this paper to disclose.

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months with atorvastatin 80 mg daily (5). Only 9.4% of our

subjects met the study denition of statin myalgia, which
required new muscle symptoms that persisted for at least
2 weeks, resolved within 2 weeks of drug cessation, and
reappeared within 4 weeks of restarting the atorvastatin (5).
Interestingly, 6.0% of the placebo control group (n 217)
developed similar muscle symptoms and 4.6% of these
placebo-treated individuals met the study criteria for drugrelated myalgia. These results suggest that the true incidence of statin myalgia with high-dose statins during
6 months of treatment is only approximately 4.8%, or the
rate in the atorvastatin minus the placebo-treated subjects.
Notably, this is only one-half the rate reported in the
PRIMO study, which was not placebo-controlled and did
not use a standardized challengedechallenge denition of
myalgia (4).
The mechanisms mediating statin myopathy are unclear,
but possibilities include decreased sarcolemmal or endoplasmic reticulum cholesterol, reduced production of prenylated proteins including the mitochondrial electron
transport protein coenzyme Q10, reduced fat catabolism,
increased myocellular concentrations of cholesterol and plant
sterols, failure to repair damaged skeletal muscle, vitamin D
deciency, and inammation (2). Increasingly, interest has
focused on altered cellular energy use and mitochondrial
dysfunction, with the dysfunction activating pathways leading to muscle atrophy (68).
This issue of the Journal presents results from an exercise
training study that further implicate altered mitochondrial
function in statin-associated muscle dysfunction. Mikus et al.
(9) randomized previously sedentary, statin-naive adults with
at least 2 risk factors for metabolic syndrome to 12 weeks of
supervised, aerobic exercise training alone (n 19) or in
combination with 40 mg of simvastatin (n 18). Maximal
oxygen uptake, expressed either as an absolute value or
relative to body weight, increased 10% with training in the
exercise-only group, but only 1.5% in the exerciseand-simvastatin group (p < 0.01 for interaction). Citrate
synthase activity, a measure of muscle mitochondrial content
obtained from vastus lateralis biopsies in 12 exerciseplus-statin and 17 exercise-only subjects, increased 13%
following exercise training in the exercise-only subjects but
decreased 4.5% in the exercise-plus-statin subjects (p < 0.05
for interaction). There were also changes in skeletal muscle
mitochondrial complexes I, II, III, and IV with exercise

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JACC Vol. 62, No. 8, 2013

August 20, 2013:7156

Thompson and Parker

Statins, Exercise, and Exercise Training

training alone, but no changes with exercise training and

statin treatment.
Exercise training studies are difcult because they require
a large time commitment from both the subjects and the
investigators, but this trial was well done by a research
group known for their expertise in exercise physiology. The
design would have been enhanced by double-blinding with
the use of a placebo medication. This becomes particularly
relevant given data suggesting that statin-treated subjects
overestimate the effects of statins on skeletal muscle (5). It
would also be useful to know if the training intensity was
similar in the 2 groups. We have observed a reduction in
spontaneous physical activity levels in individuals over age
55 years treated with atorvastatin (5). Knowing whether the
statin-treated subjects exercise trained less intensely in the
Mikus et al. (9) trial would indicate if statins reduced the
training stimulus itself or if they reduced the physiological
response to a similar training stimulus.
These results are not good news for clinicians trying to
convince physically active patients to stay on statins, but
other studies have also suggested that statins affect the
skeletal muscle response to exercise and exercise training.
Only 20% of 22 professional soccer players with familial
hypercholesterolemia were able to tolerate any of the 5 statins then available (10). The incidence of statin muscle
complaints in PRIMO was 14.7% in those subjects who
practiced some intense form of sport, but only 10.8% in
less active individuals (4). The creatine kinase increase after
exercise is greater in individuals randomized to lovastatin
40 mg daily (11) and in Boston marathoners treated with
statins than in runners not on these medications (12). Statins also reduce the increase in atrogin-1 gene expression
that occurs after eccentric exercise (13). Atrogin-1 is a key
component of the ubiquitin proteasome pathway and
participates in catabolizing muscle protein. Down-regulation
of atogin-1 after exercise suggests a reduced ability to clear
damaged muscle protein that could contribute to the muscle
complaints reported in physically active subjects (13). The
results reported by Mikus et al. (9) add to the evidence that
statins affect the ability of skeletal muscle to adapt to the
stress of exercise training.
These results also raise additional questions about the
statin effect. Is the reduction in the exercise training
response limited to aerobic exercise training, or do statins
also affect the muscles response to resistance training? Is the
effect limited to individuals with baseline alterations in
glucose metabolism and risk factors for metabolic syndrome
such as those who participated in this study? Do statins
reduce exercise capacity in physically active patients, or do
they only reduce the exercise-training response in previously
inactive subjects? A recent cross-sectional analysis of over
10,000 patients indicates that both statin use and increased
physical tness are separately associated with reduced
mortality, but that there is an additive benet of the
combination such that physically active patients treated with
statins demonstrate the lowest risk for premature mortality

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(14). Are the advantageous effects of improving physical

tness reduced by concomitant statin therapy? The benets
of statins clearly outweigh their risks, but there are few
studies on the effects of statins on physical activity, in
physically active subjects, and on the physiological response
to exercise training.
Mikus et al. (9) should be congratulated for a study that
further implicates the mitochondria in statin-related muscle
dysfunction. Their paper provides novel data that answer
some, but raises more, questions about the interaction of
physical activity and exercise with statin therapy.
Reprint requests and correspondence: Dr. Paul D. Thompson,
Cardiology Division, Hartford Hospital, 80 Seymour Street,
Hartford, Connecticut 06102. E-mail: pthomps@harthosp.org.

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Key Words: tness - metabolic syndrome

mitochondria - statins.

obesity

skeletal muscle