Opinion

VIEWPOINT
What to Believe and Do About Statin-Associated
Adverse Effects
Paul D. Thompson, MD Statins prevent cardiac death and reduce the inci- muscle cramps, or weakness with little or no increase in CK
Hartford Healthcare dence of acute coronary syndrome, stroke, and venous levels. Collins et al2 reviewed the possible adverse effects
Heart & Vascular thromboembolic disease. Patients who take less than found in RCTs of statin therapy and concluded that statin-
Institute, Hartford
80% of their statin dose have a 45% relative increase associated muscle symptoms without marked CK eleva-
Hospital, Hartford,
Connecticut. in total mortality compared with more adherent pa- tions do not exist or are extremely rare because they are
tients, an increase greater than that observed with poor not reported in the statin RCTs. These authors suggested
adherence to other cardiac drugs including antihyper- that these symptoms may be inappropriately attributed
tensive and β-adrenergic blocking agents.1 Yet thou- to statins due in part to patients being warned of such pos-
sands of patients avoid these life-saving medications be- sible adverse effects by their clinicians.
cause of the presence of or concern about possible Most clinicians, however, are convinced that these
statin-associated adverse effects. symptoms exist and are caused by statins. The inci-
Possible statin-associated adverse effects include dence of statin myalgia has been estimated at 10% from
diabetes mellitus, hemorrhagic stroke, decreased cog- observational studies.1 The Effect of Statins on Skeletal
nition, tendon rupture, interstitial lung disease, as well Muscle Performance (STOMP) study is the only random-
as muscle-related symptoms.1 Statins increase the risk ized, controlled double-blind study designed specifi-
of diabetes consistent with the observation that low cho- cally to examine the effects of statins on skeletal muscle.3
lesterol levels increase diabetes risk.1 Although statins The STOMP trial had predefined criteria for statin myal-
reduce total stroke, they increase the risk of hemor- gia, which included onset of symptoms during treat-
rhagic stroke consistent with the observation that low ment, persistence for 2 weeks, symptom resolution
cholesterol levels are associated with an increase in hem- within 2 weeks of treatment cessation, and symptom re-
orrhagic stroke.1 Statins appear to reduce or have no ef- appearance within 4 week of restarting treatment.
fect on cognitive decline.1 Tendinopathies and intersti- Nineteen of 203 patients treated with statins and 10 of
tial lung disease have possible mechanistic links to 217 patients treated with placebo met the study defini-
tion of myalgia (9.4% vs 4.6%, P = .054).
This finding did not reach statistical sig-
Yet thousands of patients avoid these nificance, but it indicates a 94.6% prob-
ability that statins were responsible for
life-saving medications because of the
the symptoms. This result occurred even
presence of or concern about possible though the study participants were
statin-associated adverse effects. young (mean age, 44.1 years), healthy,
and treated with statins for only 6
statins, but their association with statins is based solely months. Creatine kinase values were not different be-
on a small case series.1 The frequency of these possible tween the 2 groups. These results not only suggest that
drug-related complications is unknown but is low and the true incidence of statin myalgia is approximately 5%
outweighed by the vascular benefits of statins therapy. but also support the observation that approximately
Statin-associated muscle symptoms are the most fre- 10% of patients will report symptoms of myalgia. Collins
quent statin-related symptoms. Experts agree that stat- et al2 reanalyzed the STOMP trial data after including 29
ins can cause muscle symptoms with marked increases in patients treated with atorvastatin and 10 with placebo
creatine kinase (CK) levels, usually defined as 10 times the who discontinued participation because of personal rea-
upper limits of normal because this has been observed in sons, yielding a P value of .08 and used this finding to
randomized clinical trials (RCTs) with an estimated occur- support their assertion that statins do not cause muscle
rence of 1 additional case per 10 000 individuals treated symptoms without markedly increased CK levels.
each year.2 In addition, statins can cause a necrotizing my- Diagnosing true statin-associated muscle symp-
opathy with antibodies against hydroxyl-methyl-glutaryl toms is difficult. In the Goal Achievement After Utiliz-
Co-A reductase.1 This condition must be recognized ing an Anti PCSK9 Antibody in Statin Intolerant Sub-
Corresponding promptlybecauseitcanleadtopersistentmyopathy.These jects (GAUSS-3) study,4 the presence of statin myalgia
Author: Paul D. patients present with muscle pain and weakness plus was determined by randomly assigning patients with
Thompson, MD,
Hartford Healthcare
markedincreasesinCKlevelsthatdonotresolvewithdrug presumed statin muscle symptoms to receive either
Heart & Vascular cessation.Statin-associatednecrotizingmyopathyisnewly 20 mg of atorvastatin or placebo each day for 10 weeks
Institute, Hartford recognizedandrarebutmaybemorefrequentlydiagnosed followed by a 2-week hiatus before crossover to the
Hospital, 80 Seymour
now that a commercial test for the antibody is available. alternative treatment. Only 209 patients (42.6%) de-
St, Hartford, CT 06102
(paul.thompson Incontrast,thereisconsiderabledebateastowhether veloped muscle symptoms during atorvastatin treat-
@hhchealth.org). statins can produce milder symptoms such as myalgia, ment. An additional 130 (26.5%) developed muscle

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 Opinion Viewpoint

symptoms during placebo-only treatment, 48 (9.6%) developed
muscle symptoms during both treatments, and 85 (17.3%) did not
develop symptoms during either treatment.
Other evidence supports the idea that statins can cause skel-
etal muscle symptoms without abnormal CK values. Muscle biop-
sies show differences in gene expression among patients with statin-
associated muscle symptoms during statin treatment and compared
them with asymptomatic controls.5 Statins also produce slight in-
creases in average CK levels and augment the increase in CK ob-
served after exercise.1 Rhabdomyolysis is more frequent in partici-
pants in RCTs who are receiving statins and have variants in the gene
for solute carrier organic anion transporter family member 1B1
(SLCO1B1),2 which regulates hepatic statin uptake. The SLCO1B1 gene
variants that reduce hepatic uptake allow more statin to escape the
liver and enter the extra portal circulation and ultimately skeletal
muscle. The SLCO1B1 variants are also associated with mild muscle
adverse effects in study participants treated with statins.6
How could the statin RCTs miss detecting mild statin-related
muscle adverse effects such as myalgia? By not asking. A review of
44 statin RCTs reveals that only 1 directly asked about muscle-
related adverse effects.7 In the STOMP trial, investigators called pa-
tients twice monthly to ask specifically about muscle symptoms.
Whether statins cause muscle symptoms with no or only mild CK
elevations is probably a moot point. If patients are convinced that the
statins are responsible, it is difficult to convince them otherwise or to
ignore their symptoms. So, how should these symptoms be managed?
Managing statin-associated muscle symptoms is not evidenced
based but requires reassuring the patient, reassessing the need for
statin therapy, determining if statins may be responsible for the symp-
toms, eliminating possible contributors to the process, and develop-
ing alternative treatment plans.1 Other medications (especially gem-
fibrozil) and conditions (hypothyroidism and vitamin D deficiency) can
increase muscle symptoms. Vitamin D deficiency alone can produce
myopathy, but evidence that vitamin D supplementation reduces
statin-associated muscle symptoms is limited.1 Coenzyme Q10 supple-
mentation has not been effective in reducing symptoms in a meta-
analysis of 10 studies,1 although some patients and clinicians are con-
vinced this agent works perhaps via a placebo effect. Coenzyme Q10
can be tried after informing the patients that it has not been effec-
tive in clinical trials but has been useful in some patients.
Creatine kinase measurements are required to ensure that there
is no major muscle injury and also because even small increases in
CK levels with treatment may help identify patients with true statin
myalgia. In a double-blind, randomized, placebo-controlled, cross-
over study evaluating symptoms in 120 patients with possible statin
myalgia, CK levels were slightly but significantly higher in patients
who developed muscle pain only during statin treatment.8 Pa-
tients without major increases in CK and tolerable symptoms should
be reassured that statins rarely cause severe muscle injury and that
the muscle symptoms usually resolve with drug cessation. Symp-
toms in typical statin myalgia resolve in most patients within weeks
of stopping the statin. Failure to resolve should prompt a search for
other sources of the discomfort.
Once the patient is asymptomatic, treatment can be started with
alternative regimens or low-dose statins. Ezetimibe reduces low-
density lipoprotein cholesterol (LDL-C) by approximately 20%, pro-
viding treatment benefit for some patients. Low doses of long-
acting statins such as 5 mg of rosuvastatin or 10 mg of atorvastatin
twice weekly can then be added, and increased at 4-week intervals
as necessary and as tolerated. Guidelines recommend only moder-
ate- to high-dose statins because such regimens were studied in
RCTs, but the greatest percent reduction in LDL-C occurs with low-
statin doses.1 The combination of ezetimibe and very low doses of
a statin can produce LDL-C reductions similar to those produced by
moderate- and high-dose statin therapy.1 Other agents such as bile
acid sequestrant resins and niacin can be tried if the clinician and pa-
tient are willing to deal with gastrointestinal adverse effects of res-
ins and the cutaneous and other adverse effects niacin. Niacin is no
longer recommended as an add-on to statins because it was inef-
fective in reducing cardiovascular events in 2 recent trials.1 Niacin
alone was effective in reducing cardiac morbidity and mortality in
the Coronary Drug Project,1 so niacin may be useful for patients who
are total intolerant to statins. Perhaps the easiest but most expen-
sive approach is to use proprotein convertase subtilism/kexin type
9 (PCSK9) inhibitors. These monoclonal antibodies produce remark-
able reductions in LDL-C but are presently only indicated for pa-
tients with familial hypercholesterolemia or documented athero-
sclerotic cardiovascular disease who have not achieved a sufficiently
low LDL-C level with the highest tolerated statin therapy.
The effectiveness and safety of statins have been docu-
mented by numerous RCTs, so every effort should be made for ap-
propriate patients to continue taking these medications. Many pa-
tients can ultimately tolerate these drugs, but doing so requires
acknowledging the possible relationship of statins with primarily
muscle symptoms and developing with the patient a collaborative
treatment plan.

ARTICLE INFORMATION
Conflict of Interest Disclosures: The author has
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
Dr Thompson reports that he has spoken for
Regeneron, Sanofi, Amgen, and Amarin; consulted
for Amgen, Regeneron, Merck, Esperion, and Sanofi;
received research support from Genomas, Roche,
Sanofi, Regeneron, Esperion, Amarin, and Pfizer;
and owns stock in Abbvie, Abbott Labs, CVS, General
Electric, Johnson & Johnson, Medtronic, and Sarepta.
REFERENCES
1. Thompson PD, Panza G, Zaleski A, Taylor B.
Statin-associated side effects. J Am Coll Cardiol.
2016;67(20):2395-2410.
2. Collins R, Reith C, Emberson J, et al.
Interpretation of the evidence for the efficacy
and safety of statin therapy [published online
September 8, 2016]. Lancet. doi:10.1016/S0140
-6736(16)31357-5
3. Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of
statins on skeletal muscle function. Circulation.
2013;127(1):96-103.
4. Nissen SE, Stroes E, Dent-Acosta RE, et al;
GAUSS-3 Investigators. Efficacy and tolerability of
evolocumab vs ezetimibe in patients with
muscle-related statin intolerance: the GAUSS-3
randomized clinical trial. JAMA. 2016;315(15):1580-
1590.
5. Hubal MJ, Reich KA, De Biase A, et al.
Transcriptional deficits in oxidative phosphorylation
with statin myopathy. Muscle Nerve. 2011;44(3):
393-401.
6. Voora D, Shah SH, Spasojevic I, et al.
The SLCO1B1*5 genetic variant is associated with
statin-induced side effects. J Am Coll Cardiol. 2009;
54(17):1609-1616.
7. Ganga HV, Slim HB, Thompson PD. A systematic
review of statin-induced muscle problems in clinical
trials. Am Heart J. 2014;168(1):6-15.
8. Taylor BA, Lorson L, White CM, Thompson PD.
A randomized trial of coenzyme Q10 in patients
with confirmed statin myopathy. Atherosclerosis.
2015;238(2):329-335.

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