Diagnosis, Prevention, and Management of Statin Adverse...

iology 29 (2013) 1553e1568
Canadian Journal of Card
Review

Diagnosis, Prevention, and Management of Statin AdverseEffects and Intolerance: Canadian Working Group

Consensus UpdateG.B. John Mancini, MD,a A. Yashar Tashakkor, MD,a Steven Baker, MD,b Jean Bergeron, MD,c

David Fitchett, MD,d Jiri Frohlich, MD,e Jacques Genest, MD,f Milan Gupta, MD,g

Robert A. Hegele, MD,h Dominic S. Ng, MD,i Glen J. Pearson, PharmD,j and Janet Pope, MDk

aDivision of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, CanadabDivision of Neurology and Rehabilitation, Department of Medicine, McMaster University, Hamilton, Ontario, Canada

cDivision of Lipidology, Department of Medicine, Laval University, Quebec City, Quebec, CanadadDivision of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada

eDivision of Laboratory Medicine, Department of Pathology, University of British Columbia, Vancouver, British Columbia, CanadafDivision of Cardiology, Department of Medicine, McGill University, Montreal, Quebec, Canada

gDivision of Cardiology, Department of Medicine, McMaster University, Hamilton, Ontario, CanadahDepartment of Medicine and Robarts Research Institute, Schulich School of Medicine, London, Ontario, Canada

iDivision of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, CanadajDivision of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

kDivision of Rheumatology, Department of Medicine, Schulich School of Medicine, London, Ontario, Canada

ABSTRACTThe Proceedings of a Canadian Working Group Consensus Conference,first published in 2011, provided a summary of statin-associatedadverse effects and intolerance and management suggestions. Inthis update, new clinical studies identified since then that providefurther insight into effects on muscle, cognition, cataracts, diabetes,kidney disease, and cancer are discussed. Of these, the arenas ofgreatest controversy pertain to purported effects on cognition and theemergence of diabetes during long-term therapy. Regarding cognition,the available evidence is not strongly supportive of a major adverse

Received for publication September 18, 2013. Accepted September 24, 2013.

Corresponding author: Dr G.B. John Mancini, Cardiovascular ImagingResearch Core Laboratory, Vancouver Hospital Research Pavilion, Room 489,878 West 10th Ave, Vancouver, British Columbia V5Z 1M9, Canada.Tel.: þ1-604-875-5477; fax: þ1-604-875-5471.

E-mail: [email protected] page 1563 for disclosure information.

0828-282X/$ - see front matter � 2013 Canadian Cardiovascular Society. Publishehttp://dx.doi.org/10.1016/j.cjca.2013.09.023

R�ESUM�ELa conf�erence de consensus Proceedings of a Canadian WorkingGroup Consensus Conference, publi�ee pour la première fois en 2011,a fourni un r�esum�e sur les effets ind�esirables et l’intol�erance associ�esaux statines et des suggestions de prise en charge. Dans cette mise àjour, nous discutons des autres perspectives sur les effets sur lesmuscles, la cognition, les cataractes, le diabète, la maladie r�enale et lecancer que les nouvelles �etudes cliniques ont depuis offert. Parmiceux-ci, les aspects les plus controvers�es concernent les effetspr�etendus sur la cognition et l’apparition du diabète durant le traite-

Statin intolerance is a clinical syndrome that is: (1) charac-terized by inability to use statins for long-term reduction oflipids and/or cardiovascular risk because of significant symp-toms and/or biomarker abnormalities that can be temporallyattributed to the initiation or dose escalation of statins; ifappropriate, drug withdrawal and rechallenge can strengthen

the association; (2) either “complete” (intolerant to any statinat any dose) or “partial” (intolerant to some statins at somedoses); and (3) not attributable to established predispositionssuch as drug-drug interactions, untreated hypothyroidism,febrile illness, etc.

Because many statins are available, a pragmatic additionalconsideration to the 3 characterizations of statin intolerancealready mentioned has been proposed whereby intolerance toat least more than the starting dose of 1 statin and any dose ofanother statin is considered to represent clinical statin intol-erance. The latter is encompassed by the definition of a partialstatin intolerance. Further complicating this clinical arena aremultiple reports of diverse, nonspecific, rare, and probablyidiosyncratic adverse effects that are inevitable with commonly

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http://dx.doi.org/10.1016/j.cjca.2013.09.023



effect of statins. In contrast, the linkage between statin therapy andincident diabetes is more firm. However, this risk is more stronglyassociated with traditional risk factors for new-onset diabetes thanwith statin itself and any possible negative effect of new-onset dia-betes during statin treatment is far outweighed by the cardiovascularrisk reduction benefits. Additional studies are also discussed, whichsupport the principle that systematic statin rechallenge, and lower orintermittent statin dosing strategies are the main methods for dealingwith suspected statin intolerance at this time.

ment à long terme. En ce qui concerne la cognition, les donn�ees sci-entifiques disponibles n’appuient pas de manière ferme un effetind�esirable majeur des statines. Par opposition, le lien entre letraitement par statines et l’incidence du diabète est plus solide.Cependant, ce risque est plus �etroitement associ�e aux facteurs derisque traditionnels d’un diabète d’apparition r�ecente que les statinesen soi, et tout effet n�egatif possible d’un diabète d’apparition r�ecentedurant le traitement par statines est de loin compens�e par les effetspositifs de la r�eduction du risque de maladie cardiovasculaire. Ondiscute �egalement d’�etudes additionnelles, qui soutiennent le principeque la reprise syst�ematique des statines, et des strat�egies deposologies plus faibles ou intermittentes des statines sont pour lemoment les principales m�ethodes pour composer avec la suspiciond’intol�erance li�ee aux statines.

1554 Canadian Journal of CardiologyVolume 29 2013

used drugs. Finally, another category of adverse effects is thatpertaining to long-term consequences such as promotion ofcancer, diabetes, or hemorrhagic stroke. The Proceedings ofa Canadian Working Group Consensus Conference, firstpublished in 2011, provided a summary of statin-associatedadverse effects and intolerance, and management sugges-tions.1 This is an area with extensive and growing literatureand so the purpose of this paper is to provide an update.

MethodsA literature search was undertaken extending from January

1, 2011 to May 16, 2013. Embase, MedLine, and PubMedwere comprehensively searched using search terms(Supplemental Table S1) pertaining to statin therapy, adverseeffects, and clinical management. Identified abstracts werereviewed manually to assure relevance to this review article,and then full articles were categorized and examined in moredetail. Two authors (G.B.J.M.) and (A.Y.T.) drafted thereport which was then iteratively reviewed, edited, andapproved by remaining members of the Canadian ConsensusWorking Group, who also added new citations. Case reportspertaining to purported statin-induced complications are notreviewed herein but are instead summarized (SupplementalTable S2). Reports with more extensive patient numbersand analyses are summarized in the main text (see the AdverseEffects section). In general, when both types of studies wereavailable, conclusions were most strongly influenced by resultsof randomized clinical trials (RCTs) or meta-analyses of RCTsthan by analyses from large databases because the latter mightoften be affected by residual confounding. Reports focused onpleiotropic benefits of statins are not a focus of this review.

Adverse Effects

Myopathy

Adverse muscle effects resulting from statin use have beenextensively reported in the literature.2 Table 1 shows theCanadian Consensus Working group definitions.1 Statin-induced rhabdomyolysis is dose-dependent, with a reportedrisk of approximately 0.04%-0.2%, a mortality rate of 7.8%,and a rate of 0.15 deaths per million prescriptions.3 Lesssevere myopathies are also dose-dependent and occur at a rateof approximately 0.1%-1%.4

Although transient and asymptomatic creatine kinase (CK)elevations are common, persistently elevated CK levels canalso occur. Although most do not necessitate a musclebiopsy,5 CK levels must be checked repeatedly to detectpersistence and possible onset of myopathy (symptomatic ornot). Pre-existing diagnoses (eg, spinal stenosis, poly-radiculopathy, etc) associated with muscle pain should notdiminish the possibility of a statin-associated worsening evenwhen CK levels are normal.6

Toxic effects of statins. The molecular mechanismsexplaining statin myopathy remain unknown but pre-existingdeficiencies in energy production might contribute tosymptom development.7 Recent in vivo and in vitro studieshave suggested that statin therapy might provoke cellularoxidative stress, and impairments of mitochondrial functionand muscular calcium homeostasis leading to myotoxicity.8,9

Decreased skeletal muscle coenzyme Q10 content wasaccompanied by a reduction in maximal mitochondrialoxidative phosphorylation in simvastatin-treated patients,compared with control subjects who had not been exposed tostatins. This observation might partially account for theunderlying mechanism for statin-induced myalgia and exerciseintolerance.10

Muscle cramping is generally considered to be a neurogenicphenomenon rather than myogenic, however, statins havebeen implicated in a study using population databases whichreported an augmented risk of 1.16 (95% confidence interval[CI], 1.04-1.29; P ¼ 0.004) for nocturnal leg cramps in adultsusing statins who were 50 years old or older.11

Using 31-phosphorus magnetic resonance (MR) spectros-copy, the effects of statins on mitochondrial oxidative func-tion during and after exercise on a calf flexion pedal ergometerhave been assessed. Metabolic recovery time was adverselyaffected during statin therapy in the absence of any symptomsor overt CK changes.12 Whether this potential derangement ismore pronounced in symptomatic statin-intolerant patients isunknown. But because it is known that patients with pre-existing mitochondrial disease might be prone to statinintolerance, this method might have a future role in assessingstatin-associated muscle problems.13 However, the observa-tion that many symptomatic patients can be successfullytreated with an alternative statin implies the existence ofmultiple pathogenic mechanisms that might act singly or in

Table 1. Integrated Canadian Working Group consensus terminologyfor myopathic syndromes and hyperCKemia

Term

Characteristics

Laboratory Clinical

Myopathy NA General term referring to anydisease of muscle

Symptomatic myopathyMyalgia CK � ULN Muscle ache/weaknessMyositis CK > ULN Muscle ache/weaknessRhabdomyolysis CK > 10 times ULN

(CK > 10,000 U/L)Muscle ache/weakness; renal

dysfunction might resultfrom myoglobinuria; needfor hydration therapy

HyperCKemiaMild, grade 1 CK > ULN, � 5 times

ULNMight/might not have

myositisMild, grade 2 CK > 5 times ULN,

� 10 times ULNMight/might not have

myositisModerate CK > 10 times ULN,

� 50 times ULNMight/might not have

rhabdomyolysis with/without renal dysfunction

Severe CK > 50 times ULN Might/might not haverhabdomyolysis with/without renal dysfunction

In patients with benign or idiopathic and chronic elevations of CK,symptom and severity descriptors should be referenced to the patient-specificbaseline level of CK.

CK, creatine kinase; NA, not applicable; ULN, upper limit of normal.Reproduced from Mancini et al.1 with permission from Elsevier.

Mancini et al. 1555Statin Adverse Effects and Intolerance

concert among patients, highlighting the need for furtherresearch. Furthermore, there is evidence to suggest thatpatients with proven mitochondrial disease can toleratestatins.14,15

Immune-mediated effects of statins. Statin myopathymight persist after drug discontinuation2 and might requireimmunosuppressive therapy.16 A number of studies haveassociated statin use with a variety of inflammatory myopathiesincluding polymyositis, dermatomyositis, and necrotizingmyopathy as outlined in a recent systematic review.16 Theconcept of statin-induced or unmasked autoimmune myopathyis strengthened by identification of a serum anti-3-hydroxy-methylglutaryl coenzyme A reductase (HMGCR) antibody insome symptomatic patients.17 In statin-exposed patients, theHMGCR antibodies correlated with elevated CK levels andarm and leg strength in a small cohort.17 The subsequentinflammatory myositis might be very persistent and notimprove despite statin withdrawal. With immunosuppressivetreatment, antibody levels declined, CK levels declined, andarm and hip strength improved,17 suggesting a phenotypicdifference between statin-exposed and statin-naive anti-HMGCR-positive patients. This antibody is especially found inpatients with necrotizing autoimmune myopathy and might bethe reason that the disease continues after the statin is dis-continued.18 Relationships between anti-HMGCR myopathyand HLA classes in statin intolerant patients might be a focusfor future studies.4 However, the prevalence of these antibodiesin statin users, with and without symptoms was unknown untila recent study in subjects taking part in the Atherosclerosis Riskin Communities (ARIC) study. Nearly 2000 patients werestudied and no individual was found to have such antibodies,including patients with documented statin intolerance or

statin-tolerant patients taking maximal doses. Thus, this type ofmyopathy is quite rare because the antibody reaction might beidiosyncratic, and establishing direct pathogenicity requiresfurther research.19

Role of exercise. Investigating the effect of statin therapy onexercise tolerance is a relatively new and controversial arena, butemerging evidence suggests that exercise might exacerbatestatin-associated side effects, possibly through an inflammatorymechanism.20 Simvastatin attenuated cardiorespiratory adapta-tions and skeletal muscle mitochondrial biogenesis in 37exercise-trained, sedentary, overweight, or obese adults with atleast 2 metabolic syndrome risk factors.21 An exercise-relatedincrease in serum total CK 24 hours after running a mara-thon was observed to be greater in statin users compared withcontrol subjects, particularly in older patients.22 The Effect ofStatins on Skeletal Muscle Function and Performance(STOMP) was a blinded, controlled study that assessedsymptoms and measured CK, exercise capacity, and musclestrength before and after either atorvastatin 80 mg or placebo(6-month trial) in 420 healthy, statin-naive subjects.23 High-dose atorvastatin did not decrease average muscle strength orexercise performance, but more atorvastatin-treated subjectsthan placebo-treated subjects developed myalgia and higheraverage CK level, suggesting that high-dose statins mightproduce mild muscle injury in the context of exercise.24

Central nervous system

Cognitive impairment. The US Food and Drug Adminis-tration (FDA) recently mandated label changes on statins,warning of memory loss and confusion. These adverse effectshave not emerged as consistent signals in large clinical trialsand, when encountered, have generally not been serious andhave reversed with statin cessation. Time to onset has beenhighly variable, ranging from 1 day to many years afterinitiation of statin treatment. Statin-associated cognitivechanges are rare, and insufficient evidence is currently avail-able to establish causality or association with fixed orprogressive dementia or Alzheimer’s disease.25 There is noclear association with type or dose of statins, even though 1literature review suggested a need to consider the effect ofhydrophilic and lipophilic statins on cognition, aggression,and other quality of life domains.26 A randomized trial of theeffects of simvastatin provides partial support for minordecrements in cognitive functioning.27 In another study,lovastatin neither caused psychological distress nor substan-tially altered cognitive function, and the small attenuation onneuropsychological tests of attention and psychomotor speedwere of uncertain clinical significance.28 A narrative literaturereview concluded that statin-associated cognitive impairmentis rare, potentially resolvable by switching from lipophilic tohydrophilic statins, and far outweighed by the cardiovascularbenefits.29 A recent, comprehensive meta-analysis ofrandomized clinical trials found no significant relationshipbetween statin therapy and cognitive decline or adversecognitive events in cognitively healthy people and those withdementia.30 Two meta-analyses of randomized trials ofpatients with Alzheimer’s disease have shown a neutral effectof statins on cognitive function.31,32


Fatigue, headache, dizziness. A questionnaire-based, cross-sectional study reported relatively higher incidences of head-ache, dizziness, and paresthesia during statin therapycompared with control subjects not receiving statins.33 Riskfactors identified for these adverse reactions were male sex,alcohol consumption, duration of therapy more than 5 years,and high-dose lovastatin.33

Golomb et al.34 reported on patients in a single centrestudied for tertiary or exploratory, noncardiac end points ina randomized clinical trial comparing placebo, simvastatin 20mg. and pravastatin 40 mg. Patients (n ¼ 1016) reported on“energy” and a subset (397 patients) also reported on “fatiguewith exertion.” An “EnergyFatigueEx” index was analyzedusing imputational methods for missing data.34 The explor-atory report showed statistical deterioration in this compositeindex that was more evident for simvastatin than for pravas-tatin and of somewhat greater magnitude in women.34

However, the clinical relevance of the findings of this rela-tively small and so far nonreplicated study is unclear.

Psychiatric. Definite psychiatric complications from statintherapy have not been well established. A study of 409patients after cardioverter-defibrillator implantation foundthat statin therapy was associated with impaired health statuspertaining to physical, social, and emotional domains.35

Moreover, there was a borderline significant associationbetween statin therapy and depression but no association withanxiety.35 In contrast, a retrospective, observational studyconsisting of more than 46,000 patients concluded that therewas no increased risk of developing psychological disordersincluding schizophrenia, psychosis, major depression, andbipolar disorder in a military cohort of propensity score-matched statin users and nonusers.36 Other groups havesuggested a potential beneficial effect of statin use ondepression in patients with coronary heart disease.37 Accord-ingly, it is difficult to accept a direct link between statin usageand psychiatric adverse effects based on these studies.

Intracranial hemorrhage. The association of subarachnoidhemorrhage and lipid-lowering therapy has been re-evaluatedin a meta-analysis of 31 randomized controlled trials incor-porating more than 180,000 patients.38 Active statin therapywas not associated with a significant increase in intracranialhemorrhage. Moreover, a significant reduction in all strokesand even all-cause mortality was observed in the aggregatedresults of the trials.38 A small post hoc analysis froma prospective, randomized, placebo-controlled trial of 80 mgof atorvastatin daily demonstrated a significant increase inhemorrhagic strokes in the statin arm compared with theplacebo arm (hazard ratio, 1.66; 95% CI, 1.08-2.55), but thisincrease was offset by a considerably larger decrease inischemic events.39 Similar findings are reported in a recentmeta-analysis.40

In a single study of 163 patients with spontaneous intra-cranial hemorrhage, statin users were older, had significantlylower cholesterol levels, and higher prevalence of hyperten-sion, dyslipidemia, diabetes, and antiplatelet use. However,age and statin use were independently associated with thepresence and increased number of micro hemorrhages; statin-treated patients had almost twice as many cortico-subcorticalmicrobleeds compared with untreated patients, detected

using MR imaging.41 It is not clear if the confounding riskfactors for bleeding could be adequately taken into accountstatistically in this small study.

Ophthalmological

An early concern over a possible association between statinsand cataracts has been alleviated by findings from clinical trialsand through clinical experience. However, this issue has beenraised again in several recent reports. Cataracts are a knowncomplication of diabetes mellitus (DM) and most patientswith DM, based on their high cardiovascular (CV) risk,receive statins. In a cross-sectional study of 780 patients withtype 2 diabetes at a very high risk of diabetic retinopathy andcataracts, there was no evidence of an association betweenstatin use or other lipid-lowering agents and cataract forma-tion.42 These findings are in contrast to a cross-sectionalanalysis of 6397 patients, suggesting statin use is associatedwith age-related cataracts, including nuclear sclerosis (oddsratio [OR], 1.48; 95% CI, 1.09-2.00) and posterior subcap-sular cataract (OR, 1.48; 95% CI, 1.07-2.04).43 Theseabnormalities occurred on average 2.4-3.4 years earlier indiabetic statin users compared with control subjects not usingstatins.43

A case-control study consisting of approximately 48,000participants44 reported that the proportion of statin usersappeared to be greater among those with cataract surgery(64.3%) compared with those without a diagnosis of cataractor cataract surgery (55.5%). Interestingly, after adjustment forage, sex, race, smoking status, DM, and coronary arterydisease, longer-term statin use was found to be protectiveagainst cataract extraction (OR, 0.93; P ¼ 0.02), and shorter-term use was associated with cataract surgery (OR, 1.11; P <0.0001).44 Age-stratified logistic regression analysis showedthat statin use of 5 years or more was protective againstcataract surgery in the younger age group (50-64 years), andstatin use of less than 5 years was associated with an increasedrisk of surgery in younger and older age groups.44 Finally,a recently published propensity score-matched analysis alsoshowed an increased risk for cataract in statin users vs non-users, which was noted also in patients with no knowncomorbidities for cataract formation.45

Rheumatologic and dermatologic

Assessment of musculoskeletal side effects in patients witharthritis is complex. In a cross-sectional study based on theNational Health and Nutrition Examination Survey(NHANES), investigators noted no association betweenmusculoskeletal side effects and statin use in patients witharthritis, whereas in patients without arthritis, musculoskeletalsymptoms were significantly associated with statin use.46

In a cohort of 508 patients 40 years old or older witha first-time diagnosis of rheumatoid arthritis (RA), there wasno consistent trend of increasing risk of RA with increasedcumulative duration, cumulative daily doses, or number ofprescriptions of statins.47 However, a small positive trendbetween the potency of statin treatment and the risk of RAwas found.47 This study is different from others in whichprevious use of statins was considered protective against thedevelopment of RA. Also, other older reports have demon-strated that statins could improve RA disease activity, but


a recent RCT of rosuvastatin in RA showed an improvementin C-reactive protein but not RA disease activity.48 In RA,statin use might be less effective in achieving low-densitylipoprotein (LDL) targets compared with control subjects,especially if patients have a high baseline erythrocyte sedi-mentation rate.49 However, discontinuation of statin use inRA in a large population study from Canada, resulted inincreased cardiovascular and all-cause mortality in RA, soadherence to statin treatment when prescribed in this higher-risk population should be encouraged.50 Diseases such as RAand systemic lupus erythematosus are associated withincreased atherosclerosis and adverse lipid profiles. However,routine statin use in pediatric-onset patients with systemiclupus erythematosus over 3 years did not affect subclinicalatherosclerosis despite improved C-reactive protein and lipidprofiles. The study might have been too short to observechanges in carotid intima-media thickening.51 A case-controlstudy of 3362 lupus-like cases and 27,092 control subjectsfrom adverse drug reaction reports obtained from the WorldHealth Organization (WHO) global individual case safetyreports database (VigiBase) found that statins were twice aslikely to be used in those who had a lupus-like adverse drugevent than in other control subjects; however, the rates werevery low at 3.2% in cases and 1.5% in control subjects, so ifthis is a causal association of statins and lupus-like syndromes,it would not be a major cause of this syndrome.52 An asso-ciation between statin use and the occurrence of polymyalgiarheumatica in the spontaneous reporting database of theWHO has been noted.53 A pharmacoepidemiological studyreported an OR for statin exposure associated with lupus at1.67 (95% CI, 1.02-2.74).54 One case series reports 2 patientstaking pravastatin and 1 patient taking rosuvastatin whodeveloped presumed statin-induced Pityriasis lichenoideschronica.55 These are likely to represent idiosyncraticreactions.

Hepatic effects

The mechanisms of statin-induced adverse liver effects arenot entirely understood and in practice, alcohol- andnonalcohol-related underlying fatty liver disease mightcomplicate statin association. Although elevation of liverenzymes is observed in a small proportion of patients takingstatins, an even smaller fraction of these patients mightprogress to clinically significant statin-associated hepatitis.Pharmacovigilance data consisting of 9360 cases of adversedrug events as defined by the WHO Reaction Terminologyresulted in statins being associated with an increased oddsratio of 3.0 (95% CI, 1.3-6.9; P < 0.05) for causing anyhepatic adverse drug reaction, with elevated liver enzymes asthe most common.56 A recent analysis of the Swedish AdverseDrug Reactions Advisory Committee estimated the incidenceof statin-related transaminitis at 1.2 per 100,000 patientstaking statins.57 Most patients experienced liver abnormalitiesapproximately 3 to 4 months after therapy initiation and witha reproducible pattern of liver injury on re-exposure afterrecovery.57 Atorvastatin and simvastatin were the mostresponsible agents, particularly for cholestatic/mixed patternsand hepatocellular injury patterns, respectively.57 In thiscohort, there was a “high probability” of statin causality forthe death of 1 patient who died of acute liver failure and also

another who required liver transplantation. There wasa “possible” statin-related case in a patient who died fromacute liver failure. In contrast to other reported cases, thesepatients each had a thorough diagnostic work-up thatexcluded common comorbidities that might have affectedoutcomes.57 Statin-induced jaundice is calculated at a risk of 1in 17,434 users per year, based on a population in Iceland.58

Periodic monitoring of liver enzyme levels does not appear tobe effective in detecting or preventing serious liver injury fromstatin use, thus justifying the discontinuation of the previousrecommendation for routine, serial liver enzyme monitoringduring chronic statin therapy.25

Use of statins in patients with compensated liver disease isgenerally considered to be safe. Malaguarnera et al.59 per-formed a randomized assessment of the addition of rosuvas-tatin 5 mg/d in patients with nonalcoholic fatty liver diseaseand hepatitis C being treated with a-interferon and ribavirin.In addition to improved lipid levels, the statin-treated groupshowed reductions in viremia associated with reduced hepaticfibrosis and hepatosteatosis along with an improvement insustained virological response.59 Another prospective,randomized trial observed that after 12 weeks, atorvastatin(10 mg/d) and pitavastatin (2 mg/d) reduced transaminitis in189 patients with mild to moderate elevation of alanineaminotransferase60; all subjects were not alcoholics and sero-logically negative for viral hepatitis markers, and none hadbeen treated with statins for more than 3 months beforescreening.60

Gastrointestinal

A cross-sectional questionnaire-based study reported flatu-lence as the most prevalent statin-induced gastrointestinal sideeffect with 4.8% of patients discontinuing statin therapybecause of any gastrointestinal side effects.61 Other observedside effects included swallowing difficulty, dyspepsia, con-stipation, diarrhea, nausea and vomiting, and abdominalcramps, with risk factors identified as female sex, East Indianrace, consumption of alcohol, higher lovastatin dose, secondarydyslipidemia, DM, and concurrent b-blocker administra-tion.61 However, the aggregate of data and meta-analyses ofclinical trials indicate that the incidence of such adverse effectsis not greater in statin-treated patients compared with controlsubjects who had not been exposed to statins.

Renal

Controversy exists regarding the effects of high-potencystatins on renal function. In 72,488 patient-years of follow-up in 36 studies of rosuvastatin involving more than 40,000patients, renal impairment or renal failure were reported inonly 536 participants.62 Rates of renal end points were higherin patients with risk factors for renal problems (eg, hyper-tension, heart failure, diabetes, or patients with baseline esti-mated glomerular filtration rate less than 60 mL/min/1.73m2) but there was no difference even in these groups betweenplacebo- and statin-treated patients or between the maximal40 mg and 10 mg daily doses.62 In addition, 2 meta-analysesthat assessed benefits and harms of statin use in patients withrenal disease showed no deterioration, and a trend towardimprovement or maintenance of renal function.63,64 Thesecurrent meta-analyses also showed decreased mortality and


cardiovascular events in patients with chronic kidneydisease,63,64 but showed little or no benefit in personsreceiving dialysis and uncertain effects in kidney transplantrecipients.64 One small study concluded that pitavastatinmight be safe and well tolerated in subjects with severe renalimpairment and not using hemodialysis.65

A large retrospective study quantified the associationbetween acute kidney injury (AKI) and use of high-potencystatins vs low-potency statins by analyzing data from morethan 2 million patients 40 years old or older and newly treatedwith statins66; high-potency statin treatment was defined as �10 mg rosuvastatin, � 20 mg atorvastatin, and � 40 mgsimvastatin, with all other statins and doses defined as lowpotency.66 In patients with nonchronic kidney disease,current users of high-potency statins were 34% more likely tobe hospitalized with AKI within 120 days after startingtreatment and users of high potency statins with chronickidney disease did not have as large an increase in admissionrate.66 These observations from administrative databasesappear quite discordant with randomized trial data.63,64

An association between statin therapy and hematuria andproteinuria has been well established. Statin-induced micro-albuminuria is thought to be secondary to statin interferencewith the tubular reabsorption of albumin. In 2 observational,cross-sectional descriptive studies, the prevalence of micro-albuminuria was greater among patients taking statins.67,68

This mechanism of microalbuminuria is not believed to beindicative of renal dysfunction.

DM

An increased incidence of new-onset type 2 DM has beenassociated with several drugs including thiazide diuretics, b-blockers, glucocorticoids, niacin, protease inhibitors, andstatins.69-72 These findings contrast with protective effects ofstatins on b-cell function, through immunomodulatorymechanisms which have been postulated, but not substanti-ated.73 An FDA drug safety communication reports that sta-tins appear to moderately increase the risk of developing DM,and regular screening for diabetes should be considered,especially for patients taking high-dose statins and patientswith multiple risk factors for DM.25,74

In a retrospective analysis of the Justification for the Use ofStatins in Prevention: An Intervention Trial EvaluatingRosuvastatin (JUPITER) trial, participants were stratified onthe basis of having none or at least 1 of 4 major risk factors fordeveloping DM: metabolic syndrome, impaired fastingglucose, elevated body mass index (BMI), or elevated hemo-globin A1c.75 In participants with 1 or more DM risk factors,statin therapy was associated with a 28% increased risk ofdeveloping DM, and for participants with no major riskfactors, statin allocation was not associated with an increase inDM.75 The absolute numbers of new cases of DM was verysmall overall (270 in patients taking rosuvastatin vs 216 takingplacebo; hazard ratio, 1.25; 95% CI, 1.05-1.49; P ¼ 0.01).Cardiovascular and mortality benefits of statin therapyexceeded the DM hazard, even in participants at high risk ofdeveloping diabetes.75 A population-based study used pra-vastatin as the reference drug and observed an increased risk ofincident DM with atorvastatin, rosuvastatin, and simvastatin,but not with fluvastatin or lovastatin.76 The absolute risk for

incident DM was approximately 31 and 34 events per 1000person-years for atorvastatin and rosuvastatin, respectively.76

Similarly, in a large cohort with hypertension and dyslipide-mia, a retrospective study reported that the risk of new-onsetDM was higher among users of pravastatin than amongnonusers, and patients who took fluvastatin, lovastatin, androsuvastatin were at lower risk of developing new-onset DMthan nonusers77; simvastatin and atorvastatin demonstrateda neutral effect.77 An in-hospital cohort was followed fora median of 7.2 years, and annual rates of diabetes were re-ported modestly greater in statin users (2.4% vs 2.1%; P <0.001), which were more than offset by attenuation of majoradverse cardiovascular events and in-hospital mortality rates.78

Last, a large study included 153,840 nondiabetic womenparticipating in the Women’s Health Initiative (WHI) atbaseline, of which 7.04% reported taking statin medica-tions.79 There were 10,242 incident cases of self-reported DMover 1,004,466 person-years of follow-up79; all types of statintherapy at baseline were associated with an increased risk ofDM after adjusting for potential confounders.79 A specificeffect on glucose levels with concomitant use of pravastatinand paroxetine was noted in the FDA’s Adverse EventReporting System that was not observed when either wasgiven separately, and not observed with other selective sero-tonin reuptake inhibitors.80

The brain-derived neurotrophic factor Val66Met variantmight influence statin-associated insulin resistance andincreased risk of DM.81 Results suggest that in a metabolicallyhigh-risk population with schizophrenia, but not bipolardisorder, the brain-derived neurotrophic factor Val66Met allelealone and in combination with statin medications is associatedwith greater insulin resistance.81

In contrast to these results, Ko et al.82 studied more than17,000 older patients with myocardial infarction and at 5 years,observed similar rates of new-onset DM in patients receivingintensive-dose and moderate-dose statins (13.6% vs 13.0%,respectively; P¼ 0.19)82 although the former was found effectivein reducing repeat hospitalization for acute coronary syndrome. Arecent analysis of 3 large trials emphasized that fasting glucoselevels and features of themetabolic syndrome aremore consistentdeterminants of DM than statin use.83 Thus, the development ofnew-onset DM with statin treatments appears to be relativelyuncommon in comparisonwith the expectedCVbenefits, relatedmainly to use of highest doses and most apparent in patientsalready at risk for development of DM.Moreover, cardiovascularbenefits of statins have previously been demonstrated specificallyin patients with metabolic syndrome who are at risk for devel-oping diabetes and in those with established diabetes.84-86

Erectile dysfunction and gynecomastia

Conflicting data are available regarding an association ofstatin use with erectile dysfunction (ED). This might bepartially attributable to overlapping risk factors for ED andcardiovascular pathology necessitating statin therapy. Statinsmight be protective against ED, secondary to their contribu-tion to an overall enhanced endothelial function. A prospec-tive randomized trial observed that 10 mg of atorvastatin dailywas inferior to regular tadalafil use, but superior to nomedications, in improving ED, particularly in patients withdyslipidemia.87


Data from the Italian spontaneous adverse drug reaction-reporting database suggested a possible association betweengynecomastia and statins as a drug class, particularly withhigher potencies.88 However, this isolated observation hasnever been replicated in other studies or databases.

Interstitial lung disease

Interstitial lung disease is considered to be an idiosyncraticand rare reaction to statin therapy. However, using regressionanalyses and after adjustments for covariates such as highcholesterol or coronary artery disease, statin use in smokers inthe Chronic Obstructive Pulmonary Disease Gene(COPDGene) study was associated with an increased risk ofinterstitial lung abnormalities, not necessarily clinical inter-stitial lung disease.89 Furthermore, in an animal model,pretreatment with statins augmented bleomycin-induced lunginflammation and fibrosis, possibly through increased mito-chondrial reactive oxygen species generation that enhancednucleotide-binding oligomerization domain-like receptorfamily, pyrin domain containing 3 (NLRP3) inflammasomeactivation.89 Currently, however, all dyslipidemia guidelinessupport use of statins to prevent an increased risk of cardio-vascular disease in smokers. In addition, other analyses suggesta benefit of statins for other pulmonary conditions includingpneumonia, influenza, and chronic obstructive pulmonarydisease.90 In fact, the combination of statins and eitherangiotensin-converting enzyme inhibitors or angiotensinreceptor blockers was associated with a reduction in chronicobstructive pulmonary disease hospitalization and totalmortality in low and high cardiovascular risk cohorts.91

Cancer

The concern of statins promoting cancer has been dispelledby a large collaborative meta-analysis published in 2010, whichreinforced the safety of statin therapy and lack of associationwith incidence of cancer.40 Moreover, an analysis of nearly46,000 propensity-matched pairs of older adults showed nodifferences in rates of any type of cancer over 10 years, betweenpatients taking a statin and those not taking a statin.92

Furthermore, investigators using sophisticated methods toinvestigate an association between statin and specific subtypesof colorectal cancer based on anatomical location and molec-ular markers did not show any association.93

A population-based case-control study found no evidenceto support either beneficial or harmful associations betweenstatin use and bladder cancer risk.94 Similar findings werenoted regarding the risk of long-term statin use and overallcancer risk, but intriguingly, potential protective effects ofstatins for lowering the risk of melanoma, endometrial cancer,and non-Hodgkin lymphoma were observed.95 Moreover,statin use was possibly associated with improved cancer-freeand overall survival in 255 patients after heart trans-plantation.96 In a large population-based study, the risk ofglioma was reduced among long-term statin users (OR, 0.76;95% CI, 0.59-0.98) compared with subjects who had neverused statins, and was inversely related to the intensity of statintreatment among users, particularly in patients 60 years old oryounger.97 In a population-based cohort study of 260,864hepatitis C virus-infected patients, an inverse dose-responserelationship between statin use and hepatocellular carcinoma

risk was observed.98 Last, a prospective study in 50 womenwith a history of breast cancer concluded that simvastatinappears to modulate estrone sulfate concentrations and theirpotential chemopreventive activity in breast cancer warrantsfurther investigation.99

In contrast, in a study that assessed pathological character-istics of 588 radical prostatectomy specimens, an increased rateof high Gleason score, pathologic stage, and recurrences werenoted in patients receiving statins for more than 2 years.100

Endogenous and Exogenous Risk Factors forStatin Intolerance and Adverse Effects

A summary of endogenous and exogenous risk factors forstatin intolerance and adverse effects is provided in Table 2.

Genetic considerations

Much of the genetic work is driven by the fact that statin-associated muscle symptoms dominate our clinical focus.101

There is growing evidence that some carriers of geneticpolymorphisms in the enzymes and transporters implicated instatin disposition, particularly the rs4149056 variant in thesolute carrier organic anion transporter gene (SLCO1B1), areat increased risk of statin-induced adverse effects and specifi-cally myotoxicity with very high doses of simvastatin inparticular. A common nonsynonymous coding variant inSLCO1B1 has been demonstrated to be strongly associatedwith the risk of development of simvastatin (80 mg daily)-induced myopathy in a whole-genome association analysis ofthe Study of the Effectiveness of Additional Reductions inCholesterol and Homocysteine (SEARCH) study.102 A recentreview reported statin-induced myopathy in a family with 2patients who were carriers of the rare allele of the SLCO1B1rs4363657 polymorphism, re-enforcing the potential effect ofsuch genetic factors on the risk of myopathy with statinuse.103 In 25 cases of severe statin-associated myopathy,Brunham et al.104 reported that SLCO1B1 rs4149056 geno-type was significantly associated with myopathy in patientswho received simvastatin, but not in patients who receivedatorvastatin. Other common SLCO1B1 variants were exam-ined in a large population of patients with DM who werereceiving diverse statins; the rs4149056 (Val174Ala) genotypewas associated with higher intolerance and less cholesterol-lowering in response to statins, whereas the rs2306283(Asp130Asn) genotype was associated with lower intolerancerates.105 Another genomic study suggested that presence ofindividual intronic single nucleotide polymorphisms inSLCO1B1 might predict the ability of simvastatin and rosu-vastatin to lower LDL cholesterol (LDL-C).106

A genome-wide association study was undertaken ina group with severe statin myopathy vs a statin-tolerant groupof patients and resulted in identification of 3 single-nucleotidepolymorphisms in the “eyes shut” homolog (EYS) on chro-mosome 6, suggestive of an association with risk. The EYSgene products have similarities to members of the Notchsignalling pathway and to agrin, leading these investigators topostulate that the polymorphisms might affect the mainte-nance and regeneration of skeletal muscle.107

The C34353T polymorphism in ABCB1 also appears toexplain some heterogeneity of adverse response to statins. TheT allele appears to be more frequent than the C allele in

Table 2. Predisposing factors for statin-associated adverse effects

Endogenous factorsAdvanced age (older than 80 years)Female sexAsian ethnicityLow body mass index, small body frame, frailtyHistory of pre-existing/unexplained muscle/joint/tendon painHistory of creatine kinase elevationFamily history of myopathyFamily history of myopathy with statin therapyNeuromuscular diseases (eg, acid maltase deficiency, amyotrophic lateral

sclerosis, carnitine palmitoyl transferase II deficiency, cytoplasmic bodymyopathy, dermatomyositis, hyaline inclusion myopathy, inclusion bodymyositis, McCardle disease, malignant hypothermia, mitochondrialmyopathy [MELAS: mitochondrial myopathy, encephalopathy, lacticacidosis, and stroke-like episodes], muscle phosphorylase B kinasedeficiency, myasthenia gravis, myoadenylate deaminase deficiency,myotonic dystrophy types I and II, necrotizing myopathy, peripheralneuropathy [length-dependent, mononeuritis multiplex], polymyositis[idiopathic, paraneoplastic], recurrent acute myoglobinuria [Lipin-1mutation], rippling muscle disease (sporadic, autoimmune), spinobulbarmuscular atrophy)

Severe renal diseaseAcute/decompensated hepatic diseaseHypertension/heart failure (renal side effects mainly)Hypothyroidism (untreated)Diabetes mellitusGenetic polymorphisms (eg, cytochrome P isoenzymes, SLCO1B1 gene

variants, “eyes shut” homolog [EYS] on chromosome 6, C34353Tpolymorphismin ABCB1, ABCG2 polymorphisms, ryanodine receptor (RYR1) gene,brain-derived neurotrophic factor [BDNF] Val66Met variant, Lipin-1[LIPIN1] mutation, rs9806699 variant in glycine amidinotransferase[GATM])

Exogenous factorsHigh statin dose*Alcohol abuseIllicit drug use (cocaine, amphetamines)AntipsychoticsDrug-statin interactionsFibrates (particularly gemfibrozil)Nicotinic acidAmiodaroneVerapamilWarfarinCyclosporineMacrolide antibioticsAzole antifungalsProtease inhibitorsNefazodoneLarge quantities of grapefruit (> 1 quart per day), pomegranate juice (?)Surgery with severe metabolic demandsHeavy and/or unaccustomed exercise

* See text for specific precautions regarding simvastatin and lovastatin use.Modified from Mancini et al.1 with permission from Elsevier.


patients with atorvastatin-induced myalgia.108 Malignanthyperthermia is an autosomal dominant disorder of skeletalmuscle triggered by volatile anaesthetic use, extreme exertion,or heat exposure, and is determined by mutations in theryanodine receptor gene, RYR1, in 50%-70% of cases. Someof these variants might contribute to underlying genetic riskfor statin myopathy in carriers.109

One study identified a downstream target of statin treatmentby screening for the effects of in vitro statin exposure on geneticassociations with gene expression levels in lymphoblastoid celllines derived from 480 participants of a clinical trial of simvas-tatin treatment.110 This analysis identified 6 expression-quantitative trait loci that interacted with simvastatin exposure,

including rs9806699, which was a marker for a cis-expression-quantitative trait locus for the gene glycine amidinotransferase(GATM) that encodes the rate-limiting enzyme in creatinesynthesis and found this locus to be associated with incidence ofstatin-induced myotoxicity in 2 separate populations.110 GATMknockdown in hepatocyte-derived cell lines attenuated tran-scriptional response to sterol depletion, implying that GATMmight act as a functional link between statin-mediated loweringof cholesterol and susceptibility to statin-induced myopathy.110

A 45-fold variation in atorvastatin or rosuvastatin systemicconcentrations can be observed among patients taking thesame dose. High levels of these agents have been related toreduced-function polymorphisms in the SLCO1B1 and theABCG2 genes and 4-beta-hydroxycholesterol, a cytochrome P3A (CYP3A) activity marker.111 Knowledge of these poly-morphisms might be useful to help avoid high drug levels inspecific patients, particularly in elderly patients.111

Clinical pharmacology and drug-drug interactions

Although clinicians have long accepted the relationshipbetween dose of statins and symptoms and rhabdomyolysis,this relationship has not always been clear from informationpertaining to individual statins. Holbrook et al.112 evaluatedall cases of statin-associated rhabdomyolysis reported toHealth Canada’s Canadian Vigilance Program and to theFDA’s Adverse Event Reporting System; considering all sta-tins and using atorvastatin 10 mg daily as the reference dosepotency, risk of rhabdomyolysis increased by a factor of 4 fora 4-fold increase in dose and by 11 for an 8-fold increase indose.112 Patients were an average age of 64 years old, 2/3 weremale, and cases often showed secondary consequences such asrenal dysfunction (17% of cases), acute renal failure (20% ofcases), dialysis (5% of cases), or death (8% of cases).112 Aslightly updated review of cases reported to the FDA founda male:female preponderance (5:3), an association with veryyoung age groups (younger than 10 years old), and bodyweight less than 50 kg, onset within a month of drug exposurein more than 50% of cases, and a higher risk of fatal outcomewhen complicated by renal dysfunction.113

In a prospective study of patients receiving statinscompared with an age- and sex-matched control group, only3.2% of the entire cohort complained of muscle symptomsand, among these, objective weakness was noted in only 15%.Adverse reactions, noted in up to 21% of patients and only5.9% of control subjects, were predicted by older age, longerduration of statin use, DM, stroke, and lower BMI.114

The risks of many statin-induced adverse effects are relatedto drug serum levels. Coprescription with certain other drugscan increase serum statin concentrations. Practitioners shouldremain aware of drug-drug interactions generally related toshared metabolic pathways,115-127 particularly CYP3A4.128,129

In contrast, a large retrospective cohort study spanning 18years independently evaluated muscle toxicity, renaldysfunction, and hepatic dysfunction secondary to druginteractions, finding no difference in the relative hazards forpatients prescribed a CYP3A4-dependent statin substrate vsa non-CYP3A4-dependent statin substrate with a concomi-tant CYP3A4 inhibitor.130 Although statins are not generallyconsidered to have a marked effect on coagulation, the effectof simultaneous statin therapy and warfarin use on the


international normalized ratio suggests relatively larger effectsof rosuvastatin on international normalized ratio comparedwith pitavastatin.131

From a practical perspective, it is important to emphasizethat practitioners should no longer use the 80-mg dose ofsimvastatin because of the increased risk of myopathy, andsuch doses are to be continued only in patients already knownto be doing well with long-term therapy. Most of this risk hasbeen observed with concomitant use of amiodarone, diltia-zem, and amlodipine. With amlodipine, simvastatin shouldnot exceed 20 mg, and it should not exceed 10 mg if amio-darone, verapamil, or diltiazem are being used. Simvastatinshould not be used at all with antifungal agents, gemfibrozil,cyclosporine, or the macrolide antibiotics. Lovastatin hasproperties similar to simvastatin and is also contraindicated foruse with antifungal agents, macrolide antibiotics, proteaseinhibitors, and nefazodone. Lovastatin should be avoidedwhen cyclosporine or gemfibrozil are required. Doses shouldnot exceed 20 mg when using danazol, diltiazem, or verap-amil, and should not exceed 40 mg when using amiodarone.

Table 3. Principles for the management of statin intolerance andadverse effects*

Principle

Ensure that there is an indication for statin use and that the patient is fullyaware of the expected cardiovascular risk reduction benefit that can beachieved with this method of lipid-lowering.

Ensure there are no contraindications for statin use. Be vigilant for factorsoutlined in Table 2.

Counsel patients regarding potential side effects, their frequency, and highlikelihood of successful, long-term statin therapy. Long-term concernsregarding diabetes should not prevent indicated use of statin.

Emphasize dietary and health behaviour interventionsUse statin-based strategies preferentially if intolerance arisesIf rechallenge is appropriate but does not workUse lower and/or intermittent statin dosingUse a different statin

Use nonstatins as adjuncts if needed to achieve lipid targetsDo not recommend supplements to alleviate myalgias because none have yet

been shown consistently to allow continuation of statins

* See flow diagrams in Mancini et al.1 (also available at www.circl.ubc.ca/cardiorisk-calculator.html).

Diagnosis of Statin IntoleranceThe challenge of making a diagnosis of statin intolerance, as

defined in the introductory section, is amplified by a recentdetailed study of a cohort of patients referred to a lipid clinic forstatin intolerance attributable to muscle pain without CKelevation (myalgia) and compared with statin-tolerantpatients.132 Although more statin-intolerant patients werewhite and hypertensive, there was no increased prevalence ofrenal disease, DM, thyroid disease, electrolyte abnormalities, orpotentially interacting medications, all of which are consideredto predispose to intolerance.132 Although most were intolerantto 2 or more statins, more than half of the cases weresuccessfully rechallenged with an alternative statin.132

The role of routine laboratory monitoring of liver enzymesor CK after initiation of statin therapy remains controversial.Recommendations for only symptom-based investigations aresupported by a recent study.133 There are, however, 2 mainreasons for persisting with a baseline and a 1-time, follow-upanalysis after initiation, dose change, or change in statin type.First, some patients are highly cognizant or concerned aboutstatin adverse effects and derive reassurance from lack of anyadverse liver/muscle enzyme changes when these are pre-sented. Second, in the rare case of symptoms arising afterstatins are initiated or changed, the inability of the practitionerto explain whether any abnormalities are new or preceding thestatin change is viewed as poor practice. These factors heavilyinfluenced the Canadian Consensus Group guideline recom-mendations.1 Routine monitoring outside of these circum-stances of initiation or change are not warranted and shouldinstead be performed selectively for assessment of symptomsthat emerge during chronic therapy.

A pilot study assessed the use of statin metabolites to aiddiagnosis of statin intolerance.134 A ratio of atorvastatinlactone to acid ratio greater than 1.1 in self-reported ator-vastatin-intolerant patients had a positive and negativepredictive value of 79% and 61%, respectively, for recurrenceof muscle symptoms during rechallenge with atorvastatin.134

These performance parameters are not sufficient to avoidthe need for standard rechallenge attempts at this time.

Imaging is not a primary diagnostic procedure in theevaluation of most statin-intolerant patients except whenneeded to exclude underlying causes that might complicatethe clinical picture (eg, detection of radiculopathy with MR orcomputed tomography studies). In acute phases, ultrasonog-raphy might demonstrate normal or increased size, lowechogenicity, and elevated perfusion of affected muscles.However, in chronic cases, this modality might show reduc-tions in size and perfusion with increased echogenicity ofaffected muscles.135 Edematous changes are better depictedusing MR imaging where a close correlation has been foundbetween MR signal intensity on T2-weighted images andcontrast-enhanced T1-weighted images and inflammatoryactivity caused by myositis.135

The prediction of statin adverse effects has been proposed.A large prospective cohort study consisting of more than 2million patients evaluated the performance of the QStatinscore for predicting the 5-year risk of developing AKI, cataract,liver dysfunction, and myopathy with good discriminative andcalibration properties except for predicting risk of developingliver dysfunction.136 The score is based on an assessment ofage, BMI, ethnicity, and smoking status, among other riskfactors, but the rarity and complexity of the genesis of AKI,cataract, and myopathy based on randomized clinical trialssuggests that this method retains major confounding factorsnot yet well understood and the score should not be used topreclude statin use if indications for their use are present.

Therapy for Statin IntoleranceTable 3 outlines the principles of therapy previously

described.1 The following update provides further support.

Statin-based therapies

Effective patient-practitioner dialogue might increasepersistence of statin use, particularly when the patient hasconcerns about side effects and drug costs.137 A retrospectivestudy showed that after documentation of simvastatin-induced myopathy, no statistical difference in tolerabilityrates between atorvastatin, rosuvastatin, pravastatin, and

http://www.circl.ubc.ca/cardiorisk-calculator.html

http://www.circl.ubc.ca/cardiorisk-calculator.html


fluvastatin were observed138; 62%-81% of these patientssubsequently developed statin myopathy to 1 or more statins.Fibrates, cholestyramine, and ezetimibe were statisticallybetter tolerated in this cohort,138 with only 17%-32% ofpatients developing myopathy.

Despite this, use of a statin rechallenge in most patientsexperiencing adverse effects was corroborated in a large retro-spective cohort study, which reported that of the 11,124patients in whom statins were discontinued at least temporarilybecause of clinical events or symptoms believed to have beencaused by statin use, 92% of those who were rechallenged werestill taking a statin 12 months after the statin-related event139;among the 2721 patients who were rechallenged with the samestatin they were using when they had an event, 1295 werereceiving the same statin 12 months later, and 996 of themwere receiving the same or a higher dose.139 A retrospectiveanalysis of medical records of 1605 patients from the ClevelandClinic further suggests that most patients with previous statinintolerance can tolerate a subsequent trial of statin.140 Subse-quently, statin-induced adverse events might have other causesor might be specific to individual statins rather than the entiredrug class.139,140

Evidence for lipid-lowering efficacy of intermittent doses ofhigh-potency statins continues to emerge. Intermittent statindosing can be an effective therapeutic strategy in somepatients and might result in reduction of LDL-C andachievement of LDL-C goals.140 In 58 statin-intolerantpatients, intermittent rosuvastatin resulted in clinically rele-vant reductions in LDL-C levels and improved compliance.141

Whole-body cholesterol synthesis was greater in intermittentrosuvastatin dosing, but no differences in plasma drugconcentrations were observed, suggesting that the improvedtolerability was independent of plasma rosuvastatin levels.141

LDL-C lowering of more than 10% was achieved withweekly 5-10 mg of rosuvastatin in a small, randomized,double-blind trial in patients with a history of statin-associatedmyalgia.142 In a multicentre retrospective observational study,rosuvastatin 5 mg was found to be safe and biochemicallyeffective, either as daily or intermittent therapy in 325 patientsintolerant to other conventional statin regimens.142 Dailyrosuvastatin (n ¼ 134) reduced mean total cholesterol (TC)by 31%, triglycerides (TG) by 15%, and LDL-C by 43%(P < 0.001).142 Rosuvastatin 5 mg 2-3 times weekly (n ¼ 79)reduced TC by 26%, TG by 16%, and LDL-C by 32% (P <0.001). Weekly rosuvastatin (n ¼ 11) reduced TC by 17%,LDL-C by 23% (P < 0.001), but had no effect on TG.143

Targets were attained in 17% of coronary heart disease risk-equivalent patients and 41% of primary prevention patientsaccording to National Cholesterol Education Program criteriaand 27% and 68% using UK targets.143

Treatments targeting muscle symptom relief

Vitamin D. Vitamin D deficiency is a rare cause of myopathyand unrecognized, mild deficiencies might represent a revers-ible cause of statin-associated myalgia or myositis. Onehundred fifty patients were selected on the basis of intoleranceto 1 or more statins because of myalgia or myositis and withlow serum 25-hydroxy (OH) vitamin D (< 32 ng/mL).144

Vitamin D at a dose of 50,000 units twice per week for 3weeks was provided to patients while they were not taking

statins and then continued once per week with introduction ofstatin therapy after the initial 3 weeks of supplementation.144

Eighty-seven percent of patients were symptom-free andtolerant of statin use over a median follow-up of 8.1 monthsalthough only 78% achieved normal serum vitamin Dlevels.144

In contrast, Kurnik et al.145 retrospectively observed nodifferences in serum vitamin D levels among patientsrequiring a switch from atorvastatin to another statin becauseof muscle pain or other reasons, compared with those whorequired no switch; surprisingly, CK levels were marginallylower in patients in the lowest quartile of serum 25-OHvitamin D levels.145 This observed lack of associationbetween statin-induced myopathy and 25-OH vitamin D wascorroborated by another study.146 Thus, placebo-controlledtrials of this intervention either in patients with low serumvitamin D or in the more general population of statin-intolerant patients are needed.

Coenzyme Q10. Coenzyme Q10 enzyme deficiency hasbeen suggested as a potential mechanism for statin-inducedmyopathy, although the role of supplementation remainscontroversial. In a recent study of 28 patients, decreasedmuscle pain and sensitivity was observed after a 6-monthadministration of coenzyme Q10 at a dose of 30 mg twicedaily.147 Fedacko et al.148 evaluated the possible benefits ofcoenzyme Q10 and selenium supplementation administeredto 60 patients with statin-associated myopathy in a smalldouble-blinded study. Selenium (200 mg/d) and coenzymeQ10 (200 mg/d) supplementation of statin-treated patientsresulted in symptomatic attenuation of statin-associatedmyopathy in absolute numbers and intensity.148 In contrast,a similarly designed double-blind study reported that coen-zyme Q10 supplementation (60 mg twice daily) for 3 monthsdid not produce a greater response than placebo in thetreatment of presumed statin-induced myalgias.149

Nonstatin lipid-lowering therapies. A double-blind,randomized clinical trial showed safety and efficacy of usingnutraceutical drinks containing niacin, phytosterol esters, L-carnitine, vitamin C, Co-Q10, and red yeast rice in 79subjects with statin intolerance.150

Future nonstatin pharmacologic treatments that mightplay a role in helping patients with high cardiovasculardisease risk who have true statin intolerance include micro-somal triglyceride transfer protein inhibitors, and novelparenteral RNA interference therapies and even monoclonalantibodies that improve uptake of LDL particles (plasmaproprotein convertasse subtilisin/kexin type 9 or “PCSK9”inhibitors). For instance, a study of mipomersen, an apoli-poprotein B synthesis inhibitor, studied in 33 high-risksubjects with severe genetic dyslipidemia151 showed thatafter 26 weeks, LDL-C was reduced by 47 � 18% (P <0.001 vs placebo).151 Apolipoprotein B and lipoprotein(a)were also significantly reduced by 46% and 27%, respec-tively (P < 0.001 vs placebo).151

PCSK9 binds to LDL receptors, promoting their degra-dation and increasing LDL-C levels. A randomized, double-blind, phase II study assessed the efficacy and tolerability ofAMGEN145, a human monoclonal antibody to PCSK9, inpatients with statin intolerance because of muscle-related side

Table 4. Odds ratios for selected adverse effects of statins

Effect Odds ratioConfidenceinterval

Long-term adverse effectsCancer

All statins 0.96 0.91-1.02Diabetes mellitus

All statins 1.09 1.02-1.16Short-term adverse effects

DiscontinuationsAll statins 0.95 0.83-1.08Atorvastatin > 20 mg and � 40 mg 2.72 1.46-5.00Atorvastatin > 40 mg 1.69 1.18-2.44Fluvastatin � 20 mg 2.26 1.07-4.90

MyalgiaAll Statins 1.07 0.89-1.29

Creatine kinase elevationsAll Statins 1.13 0.85-1.51Pitavastatin 3.63 1.10-14.10Simvastatin > 40 mg 4.14 1.08-16.24

Transaminase elevationsAll statins 1.51 1.24-1.84Atorvastatin 2.55 1.71-3.74Atorvastatin > 20 mg and < 40 mg 2.42 1.10-5.55Atorvastatin > 40 mg 5.25 3.89-7.24Fluvastatin 5.18 1.89-15.55Fluvastatin > 40 mg 4.16 1.60-14.36Lovastatin > 40 mg 1.80 1.06-2.97Rosuvastatin 1.59 1.02-2.50Simvastatin > 40 mg 2.83 1.47-5.87

Data derived from Naci et al.154 as reported in the Results section for allstatins and extracted from Figures 4 and 5 of that article for specific drug-leveland dose-level analyses that resulted in odds ratios > 1.00 and a confidenceinterval not spanning 1.00.


effects. The study observed significantly reduced LDL-C andgood short-term (12-week) tolerability.152

Finally, a single-arm open-label phase III study of themicrosomal triglyceride transfer protein inhibitor lomitapidein 29 patients with severe genetic dyslipidemia showedreduction of LDL-C by 50% with active treatment.153

Although the small early phase studies of limited durationdo not show a signal for myopathic side effects, these agentshave their own problems, such as hepatosteatosis and injectionsite reactions.

Summary and ConclusionsThis article provides a comprehensive summary of infor-

mation pertaining to statin intolerance and adverse effects thathave been published since the first 2011 Canadian consensusstatement.1 The overall analysis suggests that statin intoler-ance and the interest in statin-related adverse effects remain ofmajor clinical importance. Statin intolerance is a clinicalsyndrome requiring careful consideration of many factors(Table 2), including drug-drug interactions, elimination ofreversible factors, and systematic dechallenge and rechallenge,when feasible, before a specific statin intolerance can beconsidered.1 There are currently no routine tests or assays thatare warranted in the evaluation of statin intolerance or adverseeffects except for muscle and liver enzyme assays whensymptoms warrant. The role of exercise testing combined withimaging might eventually have a clinical role.20-24,135 Despitethe focus on statin-related adverse effects in both the lay andacademic literature, a very recent meta-analysis provides

extremely reassuring evidence that the class as a whole cannotbe shown in randomized clinical trials to be associated withmyalgia, CK elevation, cancer, or even discontinuations whencompared with placebo control.154 However, the same anal-ysis also confirms higher risk of DM (OR, 1.09) and trans-aminase elevations (OR, 1.51), particularly with very highstatin doses, and also shows numerous statistically significantdifferences in the propensity for specific adverse events amongdifferent statins and statin dosages (Table 4).154 The overallresults of this critical meta-analysis are reassuring for patientswho use and physicians who prescribe this class of agents.However, the observations in aggregate also indicate thatwhen lower doses and/or less potent statins are adequate toachieve guideline-supported lipid targets, such approachesshould be used, especially in patients reporting difficultieswith long-term statin use. This principle is concordant withgood medical practice, and also adheres to recommendedstatin intolerance management approaches (Table 3).1,155

Funding SourcesInitial literature searches undertaken for the Statin Intol-

erance section of the Canadian Cardiovascular SocietyGuidelines on dyslipidemia were supported by the CanadianCardiovascular Society. Subsequent searches and all subse-quent activities were not funded.

DisclosuresG.B. John Mancini: honoraria from Merck, Servier,

Miraculins, Roche, Amgen, Sanofi-Aventis, Regeneron, Pfizer,and Valeant; Jean Bergeron: honoraria from Merck, Roche,Amgen, Valeant, Sanofi-Aventis, Regeneron, and Genzyme;David Fitchett: honoraria from Merck, Servier, Amgen, Pfizer,and Sanofi Aventis; Jiri Frohlich: honoraria from Genzymeand Amgen; grants from Sanofi, Pfizer, and Genzyme; JacquesGenest: honoraria from Merck, Amgen, Sanofi-Aventis,Genzyme, and Aegerion; grants from Merck, Lilly, Amgen,and Novartis; Milan Gupta: Merck, Pfizer, Amgen, Sanofi-Aventis, Abbott, Tribute Pharmaceuticals, and Miraculins;Robert A. Hegele: honoraria from Merck, Amgen, Aegerion,Valeant, and Genzyme; Glen J. Pearson: honoraria fromRoche, Otsuka, Merck, Servier, Sanofi-Aventis, Pfizer, andAstra-Zeneca. The remaining authors have no conflicts ofinterest to disclose.

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Supplementary MaterialTo access the supplementary material accompanying this

article, visit the online version of the Canadian Journal ofCardiology at www.onlinecjc.ca and at http://dx.doi.org/10.1016/j.cjca.2013.09.023.

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