Statins are one of the most commonly prescribed drugs.¹ They are generally well tolerated and prevent cardiovascular events.² However, as with all drugs, they can have adverse effects (AEs). Most of the AEs are muscle-related; however, there are also other statin-associated AEs. The recent European Atherosclerosis Society (EAS) statement only focuses on statin-associated muscle symptoms (SAMS) and avoids the use of the term 'statin intolerance,' as it is not specific for SAMS.³ It has also been suggested to avoid using the term 'statin intolerance' as it might create a negative impression.

Although SAMS are the most common AEs observed with statin administration, excluding other symptoms might underestimate the number of patients who have poor adherence to this treatment. Therefore, an expert panel aimed to provide a unified definition of statin intolerance and advice on managing the most common conditions that might increase the risk of intolerance to statins.^4,5 This statement complements that of the EAS, whereas the pathophysiology, diagnosis, and the management of SAMS were comprehensively presented.³

Briefly, statin intolerance is the inability to tolerate a dose of statin required to sufficiently reduce cardiovascular risk. This could result from different statin-related side effects. Statin intolerance limits the effective treatment of patients at risk of, or with, cardiovascular disease (CVD). Therefore, knowledge of the common AEs associated with statin therapy (not only SAMS) is crucial to ensure effective treatment of lipid disorders. In turn, this awareness could significantly reduce the risk of discontinuing statin therapy (or need to reduce the dose of statin), thus improving adherence and increasing the effectiveness of treatment.^4,5

This knowledge is also necessary to manage statin intolerance effectively, that is: 1) to confirm whether AEs are indeed induced by statin therapy, 2) whether AEs are associated with a biomarker increase (e.g., creatine kinase activity), and 3) whether step-by-step management might reduce intolerance occurrence. "Take your time" – most experts strongly emphasize that a careful step-by-step approach allows for 90% of patients reporting statin-related AEs to continue statins.^3-5 However, it should be emphasized that reducing the dose of statin (e.g., in high-risk patients who require a high dose) is still a form of statin intolerance.^4,5

The position paper^4,5 considers the most common statin-related side effects that have been reported in the literature, taking into account that causality has not always been confirmed (Table 1).^4,5

Table 1

Organ/Systems	Potential Side Effects of Statins
Respiratory	↑ risk of interstitial lung disease (0.01-0.4%), ↑ risk of upper respiratory tract infection (1-16%), ↑ risk of pharyngitis (3-13%), rhinitis (1-11%), sinusitis (2-7%), bronchitis (2%), cough (1-2%)
Neurologic and Psychological Effects	↑ risk of suicide, aggressive behavior, ↑ headache (2-17%), asthenia (1-4%), dizziness (1-4%), fatigue (1-4%), ↑ risk of depressive disorder in stroke patients, ↑ risk of hemorrhagic stroke, severe irritability, insomnia, somnolence, agitation, confusion, hallucinations, and nightmares
Endocrine	↑ risk of new onset diabetes (NOD) (9-27%), Intensive-dose statin therapy is associated with a 12% higher incidence of NOD compared with moderate-dose statin therapy
Gastrointestinal Tract	↑ constipation, diarrhea, dyspepsia, flatulence heartburn, nausea vomiting
Hepatic	< 1.5% hepatotoxicity in coronary artery disease patients in 5 years, ↑ liver enzyme activity
Skin	↑ risk of alopecia, lichenoid eruption, dermographism, chronic urticaria, toxic epidermal necrolysis and rash (1-4%)
Eye	↑ risk of cataract (up to 27%), ↑ diplopia, ptosis and ophthalmoplegia
Renal	↑ risk of acute renal failure, ↑ proteinuria
Reproductive	erectile dysfunction, decrease libido, gynecomastia ,    testosterone levels (7.5-10.3%) after 48 weeks of statins
Blood	↑ risk of thrombotic thrombocytopenic purpura (TPP)
Bones and Joints	tendinitis, arthralgia, arthritis, lupus, polymyalgia rheumatica

Physicians should be aware of the most common risk factors associated with statin intolerance. According to available data, dose, duration of treatment, age, gender, co-morbidity, and/or co-treatment with certain drugs or foods (over 300 drugs are known to interact with statins) influence AEs.^3-6 Known risk factors predisposing patients to clinically relevant side effects include the follwoign: high-dose statin therapy, advanced age (>70 years), female sex, family history of muscle disorders, history of creatine kinase elevation, vitamin D deficiency, renal and hepatic impairment, previous history of muscle toxicity with other lipid-lowering therapy, untreated hypothyroidism, disorders of calcium homeostasis, alcohol abuse, Asian ethnicity, low body mass index, genetic polymorphisms (e.g., genes associated with drug and muscle metabolism), surgery with severe metabolic demands, heavy and/or unaccustomed exercise and interactions with concomitant medication.^4,5,7,8 Faced with symptoms causing statin intolerance, most lipidologists will first check for hypothyroidism, vitamin D deficiency, renal disease, and excessive physical activity.

In the position paper,^4,5 for the first time, the authors described the most common risk factors associated with statin intolerance and recommended appropriate management. For example, the authors strongly support the Food and Drug Administration recommendation to analyze aminotransferases before starting statin therapy and as clinically indicated thereafter.⁹ For individuals with regular, intense physical exertion we suggest considering low–to-moderate-intensity statin therapy and, if possible, to reduce statin dose or discontinue statin therapy for at least two days before predicted intense physical exertion (independently evaluated for each patient).

In elderly patients, who are at a higher risk of statin intolerance, treatment should be started as clinically appropriate, especially if the benefits of CVD prevention outweigh potential risks. In this group of patients, the authors also recommend discontinuing statin therapy in case of severe illness, major non-cardiovascular surgery, or major trauma until the person recovers. Considering available data, the authors also suggest considering hydrophilic statins (e.g., pravastatin, rosuvastatin, fluvastatin, pitavastatin) at moderate-intensity doses in elderly patients with CVD as they may be better tolerated.^4,5

The position paper proposes a unified definition of statin intolerance (Table 2).^4,5 The authors considered that this definition should meet two main conditions: 1) to be commonly used by physicians who manage dyslipidemic patients, and 2) to allow optimal diagnosis and avoid both over- and under-representation. Statin intolerance is a clinical syndrome that is: 1) characterized by inability to use statins for long-term reduction of lipids and/or cardiovascular risk because of significant symptoms and/or biomarker abnormalities that can be temporally attributed to the initiation or dose escalation of statins; if appropriate, drug withdrawal and rechallenge can strengthen this association; 2) either "complete" (intolerant to any statin at any dose) or "partial" (intolerant to some statins at some doses); and 3) not attributable to established predispositions such as drug-drug interactions and untreated hypothyroidism.^4,5 Clearly, a thorough and systematic review of any current symptoms (including degree and location of any muscle aches) prior to beginning statin therapy is critical to best evaluate whether symptoms occurring after beginning statin treatment can really be attributed to the drug.

Table 2: Unified Definition of Statin Intolerance The inability to tolerate at least two different statins - one statin at the lowest starting average daily dose and the other statin at any dose. Intolerance associated with confirmed, intolerable statin-related adverse effect(s) or significant biomarker abnormalities.* Symptom or biomarker changes resolution or significant improvement upon dose decrease or discontinuation. Symptoms or biomarker changes not attributable to established predispositions such as drug-drug interactions and recognized conditions increasing the risk of statin intolerance.

In conclusion, statin intolerance is a real phenomenon, which might affect up to 15% of patients treated with statins.^4,5 Health care providers can decrease the prevalence through careful management of statin intolerant patients ("take your time" approach), i.e., through eliminating all possible risk factors, as well as educating patients concerning the effectiveness of statin therapy and about all conditions that might worsen statin tolerability. It is also hard to agree with some opinions that "true" statin intolerance does not exist, it is always associated with other factors, and we should consider all efforts to continue statin therapy.

With careful management, health care providers might successfully treat over 90% of the patients previously reporting statin intolerance; however, the problem still exists for the remaining 10% – the ones with statin-related AEs causing complete intolerance due to intolerable symptoms (e.g., myositis, rhabdomyolysis, cognitive and sleep disorders, or hair loss). In such situations, physicians should consider statin discontinuation, try to decrease cardiovascular risk with other available regimens, and consider statin rechallenge after symptoms/biomarker changes resolve.

References

1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
2. Banach M, Mikhailidis DP, Kjeldsen SE, Rysz J. Time for new indications for statins? Med Sci Monit 2009;15:MS1-5.
3. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015; 36:1012-22.
4. Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci 2015;11:1-23.
5. Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Expert Opin Drug Saf 2015;14:935-55.
6. McClure DL, Valuck RJ, Glanz M, Hokanson JE. Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiol Drug Saf 2007 Feb;16:132-43.
7. Michalska-Kasiczak M, Sahebkar A, Mikhailidis DP, et al. Analysis of vitamin D levels in patients with and without statin-associated myalgia - a systematic review and meta-analysis of 7 studies with 2420 patients. Int J Cardiol 2015;178:111-6.
8. Banach M, Serban C, Sahebkar A, et al.. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc 2015;90:24-34.
9. U.S. Department of Health and Human Services. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs (2-28-2012) (FDA website). 2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed on 8/2/2015.
10. Bays H, Cohen DE, Chalasani N, Harrison SA, The National Lipid Association's Statin Safety Task Force. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol 2014;8:S47-57.

Keywords: Acute Kidney Injury, Alcoholism, Alopecia, Arthralgia, Arthritis, Asthenia, Atherosclerosis, Biomarkers, Body Mass Index, Bronchitis, Calcium, Cardiovascular Diseases, Cataract, Complement System Proteins, Confusion, Constipation, Coronary Artery Disease, Creatine Kinase, Depressive Disorder, Diabetes Mellitus, Diarrhea, Diplopia, Dizziness, Drug Interactions, Dyspepsia, Erectile Dysfunction, Exanthema, Fatty Acids, Monounsaturated, Flatulence, Fluorobenzenes, Gastrointestinal Tract, Gynecomastia, Hallucinations, Headache, Health Personnel, Heartburn, Homeostasis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypothyroidism, Indoles, Libido, Lichenoid Eruptions, Lipids, Liver, Lung Diseases, Interstitial, Metabolic Syndrome, Motor Activity, Myositis, Nausea, Ophthalmoplegia, Pharmaceutical Preparations, Pharyngitis, Physical Exertion, Polymorphism, Genetic, Polymyalgia Rheumatica, Pravastatin, Prevalence, Proteinuria, Purpura, Thrombotic Thrombocytopenic, Pyrimidines, Quinolines, Rhabdomyolysis, Rhinitis, Risk Factors, Sinusitis, Sleep Initiation and Maintenance Disorders, Stevens-Johnson Syndrome, Stroke, Suicide, Sulfonamides, Tendinopathy, Testosterone, Transaminases, Urticaria, Vitamin D Deficiency, Vomiting

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