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Assessment and management of statin-associated muscle symptoms (SAMS): A clinical perspective from the National Lipid Association

Published:September 10, 2022DOI:https://doi.org/10.1016/j.jacl.2022.09.001

      ABSTRACT

      Statin-associated muscle symptoms (SAMS) are the most common form of statin intolerance and are associated with increased risk of cardiovascular events that manifest from statin underutilization and discontinuation. The reported frequencies of SAMS are divergent in the literature. The writing group estimates the prevalence of SAMS, namely all muscle symptoms temporally related to statin use but without regard to causality, to be about 10% (range 5% to 25%), and the prevalence of pharmacological SAMS, specifically muscle symptoms resulting from pharmacological properties of the statin, to be about 1-2% (range 0.5% to 4%). In clinical practice, SAMS are likely to result from a combination of pharmacological and nonpharmacological effects, however this does not make the symptoms any less clinically relevant. Regardless of the etiology, SAMS need to be addressed in accordance with patients’ preferences and experiences. This clinical perspective reviews the epidemiology and underlying pathophysiology of SAMS, and the cardiovascular consequences resulting from statin discontinuation. We present patient-centered clinical and communication strategies to mitigate SAMS and improve medication adherence and outcomes among statin users. Treatment strategies include 1) optimizing lifestyle interventions, 2) modulating risk factors that may contribute to muscle symptoms, 3) optimizing statin tolerability by dose reduction, decreased dosing frequency, or use of an alternate statin with more favorable pharmacokinetic properties, and 4) use of non-statins, emphasizing those with evidence for atherosclerotic risk reduction, either in combination with or in place of statin therapy depending on the patient's circumstances. The focus of this clinical perspective is sustainable lipoprotein goal achievement, which is important for cardiovascular risk reduction.
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      References

        • Ference BA
        • Ginsberg HN
        • Graham I
        • et al.
        Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
        Eur. Heart J. 2017; 38: 2459-2472
        • Baigent C
        • Keech A
        • Kearney PM
        • et al.
        Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
        Lancet. 2005; 366: 1267-1278
        • Zhang H
        • Plutzky J
        • Shubina M
        • Turchin A.
        Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study.
        Ann. Intern. Med. 2017; 167: 221-227
      1. Statin Use in U.S. Adults Doubles. Content last reviewed August 2018. Agency for Healthcare Research and Quality, Rockville, MD. https://www.ahrq.gov/data/infographics/statin-use.html. Accessed August 30 2022.

        • Newman CB
        • Preiss D
        • Tobert JA
        • et al.
        Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association.
        Arterioscler. Thromb. Vasc. Biol. 2019; 39: e38-e81
        • Ward NC
        • Watts GF
        • Eckel RH
        Statin Toxicity.
        Circ. Res. 2019; 124: 328-350
        • Cheeley MK
        • Saseen JJ
        • Agarwala A
        • et al.
        NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient.
        J. Clin. Lipidol. 2022;
        • Guyton JR
        • Bays HE
        • Grundy SM
        • Jacobson TA
        The National Lipid Association Statin Intolerance P. An assessment by the Statin Intolerance Panel: 2014 update.
        J. Clin. Lipidol. 2014; 8: S72-S81
        • 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: 1012-1022
        • 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
        • Mancini GB
        • Baker S
        • Bergeron J
        • et al.
        Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Canadian Consensus Working Group Update (2016).
        Can. J. Cardiol. 2016; 32: S35-S65
        • Sposito AC
        • Faria Neto JR
        • Carvalho LS
        • et al.
        Statin-associated muscle symptoms: position paper from the Luso-Latin American Consortium.
        Curr. Med. Res. Opin. 2017; 33: 239-251
        • Rosenson RS
        • Baker SK
        • Jacobson TA
        • Kopecky SL
        • Parker BA
        The National Lipid Association's Muscle Safety Expert P. An assessment by the Statin Muscle Safety Task Force: 2014 update.
        J. Clin. Lipidol. 2014; 8: S58-S71
        • Adhyaru BB
        • Jacobson TA.
        Safety and efficacy of statin therapy.
        Nat. Rev. Cardiol. 2018; 15: 757-769
        • Brewster LM
        • Mairuhu G
        • Sturk A
        • van Montfrans GA.
        Distribution of creatine kinase in the general population: implications for statin therapy.
        Am. Heart J. 2007; 154: 655-661
        • George MD
        • McGill NK
        • Baker JF.
        Creatine kinase in the U.S. population: Impact of demographics, comorbidities, and body composition on the normal range.
        Medicine (Baltimore). 2016; 95: e4344
        • Bruckert E
        • Hayem G
        • Dejager S
        • Yau C
        • Bégaud B.
        Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study.
        Cardiovasc. Drugs Ther. 2005; 19: 403-414
        • Link E
        • Parish S
        • Armitage J
        • et al.
        SLCO1B1 variants and statin-induced myopathy–a genomewide study.
        N. Engl. J. Med. 2008; 359: 789-799
        • Taylor BA
        • Lorson L
        • White CM
        • Thompson PD.
        A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy.
        Atherosclerosis. 2015; 238: 329-335
        • Rosenson RS
        • Miller K
        • Bayliss M
        • et al.
        The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): Revision for Clinical Use, Content Validation, and Inter-rater Reliability.
        Cardiovasc. Drugs Ther. 2017; 31: 179-186
        • Taylor BA
        • Sanchez RJ
        • Jacobson TA
        • et al.
        Application of the Statin-Associated Muscle Symptoms-Clinical Index to a Randomized Trial on Statin Myopathy.
        J. Am. Coll. Cardiol. 2017; 70: 1680-1681
        • Wiggins BS
        • Saseen JJ
        • Page 2nd, RL
        • et al.
        Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association.
        Circulation. 2016; 134: e468-e495
        • Collins R
        • Reith C
        • Emberson J
        • et al.
        Interpretation of the evidence for the efficacy and safety of statin therapy.
        Lancet. 2016; 388: 2532-2561
      2. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials.
        Lancet. 2022;
        • Scott RS
        • Lintott CJ
        • Wilson MJ.
        Simvastatin and side effects.
        N. Z. Med. J. 1991; 104: 493-495
        • Shepherd J.
        Fibrates and statins in the treatment of hyperlipidaemia: an appraisal of their efficacy and safety.
        Eur. Heart J. 1995; 16: 5-13
        • Parker BA
        • Capizzi JA
        • Grimaldi AS
        • et al.
        Effect of statins on skeletal muscle function.
        Circulation. 2013; 127: 96-103
        • Cohen JD
        • Brinton EA
        • Ito MK
        • Jacobson TA.
        Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
        J. Clin. Lipidol. 2012; 6: 208-215
        • Herrett E
        • Williamson E
        • Brack K
        • et al.
        Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials.
        BMJ. 2021; 372: n135
        • Nissen SE
        • Stroes E
        • Dent-Acosta RE
        • et al.
        Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.
        JAMA. 2016; 315: 1580-1590
        • Moriarty PM
        • Thompson PD
        • Cannon CP
        • et al.
        Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial.
        J. Clin. Lipidol. 2015; 9: 758-769
        • Howard JP
        • Wood FA
        • Finegold JA
        • et al.
        Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment.
        J. Am. Coll. Cardiol. 2021; 78: 1210-1222
        • Tudor K
        • Brooks J
        • Howick J
        • Fox R
        • Aveyard P.
        Unblinded and Blinded N-of-1 Trials Versus Usual Care: A Randomized Controlled Trial to Increase Statin Uptake in Primary Care.
        Circ. Cardiovasc. Qual. Outcomes. 2022; 15e007793
        • Thompson PD
        • Panza G
        • Zaleski A
        • Taylor B.
        Statin-Associated Side Effects.
        J. Am. Coll. Cardiol. 2016; 67: 2395-2410
        • Penson PE
        • Banach M.
        Nocebo/drucebo effect in statin-intolerant patients: an attempt at recommendations.
        Eur. Heart J. 2021; 42: 4787-4788
        • Penson PE
        • Mancini GBJ
        • Toth PP
        • et al.
        Introducing the 'Drucebo' effect in statin therapy: a systematic review of studies comparing reported rates of statin-associated muscle symptoms, under blinded and open-label conditions.
        J Cachexia Sarcopenia Muscle. 2018; 9: 1023-1033
        • Nielsen SF
        • Nordestgaard BG.
        Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study.
        Eur. Heart J. 2016; 37: 908-916
        • Nissen SE.
        Statin Denial: An Internet-Driven Cult With Deadly Consequences.
        Ann. Intern. Med. 2018; 168: 381-382
      3. US Department of Health and Human Service Food and Drug Administration. Guidance for industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-measures-use-medical-product-development-support-labeling-claims. Accessed May 30 2022.

        • Rumsfeld JS
        • Alexander KP
        • Goff Jr., DC
        • et al.
        Cardiovascular health: the importance of measuring patient-reported health status: a scientific statement from the American Heart Association.
        Circulation. 2013; 127: 2233-2249
        • Anker SD
        • Agewall S
        • Borggrefe M
        • et al.
        The importance of patient-reported outcomes: a call for their comprehensive integration in cardiovascular clinical trials.
        Eur. Heart J. 2014; 35: 2001-2009
        • Hare DL
        • Toukhsati SR
        • Johansson P
        • Jaarsma T.
        Depression and cardiovascular disease: a clinical review.
        Eur. Heart J. 2014; 35: 1365-1372
        • Jacobson TA
        • Cheeley MK
        • Jones PH
        • et al.
        The STatin Adverse Treatment Experience Survey: Experience of patients reporting side effects of statin therapy.
        J. Clin. Lipidol. 2019; 13: 415-424
        • Zaleski AL
        • Taylor BA
        • Pescatello LS
        • Dornelas EA
        • White CM
        • Thompson PD.
        Influence of Baseline Psychological Health on Muscle Pain During Atorvastatin Treatment.
        J. Cardiovasc. Nurs. 2017; 32: 544-550
        • Okunrintemi V
        • Valero-Elizondo J
        • Stone NJ
        • et al.
        Shared decision making and patient reported outcomes among adults with atherosclerotic cardiovascular disease, medical expenditure panel survey 2006-2015.
        Am J Prev Cardiol. 2021; 8100281
        • Yetman HE
        • Cox N
        • Adler SR
        • Hall KT
        • Stone VE.
        What Do Placebo and Nocebo Effects Have to Do With Health Equity? The Hidden Toll of Nocebo Effects on Racial and Ethnic Minority Patients in Clinical Care.
        Front. Psychol. 2021; 12788230
        • Riegel B
        • Dickson VV.
        A qualitative secondary data analysis of intentional and unintentional medication nonadherence in adults with chronic heart failure.
        Heart Lung. 2016; 45: 468-474
        • Jones LK
        • Tilberry S
        • Gregor C
        • et al.
        Implementation strategies to improve statin utilization in individuals with hypercholesterolemia: a systematic review and meta-analysis.
        Implement Sci. 2021; 16: 40
        • LaRosa JC.
        The clinical lipid specialist. Task Force on Cholesterol Issues, American Heart Association.
        Circulation. 1990; 82: 1548
        • Martin SC
        • Viljoen A.
        The value of a specialist lipid clinic.
        Int. J. Clin. Pract. 2008; 62: 961-966
        • Ross JL.
        The Allied Health Professional's Role in the Management of Dyslipidemia and Accreditation Council for Clinical Lipidology Certification Program.
        in: Davidson M.H. Toth P.P. Maki K.C. Therapeutic Lipidology. Contemporary Cardiology. Humana, Cham2021https://doi.org/10.1007/978-3-030-56514-5_34
        • Backman WD
        • Levine SA
        • Wenger NK
        • Harold JG.
        Shared decision-making for older adults with cardiovascular disease.
        Clin. Cardiol. 2020; 43: 196-204
        • De Vera MA
        • Bhole V
        • Burns LC
        • Lacaille D.
        Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review.
        Br. J. Clin. Pharmacol. 2014; 78: 684-698
        • Giral P
        • Neumann A
        • Weill A
        • Coste J.
        Cardiovascular effect of discontinuing statins for primary prevention at the age of 75 years: a nationwide population-based cohort study in France.
        Eur. Heart J. 2019; 40: 3516-3525
        • Thompson W
        • Morin L
        • Jarbøl DE
        • et al.
        Statin Discontinuation and Cardiovascular Events Among Older People in Denmark.
        JAMA Netw Open. 2021; 4e2136802
        • Kellick KA
        • Bottorff M
        • Toth PP
        The National Lipid Association's Safety Task F. A clinician's guide to statin drug-drug interactions.
        J. Clin. Lipidol. 2014; 8: S30-S46
        • Hirota T
        • Fujita Y
        • Ieiri I.
        An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins.
        Expert Opin. Drug Metab. Toxicol. 2020; 16: 809-822
        • Beavers CJ
        • Rodgers JE
        • Bagnola AJ
        • et al.
        Cardio-Oncology Drug Interactions: A Scientific Statement From the American Heart Association.
        Circulation. 2022; 145: e811-e838
        • Turner RM
        • Pirmohamed M.
        Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components.
        J Clin Med. 2019; 9
        • Brunham LR
        • Baker S
        • Mammen A
        • Mancini GBJ
        • Rosenson RS.
        Role of genetics in the prediction of statin-associated muscle symptoms and optimization of statin use and adherence.
        Cardiovasc. Res. 2018; 114: 1073-1081
        • Cooper-DeHoff RM
        • Niemi M
        • Ramsey LB
        • et al.
        The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms.
        Clin. Pharmacol. Ther. 2022; 111: 1007-1021
        • Taylor BA
        • Thompson PD.
        Statin-Associated Muscle Disease: Advances in Diagnosis and Management.
        Neurotherapeutics. 2018; 15: 1006-1017
        • Grundy SM
        • Stone NJ
        • Bailey AL
        • et al.
        AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        J. Am. Coll. Cardiol. 2018; 73 (2019): e285-e350
        • Backes JM
        • Ruisinger JF
        • Gibson CA
        • Moriarty PM.
        Statin-associated muscle symptoms-Managing the highly intolerant.
        J. Clin. Lipidol. 2017; 11: 24-33
        • Joy TR
        • Brennan ET.
        Management strategies in patients with statin-associated muscle symptoms: What is the best strategy?.
        J. Clin. Lipidol. 2016; 10: 1067-1072
        • Kim BK
        • Hong SJ
        • Lee YJ
        • et al.
        Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial.
        Lancet. 2022;
        • 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: 111-116
        • Duell PB
        • Abstract Connor WE.
        3701: Vitamin D Deficiency is Associated With Myalgias in Hyperlipidemic Subjects Taking Statins.
        Circulation. 2008; 118 (S_470-S_470)
        • Lowe K
        • Kubra KT
        • He ZY
        • Carey K.
        Vitamin D Supplementation to Treat Statin-Associated Muscle Symptoms: A Review.
        Sr Care Pharm. 2019; 34: 253-257
        • Raizner AE
        • Quiñones MA.
        Coenzyme Q(10) for Patients With Cardiovascular Disease: JACC Focus Seminar.
        J. Am. Coll. Cardiol. 2021; 77: 609-619
        • Taylor BA.
        Does Coenzyme Q10 Supplementation Mitigate Statin-Associated Muscle Symptoms? Pharmacological and Methodological Considerations.
        Am. J. Cardiovasc. Drugs. 2018; 18: 75-82
        • Qu H
        • Guo M
        • Chai H
        • Wang WT
        • Gao ZY
        • Shi DZ.
        Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials.
        J Am Heart Assoc. 2018; 7e009835
        • Kennedy C
        • Köller Y
        • Surkova E.
        Effect of Coenzyme Q10 on statin-associated myalgia and adherence to statin therapy: A systematic review and meta-analysis.
        Atherosclerosis. 2020; 299: 1-8
      4. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.
        JAMA. 1984; 251: 351-364
      5. Clofibrate and niacin in coronary heart disease.
        JAMA. 1975; 231: 360-381
        • Frick MH
        • Elo O
        • Haapa K
        • et al.
        Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
        N. Engl. J. Med. 1987; 317: 1237-1245
        • Rubins HB
        • Robins SJ
        • Collins D
        • et al.
        Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
        N. Engl. J. Med. 1999; 341: 410-418
        • Cannon CP
        • Blazing MA
        • Giugliano RP
        • et al.
        Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.
        N. Engl. J. Med. 2015; 372: 2387-2397
        • Schwartz GG
        • Steg PG
        • Szarek M
        • et al.
        Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.
        N. Engl. J. Med. 2018; 379: 2097-2107
        • Sabatine MS
        • Giugliano RP
        • Keech AC
        • et al.
        Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.
        N. Engl. J. Med. 2017; 376: 1713-1722
        • Lloyd-Jones DM
        • Morris PB
        • Ballantyne CM
        • et al.
        Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.
        J. Am. Coll. Cardiol. 2022; (Online ahead of print)https://doi.org/10.1016/j.jacc.2022.07.006
        • Boden WE
        • Probstfield JL
        • Anderson T
        • et al.
        Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
        N. Engl. J. Med. 2011; 365: 2255-2267
        • Landray MJ
        • Haynes R
        • Hopewell JC
        • et al.
        Effects of extended-release niacin with laropiprant in high-risk patients.
        N. Engl. J. Med. 2014; 371: 203-212
        • McGowan MP
        • Hosseini Dehkordi SH
        • Moriarty PM
        • et al.
        Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia.
        J Am Heart Assoc. 2019; 8: e013225https://doi.org/10.1161/JAHA.119.013225
        • Duell PB
        Low Density Lipoprotein (LDL) Apheresis.
        Dyslipidemias: Pathophysiology, evaluation, and management. 1st. Contemporary Endocrinology, 2015: 483-497