Abstract
Statins reduce circulating concentrations of low-density lipoprotein cholesterol (LDL-C) and thereby are effective at reducing cardiovascular (CV) events and mortality in primary and secondary prevention. As with all drugs, statins cause adverse effects in some patients. Statin intolerance occurs when adverse effects limit the maximum dose of statin (partial statin intolerance) or cause patients to cease statin therapy (complete statin intolerance). Statin intolerance is associated with poor clinical outcomes; however, many patients (even 90–95%) who initially report intolerance can tolerate some degree of statin therapy. In order that all patients receive optimal lipid-lowering therapy, it is essential that the relatively small number of patients with true intolerance is differentiated from those with symptoms misattributed to statin therapy (the drucebo effect). This chapter provides an overview of the diagnosis of statin intolerance and provides management advice aimed at achieving optimal lipid-lowering in these patients. Approaches such as dose reduction, alternate-day dosing, and add-on drugs and nutraceuticals can be effective in reaching this aim.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsAbbreviations
- ACL:
-
ATP-citrate lyase
- ACS:
-
Acute coronary syndromes
- ACSVL1:
-
Very-long-chain acyl CoA synthetase-1
- ASCVD:
-
Atherosclerotic cardiovascular disease
- CAD:
-
Coronary artery disease
- CHD:
-
Coronary heart disease
- CK:
-
Creatine kinase
- CKD:
-
Chronic kidney disease
- CVD:
-
Cardiovascular disease
- DM:
-
Diabetes mellitus
- EAS:
-
European Atherosclerosis Society
- FABP3:
-
Fatty acid-binding protein 3
- FOURIER:
-
Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk
- HDL-C:
-
High-density lipoprotein cholesterol
- HMG-CoA:
-
3-Hydroxy-3-methylglutaryl coenzyme A
- ILEP:
-
International Lipid Expert Panel
- LDL-C:
-
Low-density lipoprotein cholesterol
- Lp(a):
-
Lipoprotein(a)
- MI:
-
Myocardial infarction
- MLC1:
-
Myosin light chain 1
- NLA:
-
National Lipid Association
- NOD:
-
New-onset diabetes
- ODYSSEY Outcomes:
-
Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab
- PCSK9:
-
Proprotein convertase subtilisin/kexin type 9
- RCTs:
-
Randomized controlled trials
- SAMS:
-
Statin-associated muscle symptoms
- SMCI:
-
Statin Myalgia Clinical Index
- TG:
-
Triglycerides
- ULN:
-
Upper limit of normal
- USAGE:
-
The Understanding Statin Use in America and Gaps in Patient Education
References
Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532–61.
Toth PP, Patti AM, Giglio RV, Nikolic D, Castellino G, Rizzo M, et al. Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs. 2018;18(3):157–73.
Gregoor PJ. Atorvastatin may cause nightmares. BMJ. 2006;332(7547):950.
Lansberg PJ, Mitchel YB, Shapiro D, Kastelein JJ, Altman R, Jerums G, et al. Long-term efficacy and tolerability of simvastatin in a large cohort of elderly hypercholesterolemic patients. Atherosclerosis. 1995;116(2):153–62.
Muntean DM, Thompson PD, Catapano AL, Stasiolek M, Fabis J, Muntner P, et al. Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms? Drug Discov Today. 2017;22(1):85–96.
Banach M, Serban MC. Discussion around statin discontinuation in older adults and patients with wasting diseases. J Cachexia Sarcopenia Muscle. 2016;7(4):396–9.
Serban MC, Colantonio LD, Manthripragada AD, Monda KL, Bittner VA, Banach M, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol. 2017;69(11):1386–95.
Banach M, Mikhailidis DP. Statin intolerance: some practical hints. Cardiol Clin. 2018;36(2):225–31.
Saeed B, Wright E, Evans M, Lewis M, Steinhubl S. PS1-45: prevalence of statin intolerance in a high risk cohort and management strategies in contemporary cardiology. Clin Med Res. 2013;11(3):136.
Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308(23):2497–506.
Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541–8.
Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, 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(15):1580–90.
Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara-Dinet MT, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol. 2014;8(6):554–61.
Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8(5):473–88.
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, 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(17):1012–22.
Banach M, Rizzo M, Toth PP, Farnier M, Davidson MH, Al-Rasadi K, et al. Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Expert Opin Drug Saf. 2015;14(6):935–55.
Banach M, Rizzo M, Toth PP, Farnier M, Davidson MH, Al-Rasadi K, et al. Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;11(1):1–23.
Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group Update (2016). Can J Cardiol. 2016;32(7 Suppl):S35–65.
Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA, The National Lipid Association’s Muscle Safety Expert Panel. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S58–71.
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(3 Suppl):S47–57.
Penson PE, Mancini GBJ, Toth PP, Martin SS, Watts GF, Sahebkar A, 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(6):1023–33.
Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, et al. 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 Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68(1):92–125.
Stulc T, Ceska R, Gotto AM Jr. Statin intolerance: the clinician’s perspective. Curr Atheroscler Rep. 2015;17(12):69.
Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565–71.
Jacobson TA. Toward “pain-free” statin prescribing: clinical algorithm for diagnosis and management of myalgia. Mayo Clin Proc. 2008;83(6):687–700.
Thompson PD, Clarkson PM, Rosenson RS, National Lipid Association Statin Safety Task Force Muscle Safety Expert Panel. An assessment of statin safety by muscle experts. Am J Cardiol. 2006;97(8A):69C–76C.
Banach M, Jankowski P, Jozwiak J, Cybulska B, Windak A, Guzik T, et al. PoLA/CFPiP/PCS guidelines for the management of dyslipidaemias for family physicians 2016. Arch Med Sci. 2017;13:1):1–45.
Banach M, Serban C, Sahebkar A, Ursoniu S, Rysz J, Muntner P, et al. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc. 2015;90(1):24–34.
Banach M, Serban C, Ursoniu S, Rysz J, Muntner P, Toth PP, et al. Statin therapy and plasma coenzyme Q10 concentrations--a systematic review and meta-analysis of placebo-controlled trials. Pharmacol Res. 2015;99:329–36.
Di Stasi SL, MacLeod TD, Winters JD, Binder-Macleod SA. Effects of statins on skeletal muscle: a perspective for physical therapists. Phys Ther. 2010;90(10):1530–42.
Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol. 2007;49(17):1753–62.
Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50(5):409–18.
Tonomura Y, Mori Y, Torii M, Uehara T. Evaluation of the usefulness of biomarkers for cardiac and skeletal myotoxicity in rats. Toxicology. 2009;266(1–3):48–54.
Vaklavas C, Chatzizisis YS, Ziakas A, Zamboulis C, Giannoglou GD. Molecular basis of statin-associated myopathy. Atherosclerosis. 2009;202(1):18–28.
Calvano J, Achanzar W, Murphy B, DiPiero J, Hixson C, Parrula C, et al. Evaluation of microRNAs-208 and 133a/b as differentialss biomarkers of acute cardiac and skeletal muscle toxicity in rats. Toxicol Appl Pharmacol. 2016;312:53–60.
Min PK, Park J, Isaacs S, Taylor BA, Thompson PD, Troyanos C, et al. Influence of statins on distinct circulating microRNAs during prolonged aerobic exercise. J Appl Physiol (1985). 2016;120(6):711–20.
Rosenson RS, Miller K, Bayliss M, Sanchez RJ, Baccara-Dinet MT, Chibedi-De-Roche D, 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(2):179–86.
Jacobson TA, Khan A, Maki KC, Brinton EA, Cohen JD. Provider recommendations for patient-reported muscle symptoms on statin therapy: insights from the understanding statin use in America and gaps in patient education survey. J Clin Lipidol. 2018;12(1):78–88.
Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127(1):96–103.
Patel J, Martin SS, Banach M. Expert opinion: the therapeutic challenges faced by statin intolerance. Expert Opin Pharmacother. 2016;17(11):1497–507.
Rosenson RS, Baker S, Banach M, Borow KM, Braun LT, Bruckert E, et al. Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol. 2017;70(10):1290–301.
Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37(39):2999–3058.
Sosnowska B, Penson P, Banach M. The role of nutraceuticals in the prevention of cardiovascular disease. Cardiovasc Diagn Ther. 2017;7(Suppl 1):S21–31.
Gluba-Brzozka A, Franczyk B, Toth PP, Rysz J, Banach M. Molecular mechanisms of statin intolerance. Arch Med Sci. 2016;12(3):645–58.
Buettner C, Rippberger MJ, Smith JK, Leveille SG, Davis RB, Mittleman MA. Statin use and musculoskeletal pain among adults with and without arthritis. Am J Med. 2012;125(2):176–82.
McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, et al. Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363(9426):2015–21.
Mihos CG, Artola RT, Santana O. The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in rheumatologic disorders: a comprehensive review. Rheumatol Int. 2012;32(2):287–94.
Sathasivam S, Lecky B. Statin induced myopathy. BMJ. 2008;337(3):a2286.
Wei MY, Ito MK, Cohen JD, Brinton EA, Jacobson TA. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol. 2013;7(5):472–83.
Awad K, Mikhailidis DP, Toth PP, Jones SR, Moriarty P, Lip GYH, et al. Efficacy and safety of alternate-day versus daily dosing of statins: a systematic review and meta-analysis. Cardiovasc Drugs Ther. 2017;31(4):419–31.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97.
Pandor A, Ara RM, Tumur I, Wilkinson AJ, Paisley S, Duenas A, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med. 2009;265(5):568–80.
Awad K, Mikhailidis DP, Katsiki N, Muntner P, Banach M, Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group. Effect of ezetimibe monotherapy on plasma lipoprotein(a) concentrations in patients with primary hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials. Drugs. 2018;78(4):453–62.
Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014;11(10):563–75.
Sattar N, Preiss D, Robinson JG, Djedjos CS, Elliott M, Somaratne R, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol. 2016;4(5):403–10.
Stein EA, Giugliano RP, Koren MJ, Raal FJ, Roth EM, Weiss R, et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J. 2014;35(33):2249–59.
Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, 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(6):758–69.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22.
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–107.
Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376(15):1430–40.
Penson P, McGowan M, Banach M. Evaluating bempedoic acid for the treatment of hyperlipidaemia. Expert Opin Investig Drugs. 2017;26(2):251–9.
Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022–32.
Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8(7):e011662.
Ruscica M, Banach M, Sahebkar A, Corsini A, Sirtori CR. ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials. Expert Opin Pharmacother. 2019;27:1–13. https://doi.org/10.1080/14656566.2019.1583209.
Banach M, Patti AM, Giglio RV, Cicero AFG, Atanasov AG, Bajraktari G, et al. The role of nutraceuticals in statin intolerant patients. J Am Coll Cardiol. 2018;72(1):96–118.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Bartlomiejczyk, M.A., Penson, P.E., Banach, M. (2021). Management of Statin Intolerance. In: Davidson, M.H., Toth, P.P., Maki, K.C. (eds) Therapeutic Lipidology. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-030-56514-5_12
Download citation
DOI: https://doi.org/10.1007/978-3-030-56514-5_12
Published:
Publisher Name: Humana, Cham
Print ISBN: 978-3-030-56513-8
Online ISBN: 978-3-030-56514-5
eBook Packages: MedicineMedicine (R0)