Curr Cardiol Rep (2015) 17: 27 DOI 10.1007/s11886-015-0582-z
LIPID ABNORMALITIES AND CARDIOVASCULAR PREVENTION (G DE BACKER, SECTION EDITOR)
Statin Intolerance: Diagnosis and Remedies Angela Pirillo & Alberico Luigi Catapano
Published online: 18 April 2015 # Springer Science+Business Media New York 2015
Abstract Despite the efficacy of statins in reducing cardiovascular events in both primary and secondary prevention, the adherence to statin therapy is not optimal, mainly due to the occurrence of muscular adverse effects. Several risk factors may concur to the development of statin-induced myotoxicity, including patient-related factors (age, sex, and race), statin properties (dose, lipophilicity, and type of metabolism), and the concomitant administration of other drugs. Thus, the management of patients intolerant to statins, particularly those at high or very high cardiovascular risk, involves alternative therapies, including the switch to another statin or the use of intermittent dosage statin regimens, as well as nonstatin lipid lowering drugs (ezetimibe and fibrates) or new hypolipidemic drugs such as PCSK9 monoclonal antibodies, the antisense oligonucleotide against the coding region of human apolipoprotein B mRNA (mipomersen), and microsomal triglyceride transfer protein inhibitor lomitapide. Ongoing clinical trials will reveal whether the lipid-lowering effects of alternative therapies to statins can also translate into a cardiovascular benefit.
This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention A. Pirillo (*) Center for the Study of Atherosclerosis, E. Bassini Hospital, Via M. Gorki 50, Cinisello Balsamo, Milan, Italy e-mail: [email protected] A. Pirillo : A. L. Catapano IRCCS Multimedica, Milan, Italy A. L. Catapano e-mail: [email protected] A. L. Catapano Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milan, Italy
Keywords Statins . Statin intolerance . Myopathy . Myalgia
Introduction A large number of clinical trials have shown the efficacy of statins in reducing cardiovascular morbidity and mortality in both primary and secondary prevention [1–7]. Current guidelines recommend serum low density lipoprotein cholesterol (LDL-C) levels 40 000 patients. Eur Heart J. 2011;32: 1409–15. Chan DK, O’Rourke F, Shen Q, et al. Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins. Acta Neurol Scand. 2011;124:188–95. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD004816. Catapano AL, Reiner Z, de Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011;217:3–46. Corrao G, Conti V, Merlino L, et al. Results of a retrospective database analysis of adherence to statin therapy and risk of nonfatal ischemic heart disease in daily clinical practice in Italy. Clin Ther. 2010;32:300–10. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150:858–68. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97:52C–60.
Page 7 of 9 27 12.
Fernandez G, Spatz ES, Jablecki C, et al. Statin myopathy: a common dilemma not reflected in clinical trials. Cleve Clin J Med. 2011;78:393–403. 13. Maningat P, Breslow JL. Needed: pragmatic clinical trials for statinintolerant patients. N Engl J Med. 2011;365:2250–1. 14. Taha DA, de Moor CH, Barrett DA, et al. Translational insight into statin-induced muscle toxicity: from cell culture to clinical studies. Transl Res. 2014;164:85–109. 15. Chatzizisis YS, Koskinas KC, Misirli G, et al. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010;33: 171–87. 16.•• Alfirevic A, Neely D, Armitage J, et al. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther. 2014;96:470– 6. In this paper, the authors defined phenotypic criteria to standardize statin-induced myotoxicity phenotypes, based on a previously described consensus approach. 17. Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve. 2013;48:477– 83. 18. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403–14. 19.• Rosenbaum D, Dallongeville J, Sabouret P, et al. Discontinuation of statin therapy due to muscular side effects: a survey in real life. Nutr Metab Cardiovasc Dis. 2013;23:871–5. This survey revealed the higher frequency of muscular symptoms associated with statin therapy in real life than in clinical trials. 20. Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127:96–103. 21. Ballard KD, Parker BA, Capizzi JA, et al. Increases in creatine kinase with atorvastatin treatment are not associated with decreases in muscular performance. Atherosclerosis. 2013;230:121–4. 22. Marcoff L, Thompson PD. The role of coenzyme Q10 in statinassociated myopathy: a systematic review. J Am Coll Cardiol. 2007;49:2231–7. 23. Kaufmann P, Torok M, Zahno A, et al. Toxicity of statins on rat skeletal muscle mitochondria. Cell Mol Life Sci. 2006;63:2415–25. 24. Masters BA, Palmoski MJ, Flint OP, et al. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol. 1995;131:163–74. 25. Ho RH, Tirona RG, Leake BF, et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006;130:1793–806. 26. Nakai D, Nakagomi R, Furuta Y, et al. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J Pharmacol Exp Ther. 2001;297:861–7. 27. Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of druginduced adverse events associated with intensive-dose statin therapy. Clin Ther. 2007;29:253–60. 28. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539–40. 29. Wang JS, Neuvonen M, Wen X, et al. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos. 2002;30:1352–6. 30. Ogilvie BW, Zhang D, Li W, et al. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug–drug interactions. Drug Metab Dispos. 2006;34:191–7. 31. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19:117–25. 32. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipidlowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565–81.
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LIPID ABNORMALITIES AND CARDIOVASCULAR PREVENTION (G DE BACKER, SECTION EDITOR)
Statin Intolerance: Diagnosis and Remedies Angela Pirillo & Alberico Luigi Catapano
Published online: 18 April 2015 # Springer Science+Business Media New York 2015
Abstract Despite the efficacy of statins in reducing cardiovascular events in both primary and secondary prevention, the adherence to statin therapy is not optimal, mainly due to the occurrence of muscular adverse effects. Several risk factors may concur to the development of statin-induced myotoxicity, including patient-related factors (age, sex, and race), statin properties (dose, lipophilicity, and type of metabolism), and the concomitant administration of other drugs. Thus, the management of patients intolerant to statins, particularly those at high or very high cardiovascular risk, involves alternative therapies, including the switch to another statin or the use of intermittent dosage statin regimens, as well as nonstatin lipid lowering drugs (ezetimibe and fibrates) or new hypolipidemic drugs such as PCSK9 monoclonal antibodies, the antisense oligonucleotide against the coding region of human apolipoprotein B mRNA (mipomersen), and microsomal triglyceride transfer protein inhibitor lomitapide. Ongoing clinical trials will reveal whether the lipid-lowering effects of alternative therapies to statins can also translate into a cardiovascular benefit.
This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention A. Pirillo (*) Center for the Study of Atherosclerosis, E. Bassini Hospital, Via M. Gorki 50, Cinisello Balsamo, Milan, Italy e-mail: [email protected] A. Pirillo : A. L. Catapano IRCCS Multimedica, Milan, Italy A. L. Catapano e-mail: [email protected] A. L. Catapano Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milan, Italy
Keywords Statins . Statin intolerance . Myopathy . Myalgia
Introduction A large number of clinical trials have shown the efficacy of statins in reducing cardiovascular morbidity and mortality in both primary and secondary prevention [1–7]. Current guidelines recommend serum low density lipoprotein cholesterol (LDL-C) levels 40 000 patients. Eur Heart J. 2011;32: 1409–15. Chan DK, O’Rourke F, Shen Q, et al. Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins. Acta Neurol Scand. 2011;124:188–95. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD004816. Catapano AL, Reiner Z, de Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011;217:3–46. Corrao G, Conti V, Merlino L, et al. Results of a retrospective database analysis of adherence to statin therapy and risk of nonfatal ischemic heart disease in daily clinical practice in Italy. Clin Ther. 2010;32:300–10. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150:858–68. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97:52C–60.
Page 7 of 9 27 12.
Fernandez G, Spatz ES, Jablecki C, et al. Statin myopathy: a common dilemma not reflected in clinical trials. Cleve Clin J Med. 2011;78:393–403. 13. Maningat P, Breslow JL. Needed: pragmatic clinical trials for statinintolerant patients. N Engl J Med. 2011;365:2250–1. 14. Taha DA, de Moor CH, Barrett DA, et al. Translational insight into statin-induced muscle toxicity: from cell culture to clinical studies. Transl Res. 2014;164:85–109. 15. Chatzizisis YS, Koskinas KC, Misirli G, et al. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010;33: 171–87. 16.•• Alfirevic A, Neely D, Armitage J, et al. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther. 2014;96:470– 6. In this paper, the authors defined phenotypic criteria to standardize statin-induced myotoxicity phenotypes, based on a previously described consensus approach. 17. Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve. 2013;48:477– 83. 18. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403–14. 19.• Rosenbaum D, Dallongeville J, Sabouret P, et al. Discontinuation of statin therapy due to muscular side effects: a survey in real life. Nutr Metab Cardiovasc Dis. 2013;23:871–5. This survey revealed the higher frequency of muscular symptoms associated with statin therapy in real life than in clinical trials. 20. Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127:96–103. 21. Ballard KD, Parker BA, Capizzi JA, et al. Increases in creatine kinase with atorvastatin treatment are not associated with decreases in muscular performance. Atherosclerosis. 2013;230:121–4. 22. Marcoff L, Thompson PD. The role of coenzyme Q10 in statinassociated myopathy: a systematic review. J Am Coll Cardiol. 2007;49:2231–7. 23. Kaufmann P, Torok M, Zahno A, et al. Toxicity of statins on rat skeletal muscle mitochondria. Cell Mol Life Sci. 2006;63:2415–25. 24. Masters BA, Palmoski MJ, Flint OP, et al. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol. 1995;131:163–74. 25. Ho RH, Tirona RG, Leake BF, et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006;130:1793–806. 26. Nakai D, Nakagomi R, Furuta Y, et al. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J Pharmacol Exp Ther. 2001;297:861–7. 27. Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of druginduced adverse events associated with intensive-dose statin therapy. Clin Ther. 2007;29:253–60. 28. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539–40. 29. Wang JS, Neuvonen M, Wen X, et al. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos. 2002;30:1352–6. 30. Ogilvie BW, Zhang D, Li W, et al. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug–drug interactions. Drug Metab Dispos. 2006;34:191–7. 31. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19:117–25. 32. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipidlowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565–81.
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