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Statin Intolerance: Diagnosis and Remedies

  • Angela PirilloEmail author
  • Alberico Luigi Catapano
Lipid Abnormalities and Cardiovascular Prevention (G De Backer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Lipid Abnormalities and Cardiovascular Prevention

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.

Keywords

Statins Statin intolerance Myopathy Myalgia 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Angela Pirillo has no conflicts of interest.

Alberico Luigi Catapano is on the advisory board or a member of the speaker bureau for AstraZeneca, Amgen, Aegerion, Eli-Lilly, Genzyme, Mediolanum, Merck-MSD, Pfizer, Recordati, Rottapharm, Sanofi, and Sigma-Tau.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Naci H, Brugts JJ, Fleurence R, et al. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol. 2013;20:641–57.CrossRefPubMedGoogle Scholar
  2. 2.
    Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81.CrossRefPubMedGoogle Scholar
  3. 3.
    Mills EJ, Wu P, Chong G, et al. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM. 2011;104:109–24.CrossRefPubMedGoogle Scholar
  4. 4.
    Tonelli M, Lloyd A, Clement F, et al. Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. CMAJ. 2011;183:E1189–202.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Mills EJ, O’Regan C, Eyawo O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. Eur Heart J. 2011;32:1409–15.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD004816.PubMedGoogle Scholar
  8. 8.
    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.CrossRefPubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150:858–68.CrossRefPubMedGoogle Scholar
  11. 11.
    Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97:52C–60.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 13.
    Maningat P, Breslow JL. Needed: pragmatic clinical trials for statin-intolerant patients. N Engl J Med. 2011;365:2250–1.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve. 2013;48:477–83.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 20.
    Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127:96–103.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol. 2007;49:2231–7.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 27.
    Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther. 2007;29:253–60.CrossRefPubMedGoogle Scholar
  28. 28.
    Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539–40.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 31.
    Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19:117–25.CrossRefPubMedGoogle Scholar
  32. 32.
    Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565–81.CrossRefPubMedGoogle Scholar
  33. 33.
    Ichimaru N, Takahara S, Kokado Y, et al. Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis. 2001;158:417–23.CrossRefPubMedGoogle Scholar
  34. 34.•
    Ito MK, Maki KC, Brinton EA, et al. Muscle symptoms in statin users, associations with cytochrome P450, and membrane transporter inhibitor use: a subanalysis of the USAGE study. J Clin Lipidol. 2014;8:69–76. This study showed the relevance of drug-drug interaction as a risk factor for muscle-related side effects in patients taking statins and concomitant therapies that interfere with statin metabolism.CrossRefPubMedGoogle Scholar
  35. 35.
    Tragni E, Casula M, Pieri V, et al. Prevalence of the prescription of potentially interacting drugs. PLoS One. 2013;8:e78827.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Kellick KA, Bottorff M, Toth PP. A clinician’s guide to statin drug–drug interactions. J Clin Lipidol. 2014;8:S30–46.CrossRefPubMedGoogle Scholar
  37. 37.
    Lee E, Ryan S, Birmingham B, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther. 2005;78:330–41.CrossRefPubMedGoogle Scholar
  38. 38.
    Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol. 2007;99:410–4.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Needham M, Mastaglia FL. Statin myotoxicity: a review of genetic susceptibility factors. Neuromuscul Disord. 2014;24:4–15.CrossRefPubMedGoogle Scholar
  40. 40.
    Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359:789–99.CrossRefPubMedGoogle Scholar
  41. 41.
    Pasanen MK, Neuvonen M, Neuvonen PJ, et al. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics. 2006;16:873–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Stewart A. SLCO1B1 Polymorphisms and statin-induced myopathy. PLoS Curr 2013;5. doi: 10.1371/currents.eogt.d21e7f0c58463571bb0d9d3a19b82203
  43. 43.
    Brunham LR, Lansberg PJ, Zhang L, et al. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. Pharmacogenomics J. 2012;12:233–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Danik JS, Chasman DI, MacFadyen JG, et al. Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy. Am Heart J. 2013;165:1008–14.CrossRefPubMedGoogle Scholar
  45. 45.
    Ramsey LB, Johnson SG, Caudle KE, et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther. 2014;96:423–8.CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Wang D, Guo Y, Wrighton SA, et al. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 2011;11:274–86.CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Elens L, Becker ML, Haufroid V, et al. Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study. Pharmacogenet Genomics. 2011;21:861–6.CrossRefPubMedGoogle Scholar
  48. 48.
    Ragia G, Kolovou V, Tavridou A, et al. No effect of CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) on lipid-lowering response to statins in Greek patients with primary hypercholesterolemia. Drug Metabol Drug Interact 2015; in press. doi: 10.1515/dmdi-2014-0021
  49. 49.
    Leusink M, de Keyser CE, Onland-Moret NC, et al. No association between CYP3A4*22 and statin effectiveness in reducing the risk for myocardial infarction. Pharmacogenomics. 2014;15:1471–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Li J, Wang X, Zhang Z, et al. Statin therapy correlated CYP2D6 gene polymorphism and hyperlipidemia. Curr Med Res Opin. 2014;30:223–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Vladutiu GD, Simmons Z, Isackson PJ, et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve. 2006;34:153–62.CrossRefPubMedGoogle Scholar
  52. 52.
    Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158:526–34.CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Mampuya WM, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J. 2013;166:597–603.CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Arca M, Pigna G. Treating statin-intolerant patients. Diabetes Metab Syndr Obes. 2011;4:155–66.CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Glueck CJ, Aregawi D, Agloria M, et al. Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies. Clin Ther. 2006;28:933–42.CrossRefPubMedGoogle Scholar
  56. 56.
    Martin PD, Warwick MJ, Dane AL, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther. 2003;25:2822–35.CrossRefPubMedGoogle Scholar
  57. 57.
    Ruisinger JF, Backes JM, Gibson CA, et al. Once-a-week rosuvastatin (2.5 to 20 mg) in patients with a previous statin intolerance. Am J Cardiol. 2009;103:393–4.CrossRefPubMedGoogle Scholar
  58. 58.
    Backes JM, Gibson CA, Ruisinger JF, et al. The high-dose rosuvastatin once weekly study (the HD-ROWS). J Clin Lipidol. 2011;6:362–7.CrossRefPubMedGoogle Scholar
  59. 59.
    Backes JM, Venero CV, Gibson CA, et al. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. Ann Pharmacother. 2008;42:341–6.CrossRefPubMedGoogle Scholar
  60. 60.
    Athyros VG, Tziomalos K, Kakafika AI, et al. Effectiveness of ezetimibe alone or in combination with twice a week Atorvastatin (10 mg) for statin intolerant high-risk patients. Am J Cardiol. 2008;101:483–5.CrossRefPubMedGoogle Scholar
  61. 61.
    Elis A, Lishner M. Non-every day statin administration—a literature review. Eur J Intern Med. 2012;23:474–8.CrossRefPubMedGoogle Scholar
  62. 62.
    Marcus FI, Baumgarten AJ, Fritz WL, et al. Alternate-day dosing with statins. Am J Med. 2013;126:99–104.CrossRefPubMedGoogle Scholar
  63. 63.
    Pandor A, Ara RM, Tumur I, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med. 2009;265:568–80.CrossRefPubMedGoogle Scholar
  64. 64.
    Kumar SS, Lahey KA, Day A, et al. Comparison of the efficacy of administering a combination of ezetimibe plus fenofibrate versus atorvastatin monotherapy in the treatment of dyslipidemia. Lipids Health Dis. 2009;8:56.CrossRefPubMedCentralPubMedGoogle Scholar
  65. 65.
    Derosa G, D’Angelo A, Franzetti IG, et al. Efficacy and safety of ezetimibe/simvastatin association on non-diabetic and diabetic patients with polygenic hypercholesterolemia or combined hyperlipidemia and previously intolerant to standard statin treatment. J Clin Pharm Ther. 2009;34:267–76.CrossRefPubMedGoogle Scholar
  66. 66.
    Blazing MA, Giugliano RP, Cannon CP, et al. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population. Am Heart J. 2014;168:205–12.CrossRefPubMedGoogle Scholar
  67. 67.
    Cannon CP on behalf of the IMPROVE-IT Investigators. IMPROVE-IT Trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Presented at the American Heart Association Scientific Session. Chicago, United States of America; November 15–19, 2014.Google Scholar
  68. 68.
    Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35:2146–57.CrossRefPubMedCentralPubMedGoogle Scholar
  69. 69.
    Akdim F, Stroes ES, Sijbrands EJ, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol. 2010;55:1611–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol. 2010;105:1413–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Kastelein JJ, Wedel MK, Baker BF, et al. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation. 2006;114:1729–35.CrossRefPubMedGoogle Scholar
  72. 72.
    McGowan MP, Tardif JC, Ceska R, et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7:e49006.CrossRefPubMedCentralPubMedGoogle Scholar
  73. 73.
    Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:998–1006.CrossRefPubMedGoogle Scholar
  74. 74.
    Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126:2283–92.CrossRefPubMedGoogle Scholar
  75. 75.
    Yu RZ, Geary RS, Flaim JD, et al. Lack of pharmacokinetic interaction of mipomersen sodium (ISIS 301012), a 2′-O-methoxyethyl modified antisense oligonucleotide targeting apolipoprotein B-100 messenger RNA, with simvastatin and ezetimibe. Clin Pharmacokinet. 2009;48:39–50.CrossRefPubMedGoogle Scholar
  76. 76.
    Sahebkar A, Watts GF. New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin Ther. 2013;35:1082–98.CrossRefPubMedGoogle Scholar
  77. 77.
    Toth PP. Emerging LDL, therapies: mipomersen-antisense oligonucleotide therapy in the management of hypercholesterolemia. J Clin Lipidol. 2013;7:S6–10.CrossRefPubMedGoogle Scholar
  78. 78.
    Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2012;33:1142–9.CrossRefPubMedCentralPubMedGoogle Scholar
  79. 79.•
    Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129:1022–32. This review describes 2 drugs that reduce LDL-C independently of LDLR, and thus effective in familial hypercholesterolemic patients who are at higher cardiovascular risk.CrossRefPubMedGoogle Scholar
  80. 80.
    Samaha FF, McKenney J, Bloedon LT, et al. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2008;5:497–505.CrossRefPubMedGoogle Scholar
  81. 81.
    Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356:148–56.CrossRefPubMedGoogle Scholar
  82. 82.
    Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381:40–6.CrossRefPubMedGoogle Scholar
  83. 83.
    Catapano AL, Papadopoulos N. The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis. 2013;228:18–28.CrossRefPubMedGoogle Scholar
  84. 84.
    Careskey HE, Davis RA, Alborn WE, et al. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res. 2008;49:394–8.CrossRefPubMedGoogle Scholar
  85. 85.
    Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;24:1454–9.CrossRefPubMedGoogle Scholar
  86. 86.
    Abifadel M, Elbitar S, el Khoury P, et al. Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs. Curr Atheroscler Rep. 2014;16:439.CrossRefPubMedGoogle Scholar
  87. 87.
    Sullivan D, Olsson AG, Scott R, 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;308:2497–506.CrossRefPubMedGoogle Scholar
  88. 88.•
    Stroes E, Colquhoun D, Sullivan D, 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;63:2541–8. This clinical trial identified evolocumab as a promising therapy for statin-intolerant patients at high cardiovascular risk.CrossRefPubMedGoogle Scholar
  89. 89.
    Li Y, Jiang L, Jia Z, et al. A meta-analysis of red yeast rice: an effective and relatively safe alternative approach for dyslipidemia. PLoS One. 2014;9:e98611.CrossRefPubMedCentralPubMedGoogle Scholar
  90. 90.
    Venero CV, Venero JV, Wortham DC, et al. Lipid-lowering efficacy of red yeast rice in a population intolerant to statins. Am J Cardiol. 2010;105:664–6.CrossRefPubMedGoogle Scholar
  91. 91.
    Becker DJ, Gordon RY, Halbert SC, et al. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009;150:830–9.CrossRefPubMedGoogle Scholar
  92. 92.
    Halbert SC, French B, Gordon RY, et al. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol. 2010;105:198–204.CrossRefPubMedGoogle Scholar
  93. 93.
    Marazzi G, Cacciotti L, Pelliccia F, et al. Long-term effects of nutraceuticals (berberine, red yeast rice, policosanol) in elderly hypercholesterolemic patients. Adv Ther. 2011;28:1105–13.CrossRefPubMedGoogle Scholar
  94. 94.
    Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004;10:1344–51.CrossRefPubMedGoogle Scholar
  95. 95.
    Cameron J, Ranheim T, Kulseth MA, et al. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis. 2008;201:266–73.CrossRefPubMedGoogle Scholar
  96. 96.
    Dong H, Zhao Y, Zhao L, et al. The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials. Planta Med. 2013;79:437–46.CrossRefPubMedGoogle Scholar
  97. 97.
    Pisciotta L, Bellocchio A, Bertolini S. Nutraceutical pill containing berberine versus ezetimibe on plasma lipid pattern in hypercholesterolemic subjects and its additive effect in patients with familial hypercholesterolemia on stable cholesterol-lowering treatment. Lipids Health Dis. 2012;11:123.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Center for the Study of AtherosclerosisE. Bassini HospitalMilanItaly
  2. 2.IRCCS MultimedicaMilanItaly
  3. 3.Department of Pharmacological and Biomolecular SciencesUniversità degli Studi di MilanoMilanItaly

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