J Lipid Atheroscler.  2018 Dec;7(2):77-87. 10.12997/jla.2018.7.2.77.

Statin Intolerance: an Overview of the Current Status and Possible Treatment Options

Affiliations
  • 1Division of Endocrinology, Dong-A University College of Medicine, Busan, Korea.
  • 2Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 3Division of Cardiology, Korea University College of Medicine, Seoul, Korea.
  • 4Division of Cardiology, Yonsei University College of Medicine, Seoul, Korea.
  • 5Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. shchoimd@gmail.com

Abstract

Lowering serum low-density lipoprotein cholesterol (LDL-C) is the mainstay for reduction of risk of cardiovascular disease (CVD), the second most common cause of death in Korea. The 2015 Korean guidelines for management of dyslipidemia strongly recommend the use of statins in patients at risk of CVD. Statin therapy, which is the gold standard for CVD, reduces LDL-C level by 40% to 60% and is generally well tolerated. However, many patients are intolerant to statins and discontinue therapy or become nonadherent to therapy because of actual/perceived side effects. The most common of these side effects is the statin-associated muscle symptom (SAMS). Discontinuation and repetitive re-challenge with statins can help identify SAMS. If serum creatinine kinase level is more than 10 times the upper limit of normal, statin therapy must be stopped immediately, and the physician should identify possible causes including rhabdomyolysis and treat appropriately. In other patients, it might help to switch to a less potent statin or to use statins at intermittent non-daily dosing. To achieve target LDL-C level, non-statin lipid-lowering therapies such as dietary modifications, ezetimibe, and bile acid sequestrants may be added. Several new drugs have recently been approved for lowering LDL-C level. Alirocumab and evolocumab are monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, and both drugs cause large reductions in LDL-C, similar to statins. Lomitapide and mipomersen are orphan drugs used as adjuncts to other lipid-lowering therapies in patients with homozygous familial hypercholesterolemia.

Keyword

Statins; Lipids; Cardiovascular disease

MeSH Terms

Antibodies, Monoclonal
Bile
Cardiovascular Diseases
Cause of Death
Cholesterol
Creatinine
Dyslipidemias
Ezetimibe
Food Habits
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors*
Hyperlipoproteinemia Type II
Korea
Lipoproteins
Orphan Drug Production
Phosphotransferases
Proprotein Convertases
Rhabdomyolysis
Antibodies, Monoclonal
Cholesterol
Creatinine
Ezetimibe
Lipoproteins
Phosphotransferases
Proprotein Convertases

Reference

1. Committee for the Korean Guidelines for the Management of Dyslipidemia. 2015 Korean guidelines for the management of dyslipidemia: executive summary (English translation). Korean Circ J. 2016; 46:275–306.
2. Vital Statistics Division, Statistics Korea. Shin HY, Lee JY, Kim JE, Lee S, Youn H, et al. Cause-of-death statistics in 2016 in the Republic of Korea. J Korean Med Assoc. 2018; 61:573–584.
Article
3. Cholesterol Treatment Trialists' (CTT) Collaborators. Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012; 380:581–590.
Article
4. Kim SH, Seo MK, Yoon MH, Choi DH, Hong TJ, Kim HS. Assessment of the efficacy and tolerability of 2 formulations of atorvastatin in Korean adults with hypercholesterolemia: a multicenter, prospective, open-label, randomized trial. Clin Ther. 2013; 35:77–86.
Article
5. 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; 36:1012–1022.
Article
6. Cho YE, Moon PG, Lee JE, Singh TS, Kang W, Lee HC, et al. Integrative analysis of proteomic and transcriptomic data for identification of pathways related to simvastatin-induced hepatotoxicity. Proteomics. 2013; 13:1257–1275.
Article
7. Endo A. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci. 2010; 86:484–493.
Article
8. Young SG, Fong LG. Lowering plasma cholesterol by raising LDL receptors--revisited. N Engl J Med. 2012; 366:1154–1155.
Article
9. Enas EA, Kuruvila A, Khanna P, Pitchumoni CS, Mohan V. Benefits & risks of statin therapy for primary prevention of cardiovascular disease in Asian Indians - a population with the highest risk of premature coronary artery disease & diabetes. Indian J Med Res. 2013; 138:461–491.
10. Khang AR, Song YS, Kim KM, Moon JH, Lim S, Park KS, et al. Comparison of different statin therapy to change low-density lipoprotein cholesterol and high-density lipoprotein cholesterol level in Korean patients with and without diabetes. J Clin Lipidol. 2016; 10:528–537.e3.
Article
11. Brautbar A, Ballantyne CM. Pharmacological strategies for lowering LDL cholesterol: statins and beyond. Nat Rev Cardiol. 2011; 8:253–265.
Article
12. Fitchett DH, Hegele RA, Verma S. Cardiology patient page. Statin intolerance. Circulation. 2015; 131:e389–e391.
13. 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; 11:1–23.
Article
14. Gulizia MM, Colivicchi F, Arca M, Abrignani MG, Perna GP, Mureddu GF, et al. ANMCO position paper: diagnostic-therapeutic pathway in patients with hypercholesterolaemia and statin intolerance. Eur Heart J Suppl. 2017; 19:Suppl D. D55–D63.
Article
15. Guyton JR, Bays HE, Grundy SM, Jacobson TA. The National Lipid Association Statin Intolerance Panel. An assessment by the statin intolerance panel: 2014 update. J Clin Lipidol. 2014; 8:Suppl. S72–S81.
Article
16. Harrison TN, Hsu JY, Rosenson RS, Levitan EB, Muntner P, Cheetham TC, et al. Unmet patient need in statin intolerance: the clinical characteristics and management. Cardiovasc Drugs Ther. 2018; 32:29–36.
Article
17. Furberg CD, Pitt B. Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med. 2001; 2:205–207.
18. Raju SB, Varghese K, Madhu K. Management of statin intolerance. Indian J Endocrinol Metab. 2013; 17:977–982.
Article
19. Sikka P, Kapoor S, Bindra VK, Sharma M, Vishwakarma P, Saxena KK. Statin intolerance: now a solved problem. J Postgrad Med. 2011; 57:321–328.
Article
20. Bitzur R, Cohen H, Kamari Y, Harats D. Intolerance to statins: mechanisms and management. Diabetes Care. 2013; 36:Suppl 2. S325–S330.
Article
21. Gluba-Brzozka A, Franczyk B, Toth PP, Rysz J, Banach M. Molecular mechanisms of statin intolerance. Arch Med Sci. 2016; 12:645–658.
Article
22. Kajinami K, McKendrick J, Gandra SR, Cheng L, Hovingh G, Dent R, et al. Management of patients with statin intolerance in Japan, South Korea and Taiwan: comparison of results from a clinician survey. Value in Health. 2016; 19:A872.
Article
23. Arca M, Pigna G. Treating statin-intolerant patients. Diabetes Metab Syndr Obes. 2011; 4:155–166.
Article
24. Stulc T, Ceška R, Gotto AM Jr. Statin intolerance: the clinician's perspective. Curr Atheroscler Rep. 2015; 17:69.
Article
25. Bohula EA, Giugliano RP, Cannon CP, Zhou J, Murphy SA, White JA, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015; 132:1224–1233.
Article
26. Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014; 349:g4379.
27. Ip CK, Jin DM, Gao JJ, Meng Z, Meng J, Tan Z, et al. Effects of add-on lipid-modifying therapy on top of background statin treatment on major cardiovascular events: a meta-analysis of randomized controlled trials. Int J Cardiol. 2015; 191:138–148.
Article
28. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365:2255–2267.
Article
29. Agouridis AP, Nair DR, Mikhailidis DP. Strategies to overcome statin intolerance. Expert Opin Drug Metab Toxicol. 2015; 11:851–855.
Article
30. Regeneron Pharmaceuticals, Inc.Regeneron announce approval of Praluent® (alirocumab) for the treatment of hypercholesterolemia in Japan [Internet]. New York, NY: PRNewswire;2016. accessed on 1 May 2018. Available from: https://www.prnewswire.com/news-releases/regeneron-and-sanofi-announce-approval-of-praluent-alirocumab-for-the-treatment-of-hypercholesterolemia-in-japan-300293422.html.
31. Amgen. Amgen's Repatha® (evolocumab) approved as first PCSK9 inhibitor in Japan for the treatment of high cholesterol [Internet]. New York, NY: PRNewswire;2016. accessed on 1 May 2018. Available from: https://www.prnewswire.com/news-releases/amgens-repatha-evolocumab-approved-as-first-pcsk9-inhibitor-in-japan-for-the-treatment-of-high-cholesterol-300208360.html.
32. McDonagh M, Peterson K, Holzhammer B, Fazio S. A systematic review of PCSK9 inhibitors alirocumab and evolocumab. J Manag Care Spec Pharm. 2016; 22:641–653q.
Article
33. Grundy SM. Dyslipidaemia in 2015: advances in treatment of dyslipidaemia. Nat Rev Cardiol. 2016; 13:74–75.
34. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012; 366:1108–1118.
Article
35. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012; 380:29–36.
Article
36. 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; 9:758–769.
Article
37. 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; 308:2497–2506.
Article
38. 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; 315:1580–1590.
Article
39. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014; 370:1809–1819.
Article
40. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1489–1499.
Article
41. 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; 376:1713–1722.
Article
42. 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; 129:1022–1032.
43. Stefanutti C, Blom DJ, Averna MR, Meagher EA, Theron H, Marais AD, et al. The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post-hoc analysis of a phase 3, single-arm, open-label trial. Atherosclerosis. 2015; 240:408–414.
Article
44. Turner T, Stein EA. Non-statin treatments for managing LDL cholesterol and their outcomes. Clin Ther. 2015; 37:2751–2769.
Article
45. 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; 376:1430–1440.
Article
46. HPS3/TIMI55–REVEAL Collaborative Group. Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017; 377:1217–1227.
Article
47. Lincoff AM, Nicholls SJ, Riesmeyer JS, Barter PJ, Brewer HB, Fox KA, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017; 376:1933–1942.
Article
48. Thompson PD, MacDougall DE, Newton RS, Margulies JR, Hanselman JC, Orloff DG, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016; 10:556–567.
Article
Full Text Links
  • JLA
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr