Review article: Biomedical intelligence
Vol. 146 No. 2728 (2016)
Current treatment of dyslipidaemia: PCSK9 inhibitors and statin intolerance
- Konstantinos Koskinas
- Matthias Wilhelm
- Stephan Windecker
Summary
Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients.
References
- Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.
- Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al.; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.
- Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010;33:171–87.
- Armitage J. The safety of statins in clinical practice. Lancet. 2007;370:1781–90.
- 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;36:1012–22.
- Bergeron N, Phan BA, Ding Y, Fong A, Krauss RM. Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. Circulation. 2015;132:1648–66.
- Giugliano RP, Sabatine MS. Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? J Am Coll Cardiol. 2015;65:2638–51.
- Shimada YJ, Cannon CP. PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future. Eur Heart J. 2015;36:2415–24.
- Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, et al.; GAUSS-2 Investigators. 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.
- 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;9:758–69.
- Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al., Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78.
- Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81.
- Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–42.
- Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Med. 2014;12:51.
- Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz HM. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006;114:2788–97.
- Heart Protection Study Collaborative Group.MRC/BHFHeart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7–22.
- Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403–14.
- Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M, Turchin A. Discontinuation of statins in routine care settings: A cohort study. Ann Intern Med. 2013;158:526–34.
- 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;6:208–15.
- Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8A):52C–60C.
- Mohaupt MG, Karas RH, Babiychuk EB, Sanchez-Freire V, Monastyrskaya K, Iyer L, et al. Association between statin-associated myopathy and skeletal muscle damage. CMAJ. 2009;181:E11–8.
- Draeger A, Monastyrskaya K, Mohaupt M, Hoppeler H, Savolainen H, Allemann C, Babiychuk EB. Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J Pathol. 2006;210:94–102.
- Mammen AL. Statin-associated autoimmune myopathy. N Engl J Med. 2016;374:664–9.
- Chodick G, Shalev V, Gerber Y, Heymann AD, Silber H, Simah V, Kokia E. Longterm persistence with statin treatment in a not-for-profit health maintenance organization: a population-based retrospective cohort study in Israel. Clin Ther. 2008;30:2167–79.
- 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;6:208–15.
- Jackevicius CA,MamdaniM,Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA. 2002;288:462–7.
- Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J. 2013;34:2940–8.
- Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, 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). Eur Heart J. 2011;32:1769–818.
- 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 Mar 28. pii: S0735-1097(16)32398–1.
- de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation. 2016;133:1067–72.
- 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;19:403–14.
- Gadbut AP, Caruso AP, Galper JB. Differential sensitivity of C2-C12 striated muscle cells to lovastatin and pravastatin. J Mol Cell Cardiol. 1995;27:2397–402.
- Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al.; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010;376:1916–22.
- Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354:731–9.
- Bader T. The myth of statin-induced hepatotoxicity. Am J Gastroenterol. 2010;105:978–80.
- Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127:96–103.
- 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:S58–71.
- Norata GD, Ballantyne CM, Catapano AL. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. Eur Heart J. 2013;34:1783–9.
- Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al.; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.
- Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.
- Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of Coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015;238:329–35.
- Fukumoto Y, Libby P, Rabkin E, Hill CC, Enomoto M, Hirouchi Y, et al. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of watanabe heritable hyperlipidemic rabbits. Circulation. 2001;103:993–9.
- Kini AS, Baber U, Kovacic JC, Limaye A, Ali ZA, Sweeny J, et al. Changes in plaque lipid content after short-term intensive versus standard statin therapy: the YELLOW trial. J Am Coll Cardiol. 2013;62:21–9.
- Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.
- Arnaud C, Braunersreuther V, Mach F. Toward immunomodulatory and anti-inflammatory properties of statins. Trends Cardiovasc Med. 2005;15:202–6.
- Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K, et al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol. 2015;66:495–507.
- 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;132:1224–33.
- Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.
- Hovingh GK, Davidson MH, Kastelein JJ, O’Connor AM. Diagnosis and treatment of familial hypercholesterolaemia. Eur Heart J. 2013;34:962–71.
- Gencer B, Lambert G, Mach F. PCSK9 inhibitors. Swiss Med Wkly. 2015;145:w14094.
- Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al.; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.
- Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al.; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.
- Lipinski MJ, Benedetto U, Escarcega RO, Biondi-Zoccai G, Lhermusier T, Baker NC, et al. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J. 2016;37:536–45.
- EMA. European Public Assessment Report (EPAR) for Rapatha (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003766/WC500191400.pdf).
- EMA. European Public Assessment Report (EPAR) for Praluent (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003882/WC500194524.pdf).
- https://www.swissmedic.ch/zulassungen/00153/00189/00200/03284 Accessed March 10, 2016.
- Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, et al.; NLA Expert Panel. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2. J Clin Lipidol 2015;9:S1–S122.
- Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: A systematic review and meta-analysis. Ann Intern Med. 2015;163:40–51.
- Tice JA, Kazi DS, Pearson SD. Proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for treatment of high cholesterol levels: Effectiveness and value. JAMA Intern Med. 2016;176:107–8.
- Choudhry NK, Patrick AR, Glynn RJ, Avorn J. The cost-effectiveness of C-reactive protein testing and rosuvastatin treatment for patients with normal cholesterol levels. J Am Coll Cardiol. 2011;57:784–91.