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Review

Efficacy and safety of PCSK9 monoclonal antibodies

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Pages 1191-1201 | Received 21 May 2019, Accepted 14 Oct 2019, Published online: 20 Nov 2019

References

  • Cardiovascular diseases (CVDs). [cited 2018 Nov 20]. Available from: http://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
  • Chen Z, Peto R, Collins R, et al. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ. 1991;303:276–282.
  • Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep. 2012;14:1–10.
  • Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Nat Acad Sci. 2003;100:928–933.
  • Benn M, Nordestgaard BG, Grande P, et al. PCSK9R46L, Low-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J Am Coll Cardiol. 2010;55:2833–2842.
  • Varret M, Rabes J-P, Saint-Jore B, et al. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34. 1-p32. Am J Hum Genet. 1999;64:1378–1387.
  • Abifadel M, Varret M, Rabès J-P, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–156.
  • Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Nat Acad Sci. 2004;101:7100–7105.
  • Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Nat Acad Sci. 2005;102:2069–2074.
  • Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005. DOI:10.1038/ng1509
  • Hopkins PN, Defesche J, Fouchier SW, et al. Characterization of autosomal dominant hypercholesterolemia caused by PCSK9 gain of function mutations and its specific treatment with alirocumab, a PCSK9 monoclonal antibody. Circ: Cardiovasc Genet. 2015;8:823–831.
  • Chen YQ, Troutt JS, Konrad RJ. PCSK9 is present in human cerebrospinal fluid and is maintained at remarkably constant concentrations throughout the course of the day. Lipids. 2014;49:445–455.
  • Pavlakou P, Liberopoulos E, Dounousi E, et al. PCSK9 in chronic kidney disease. Int Urol Nephrol. 2017;49:1015–1024.
  • Holla ØL, Cameron J, Berge KE, et al. Degradation of the LDL receptors by PCSK9 is not mediated by a secreted protein acted upon by PCSK9 extracellularly. BMC Cell Biol. 2007;8:9.
  • Persson L, Cao G, Ståhle L, et al. Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler Thromb Vasc Biol. 2010;30:2666–2672.
  • Mitchell T, Chao G, Sitkoff D, et al. Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J Pharmacol Exp Ther. 2014;350:412–424.
  • Lindholm MW, Elmén J, Fisker N, et al. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol Ther. 2012;20:376–381.
  • Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014;383:60–68.
  • Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376:1430–1440.
  • Chaudhary R, Garg J, Shah N, et al. PCSK9 inhibitors: A new era of lipid lowering therapy. World J Cardiol. 2017;9:76.
  • Hess CN, Low Wang CC, Hiatt WR. PCSK9 inhibitors: mechanisms of action, metabolic effects, and clinical outcomes. Annu Rev Med. 2018;69:133–145.
  • Stoekenbroek RM, Kastelein JJP, Huijgen R. PCSK9 inhibition: the way forward in the treatment of dyslipidemia. BMC Med. 2015;13:258.
  • Boffa MB, Koschinsky ML. Update on lipoprotein (a) as a cardiovascular risk factor and mediator. Curr Atheroscler Rep. 2013;15:360.
  • Page MM, Watts GF. PCSK9 inhibitors-mechanisms of action. Aust Prescr. 2016;39:164–171.
  • Durrington PN, Schofield JD, Siahmansur T, et al. Lipoprotein (a): Gene Genie. Curr Opin Lipidol. 2014;25:289–296.
  • Koschinsky M, Boffa M. Lipoprotein(a) as a therapeutic target in cardiovascular disease. Expert Opin Ther Targets. 2014;18:747–757.
  • Tavori H, Rashid S, Fazio S. On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects. Atherosclerosis. 2015;238:264–270.
  • Tavori H, Christian D, Minnier J, et al. PCSK9 association with lipoprotein(a). Circ Res. 2016;119:29–35.
  • Romagnuolo R, Scipione CA, Boffa MB, et al. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem. 2015;290:11649–11662.
  • Jensen LO, Thayssen P, Pedersen KE, et al. Regression of coronary atherosclerosis by simvastatin. Circulation. 2004;110:265–270.
  • Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. JAMA. 2006 [cited 2018 Nov 24]. http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.295.13.jpc60002.
  • Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. Jama. 2016;316:2373–2384.
  • Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722.
  • Murphy SA, Pedersen TR, Gaciong ZA, et al. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease. JAMA Cardiol. 2019;4:613.
  • Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107.
  • Macchi C, Banach M, Corsini A, et al. Changes in circulating pro-protein convertase subtilisin/kexin type 9 levels – experimental and clinical approaches with lipid-lowering agents. Eur J Prev Cardiol. 2019;26:930–949.
  • WHO. WHO | Prevention of recurrences of myocardial infarction and stroke study. World health organisation, 2013. [cited 2018 Nov 27]. Available from: https://www.who.int/cardiovascular_diseases/priorities/secondary_prevention/country/en/index1.html
  • Steg PG, Szarek M, Bhatt DL, et al. Effect of alirocumab on mortality after acute coronary syndromes. Circulation. 2019;140:103–112.
  • White HD, Steg PG, Szarek M, et al. Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial. Eur Heart J. 2019;40:2801–2809. .
  • Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527–1539.
  • Soran H, Schofield JD, Durrington PN. Cholesterol, not just cardiovascular risk, is important in deciding who should receive statin treatment. Eur Heart J. 2015;36:ehv340.
  • Soran H, Adam S, Durrington PN. Optimising treatment of hyperlipidaemia: quantitative evaluation of UK, USA and European guidelines taking account of both LDL cholesterol levels and cardiovascular disease risk. Atherosclerosis. 2018;278:135–142.
  • Soran H, Adam S, Durrington PN. Are recent statin recommendations to employ fixed doses and abandon targets effective for treatment of hypercholesterolaemia? Investigation based on number needed to treat. Eur J Prev Cardiol. 2017;24:76–83.
  • Soran H, Adam S, Ho JH, et al. Evidence for more intensive cholesterol lowering. Curr Opin Lipidol. 2017;28:291–299.
  • Soran H, Dent R, Durrington P. Evidence-based goals in LDL-C reduction. Clin Res Cardiol. 2017;106:237–248.
  • Linton MF, Farese RV, Young SG. Familial hypobetalipoproteinemia. J Lipid Res. 1993;34:521–541.
  • Sankatsing RR, Fouchier SW, de Haan S, et al. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2005;25:1979–1984.
  • Blom DJ, Djedjos CS, Monsalvo ML, et al. Effects of evolocumab on Vitamin E and steroid hormone level novelty and significance: results from the 52-week, Phase 3, double-blind, randomized, placebo-controlled DESCARTES study. Circ Res. 2015;117:731–741.
  • Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol. 2014;25:161–168.
  • Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–1272.
  • Kathiresan S. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med. 2008;358:2299–2300.
  • Jacobs D, Blackburn H, Higgins M, et al. Report of the conference on low blood cholesterol: mortality associations. Circulation. 1992;86:1046–1060.
  • Folsom AR, Peacock JM, Boerwinkle E. Sequence variation in proprotein convertase subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence. Cancer Epidemiol Prev Biomarkers. 2007;16:2455–2458.
  • Faselis C, Imprialos K, Grassos H, et al. Is very low LDL-C harmful? Curr Pharm Des. 2018;24(31):3658–3664.
  • Hsia J, MacFadyen JG, Monyak J, et al. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol< 50 mg/dl with rosuvastatin: the JUPITER trial (Justification for the use of statins in prevention: an intervention trial evaluating Rosuvastati. J Am Coll Cardiol. 2011;57:1666–1675.
  • Everett BM, Mora S, Glynn RJ, et al. Safety profile of subjects treated to very low low-density lipoprotein cholesterol levels (<30 mg/dl) with rosuvastatin 20 mg daily (from JUPITER). Am J Cardiol. 2014;114:1682–1689.
  • Sabatine MS, Giugliano RP, Wiviott SD, 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;372:1500–1509.
  • Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–1499.
  • Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol. 2017;69:471–482.
  • Ebrahim S, Sung J, Song Y-M, et al. Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: korean national health system prospective cohort study. BMJ. 2006;333:22.
  • Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.
  • Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742.
  • Preiss D, Seshasai SRK, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. Jama. 2011;305:2556–2564.
  • Carter AA, Gomes T, Camacho X, et al. Risk of incident diabetes among patients treated with statins: population based study. BMJ. 2013;346:f2610.
  • Sattar N, Toth PP, Blom DJ, et al. Effect of the proprotein convertase subtilisin/Kexin Type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus. Am J Cardiol. 2017;120:1521–1527.
  • Lotta LA, Sharp SJ, Burgess S, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of Type 2 diabetes: A meta-analysis. JAMA. 2016;316:1383–1391.
  • Takeshita Y, Takamura T, Honda M, et al. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia. 2014;57:878–890.
  • Besseling J, Kastelein JJP, Defesche JC, et al. Association between familial hypercholesterolemia and prevalence of Type 2 diabetes mellitus. JAMA. 2015;313:1029.
  • Mbikay M, Sirois F, Mayne J, et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett. 2010;584:701–706.
  • Langhi C, Le May C, Gmyr V, et al. PCSK9 is expressed in pancreatic δ-cells and does not alter insulin secretion. Biochem Biophys Res Commun. 2009;390:1288–1293.
  • Bonnefond A, Yengo L, Le May C, et al. The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis. Diabetologia. 2015;58:2051–2055.
  • Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 2016;375:2144–2153.
  • Schmidt AF, Swerdlow DI, Holmes MV, et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017;5:97–105.
  • Da Dalt L, Ruscica M, Bonacina F, et al. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. Eur Heart J. 2018;40:357–368.
  • Moriarty PM, Thompson PD, Cannon CP, 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.
  • Administration UF& D. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. [cited 2018 Nov 20]. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
  • Björkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol. 2004;24:806–815.
  • Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–1509.
  • Lipinski MJ, Benedetto U, Escarcega RO, 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. 2015;37:536–545.
  • Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017;377:633–643.
  • Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med. 2013;159:688–697.
  • Ridker PM, Tardif J-C, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation with Bococizumab. N Engl J Med. 2017;376:1517–1526.
  • Roth EM, Goldberg AC, Catapano AL, et al. Antidrug antibodies in patients treated with alirocumab. N Engl J Med. 2017;376:1589–1590.
  • Repatha SureClick - Summary of product characteristics (SmPC) - (emc). [cited 2019 Sept 17]. Available from: https://www.medicines.org.uk/emc/product/6962/smpc
  • Roeters Van Lennep JE, Gürgöze MT, Muller-Hansma AHG, et al. Adverse events associated with PCSK9 Inhibitors: A Real-World Experience. Clin Pharmacol Ther. 2019;105:496.
  • 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;308:2497–2506.
  • Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 stu. Lancet. 2012;380:2007–2017.
  • Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995–2006.
  • Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol–lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibiti. Circulation. 2012;126(20):2408–2417. CIRCULATIONAHA-112.
  • Hirayama A, Honarpour N, Yoshida M, et al. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk. Circ J. 2014;78:1073–1082.
  • Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–1819.
  • Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331–340.
  • 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;63:2541–2548.
  • Nissen SE, Stroes E, Dent-Acosta RE, 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.
  • Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate-or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. Jama. 2014;311:1870–1883.
  • Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531–2540.
  • Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term low-density lipoprotein cholesterol–lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label osler-1 extension study. JAMA Cardiol. 2017;2:598–607.
  • Bruckert E, Blaha V, Stein EA, et al. Trial assessing long-term use of PCSK9 inhibition in patients with genetic LDL disorders (TAUSSIG): efficacy and safety in patients with homozygous familial hypercholesterolemia receiving lipid apheresis. 2014;130:A17016. 27 Mar 2018 Circulation.
  • Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341–350.
  • McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344–2353.
  • Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891–1900.
  • Stein EA, Gipe D, Bergeron J, 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 controlle. Lancet. 2012;380:29–36.
  • Stroes E, Guyton JR, Farnier M, et al. Alirocumab in patients with hypercholesterolemia not on statin therapy: the ODYSSEY CHOICE II study. 17th Triennial International Symposium on Atherosclerosis, Amsterdam, Netherlands; 2015.
  • Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J. 2015;169:906–915.
  • Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186–1194.
  • Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996–3003.
  • Roth EM, Taskinen M-R, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014;176:55–61.
  • Bays H, Gaudet D, Weiss R, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab. 2015;100:3140–3148.
  • Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: the ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016;244:138–146.
  • Mills GL, Taylaur CE. The distribution and composition of serum lipoproteins in eighteen animals. Comp Biochem Physiol B: Biochem Mol Biol. 1971;40:489–501.
  • Bansal N, Cruickshank JK, McElduff P, et al. Cord blood lipoproteins and prenatal influences. Curr Opin Lipidol. 2005;16:400–408.
  • Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532–2561.
  • Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50:S172–7.
  • Law MR, Thompson SG Low serum cholesterol and the risk of cancer: an analysis of the published prospective studies. Cancer causes & control 1991; 2: 253–261.
  • Stroes ES, Thompson PD, Corsini A, 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.
  • Grundy SM, Stone NJ, Chair V, et al. Writing committee members cholesterol clinical practice guidelines 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol circulation. Circulation. 2018;139:1082–1143.
  • 1 Recommendations Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia. Guidance, NICE.

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