Lower is better: ezetimibe and PCSK9 inhibition join the mainstream of lipid‑lowering therapy

Cezary Wójcik

DOI: https://doi.org/10.7175/rhc.v7i1.1263


The focus of 2013 cholesterol guidelines to prevent atherosclerotic cardiovascular disease (ASCVD) released by American College of Cardiology (ACC) and American Heart Association (AHA) is the administration of high intensity statin therapy to specific four groups of patients, which were found to benefit the most from such therapy. They no longer promote achieving specific LDL-C goals with a combination therapy involving statins and other drugs, as advocated by the former ATP-III guidelines as well as current guidelines of European Atherosclerosis Society, International Atherosclerosis Society or National Lipid Association. Such approach has been dictated by the strict reliance on randomized controlled trials as the only acceptable level of evidence. However, since publication of the 2013 ACC/AHA guidelines, cardiovascular benefits of ezetimibe added to statin therapy have been established. Moreover, the advent of PCSK9 inhibitors, providing a powerful supplement and/or alternative to statin therapy, further complicates the therapeutic horizon in dyslipdiemias. It is very likely that a new set of ACC/AHA guidelines will be published in 2016, with a return of specific LDL-C and Non-HDL-C goals of therapy as well as integration of drugs other than statins. As the treatment of dyslipidemias becomes more complex, the need for the subspecialty of clinical lipidology to be officially recognized becomes more evident.


Dyslipidemia; PCSK9 inhibitors; Ezetimibe; LDL; Clinical lipidology

Full Text



  • Stone NJ, Robinson JG, Lichtenstein AH, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63: 2889-934; http://dx.doi.org/10.1016/j.jacc.2013.11.002
  • Mendis S, Puska P, Norrving B, et al. Global atlas on cardiovascular disease prevention and control. World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization: Geneva, 2011
  • Grundy SM, Cleeman JI, Merz CN, et al.; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004; 44: 720-32; http://dx.doi.org/10.1016/j.jacc.2004.07.001
  • Jung CH, Lee MJ, Kang YM, et al. 2013 ACC/AHA versus 2004 NECP ATP III Guidelines in the Assignment of Statin Treatment in a Korean Population with Subclinical Coronary Atherosclerosis. PLoS One 2015; 10: e0137478; http://dx.doi.org/10.1371/journal.pone.0137478
  • Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel, m. An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia--full report. J Clin Lipidol 2014; 8: 29-60; http://dx.doi.org/10.1016/j.jacl.2013.12.005
  • 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; http://dx.doi.org/10.1016/j.atherosclerosis.2011.06.028
  • Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol 2014; 8: 473-88; http://dx.doi.org/10.1016/j.jacl.2014.07.007
  • Anderson TJ, Grégoire J, Hegele RA, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013; 29: 151-67; http://dx.doi.org/10.1016/j.cjca.2012.11.032
  • Teo KK, Goldstein LB, Chaitman BR, et al.; AIM-HIGH Investigators. Extended-release niacin therapy and risk of ischemic stroke in patients with cardiovascular disease: the Atherothrombosis Intervention in Metabolic Syndrome with low HDL/High Triglycerides: Impact on Global Health Outcome (AIM-HIGH) trial. Stroke 2013; 44: 2688-93; http://dx.doi.org/10.1161/STROKEAHA.113.001529
  • HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; 34: 1279-91; http://dx.doi.org/10.1093/eurheartj/eht055
  • Zeman M, Vecka M, Perlík F, et al. Niacin in the Treatment of Hyperlipidemias in Light of New Clinical Trials: Has Niacin Lost its Place? Med Sci Monit 2015; 21: 2156-62; http://dx.doi.org/10.12659/MSM.893619
  • Fazio, S. The role of PCSK9 in intestinal lipoprotein metabolism: synergism of statin and ezetimibe. Atheroscler 2015; 17: 23-6; http://dx.doi.org/10.1016/S1567-5688(15)50006-8
  • Phan BA, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag 2012; 8: 415-27
  • Cannon CP, Blazing MA, Giugliano RP, et al.; IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372: 2387-97; http://dx.doi.org/10.1056/NEJMoa1410489
  • Bohula EA, Giugliano RP, Cannon CP, 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; http://dx.doi.org/10.1161/CIRCULATIONAHA.115.018381
  • Sakamoto K, Kawamura M, Kohro T, et al.; RESEARCH Study Group. Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins. PLoS One 2015; 10: e0138332; http://dx.doi.org/10.1371/journal.pone.0138332
  • Miyoshi T, Nakamura K, Doi M, et al. Impact of Ezetimibe Alone or in Addition to a Statin on Plasma PCSK9 Concentrations in Patients with Type 2 Diabetes and Hypercholesterolemia: A Pilot Study. Am J Cardiovasc Drugs 2015; 15: 213-9; http://dx.doi.org/10.1007/s40256-015-0119-2
  • White CM. Therapeutic Potential and Critical Analysis of the PCSK9 Monoclonal Antibodies Evolocumab and Alirocumab. Ann Pharmacother 2015; 49: 1327-35; http://dx.doi.org/10.1177/1060028015608487
  • Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol 2015; 115: 1212-21; http://dx.doi.org/10.1016/j.amjcard.2015.02.006
  • Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol 2009; 29: 431-8; http://dx.doi.org/10.1161/ATVBAHA.108.179564
  • Brown MS, Goldstein JL. Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc Natl Acad Sci USA 1979; 76: 3330-7; http://dx.doi.org/10.1073/pnas.76.7.3330
  • Qian YW, Schmidt RJ, Zhang Y, et al. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J Lipid Res 2007; 48: 1488-98; http://dx.doi.org/10.1194/jlr.M700071-JLR200
  • Horton JD1, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009; 50 Suppl: S172-7; http://dx.doi.org/10.1194/jlr.R800091-JLR200
  • 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; 37: 161-5; http://dx.doi.org/10.1038/ng0305-328c
  • Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154-6; http://dx.doi.org/10.1038/ng1161
  • Allard D, Amsellem S, Abifadel M, et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat 2005; 26: 497; http://dx.doi.org/10.1002/humu.9386
  • 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: 1264-72; http://dx.doi.org/10.1056/NEJMoa054013
  • Farnier M. An evaluation of alirocumab for the treatment of hypercholesterolemia. Expert Rev Cardiovasc Ther 2015; 13: 1307-23; http://dx.doi.org/10.1586/14779072.2015.1111759
  • Langslet G, Emery M, Wasserman SM. Evolocumab (AMG 145) for primary hypercholesterolemia. Expert Rev Cardiovasc Ther 2015; 13: 477-88; http://dx.doi.org/10.1586/14779072.2015.1030395
  • Cicero AF, Tartagni E, Ertek S. Efficacy and safety profile of evolocumab (AMG145), an injectable inhibitor of the proprotein convertase subtilisin/kexin type 9: the available clinical evidence. Expert Opin Biol Ther 2014; 14: 863-8; http://dx.doi.org/10.1517/14712598.2014.902929
  • Blom DJ, Hala T, Bolognese M, et al.; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014; 370: 1809-19; http://dx.doi.org/10.1056/NEJMoa1316222
  • Verbeek R, Stoekenbroek RM2, Hovingh GK. PCSK9 inhibitors: Novel therapeutic agents for the treatment of hypercholesterolemia. Eur J Pharmacol 2015; 763: 38-47; http://dx.doi.org/10.1016/j.ejphar.2015.03.099
  • Raal FJ, Honarpour N, Blom DJ, et al.; TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385: 341-50; http://dx.doi.org/10.1016/S0140-6736(14)61374-X
  • Hassan M. OSLER and ODYSSEY LONG TERM: PCSK9 inhibitors on the right track of reducing cardiovascular events. Glob Cardiol Sci Pract 2015; 2015: 20; http://dx.doi.org/10.5339/gcsp.2015.20
  • Robinson JG, Farnier M, Krempf 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; http://dx.doi.org/10.1056/NEJMoa1501031
  • Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014; 168: 682-9; http://dx.doi.org/10.1016/j.ahj.2014.07.028
  • Schulman KA, Balu S, Reed SD. Specialty Pharmaceuticals for Hyperlipidemia--Impact on Insurance Premiums. N Engl J Med 2015; 373: 1591-3; http://dx.doi.org/10.1056/NEJMp1509863
  • Yeang C, Witztum JL, Tsimikas S. ‘LDL-C’ = LDL-C + Lp(a)-C: implications of achieved ultra-low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering. Curr Opin Lipidol 2015; 26: 169-78; http://dx.doi.org/10.1097/MOL.0000000000000171
  • Gaudet D, Kereiakes DJ, McKenney JM, et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol 2014; 114: 711-5; http://dx.doi.org/10.1016/j.amjcard.2014.05.060
  • Jacobson TA. NLA Task Force on Statin Safety--2014 update. J Clin Lipidol 2014; 8(3 Suppl): S1-4; http://dx.doi.org/10.1016/j.jacl.2014.03.003
  • Moriarty PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014; 8: 554-61; http://dx.doi.org/10.1016/j.jacl.2014.09.007
  • Cromwell WC, Otvos JD, Keyes MJ, et al. LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study - Implications for LDL Management. J Clin Lipidol 2007; 1: 583-92; http://dx.doi.org/10.1016/j.jacl.2007.10.001
  • Degoma EM, Davis MD, Dunbar RL, et al. Discordance between non-HDL-cholesterol and LDL-particle measurements: results from the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2013; 229: 517-23; http://dx.doi.org/10.1016/j.atherosclerosis.2013.03.012
  • Doggrell SA, Lynch KA. Is there enough evidence with evolocumab and alirocumab (antibodies to proprotein convertase substilisin-kexin type, PCSK9) on cardiovascular outcomes to use them widely? Evaluation of 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, and Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1488-99. Expert Opin Biol Ther 2015; 15: 1671-5; http://dx.doi.org/10.1517/14712598.2015.1093109
  • Shapiro MD, Fazio S, Tavori H. Targeting PCSK9 for therapeutic gains. Curr Atheroscler Rep 2015; 17: 499; http://dx.doi.org/10.1007/s11883-015-0499-4


Abstract: 9468 views
HTML: 1540 views
PDF: 312 views


  • There are currently no refbacks.