DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20172713

Evolocumab: rising momentum as novel antidyslipidemic drug

Rekha Mehani, Ajay Shukla, V. K. Yadav, Rimjhim Sahu

Abstract


Increased levels of low density lipoprotein cholesterol are responsible for the major cardiovascular events. Low density lipoprotein cholesterol reduction has proved to be highly effective in reducing the risk of major cardiovascular (CV) events in various trials. ACC/AHA guidelines recommend lipid-lowering therapy for patients with known cardiovascular diseases (CVD). Statins are the gold standard treatment for all types hypercholeterolemia but still there is need of some other lipid-lowering therapies especially in patients with statin intolerance and in patients responding inadequately to statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was discovered in 2003 and subsequently emerged as a novel target for LDLC-lowering therapy. Evolocumab is a fully human monoclonal immunoglobulin G2 (IgG2) directed against human PCSK9. Evolocumab binds to PCSK9 enzyme rendering it unable to bind to the LDLR. More LDLR are available to bind to LDLC. Evolocumab increase the density of LDLR on the surface of hepatocytes, thereby increasing the uptake of LDL particles and decreasing the LDLC in the blood. Evolocumab has proved its efficacy with LDLC reduction from 53% to 75% and associated with minor side effects. Evolocumab has corroborated its effectiveness in reduction in the levels of LDLC. This drug has shown efficacy in heterozygous and homozygous subtypes of familial hypercholesterolemia. Statin intolerance seen in about 15% of all patients restricts the use of first line drug for dyslipidemia. Evolocumab can be a useful option in statin intolerant patients and in patients responding inadequately to statins.


Keywords


Alirocumab, Dyslipidemia, Evolocumab, Hypercholesterolemia, Proprotein convertase subtilisin/ kexin type 9

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References


Baigent C, Keech A, Kearney PM. 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. 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.

Cannon CP. Improved Reduction of Outcomes: vytorin Efficacy International Trial (IMPROVE-IT). Presented at the American Heart Association Scientific Sessions, Chicago; November 2014:15-18.

Reiner Z, Catapano 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.

Anderson TJ, Gregoire J. 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.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-97.

Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomized trials. Lancet. 2012;380(9841):581-90.

Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M, et al. Discontinuation of statins in routine care settings: a cohort study. Ann. Intern. Med. 2013;158(7):526-34.

Lambert G, Sjouke B, Choque B, Kastelein JJP, Hovingh GK. The PCSK9 decade. J. Lipid Res. 2012;53(12):2515-24.

Elguindy A, Yacoub MH. The discovery of PCSK9 inhibitors: A tale of creativity and multifaceted translational research. Glob. Cardiol. Sci. Pract. 2013;4:1-5.

Hong-mei G, Da-wei Z. Hypercholesterolemia, low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9: The Journal of Biomedical Research. 2015;29(5):356-61.

Sawhney J, Bagga S. Proprotein convertase subtilisin kexin 9 inhibitors: Current status and future directions. J Clin Prev Cardiol. 2017;6:12-7.

Giugliano RP, Desai NR. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 incombination with a statin in patients with hyper cholesterolaemia (LAPLACE-TIMI57): a randomised, placebo-controlled, dose- ranging, phase2 study. Lancet. 2012;380:2007-17.

Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. Low-density lipoprotein cholesterol- lowering effects of AMG145, a monoclonal antibody to proprotein convertase subtilisin/ kexin type9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibi. Circulation. 2012;126:2408-17.

Sullivan D. 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.

Stroes E. 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(23):2541-8.

Koren MJ, Lundqvist P, Bolognese M. MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2531-40.

Robinson JG, Nedergaard B. LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate-or high-intensity statin therapy on LDLc lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870-82.

Bloom DJ, Hala T, Bolognese M. Descartes Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370(19):1809-19.

Raal FJ, Honarpour N. Inhibition of PCSK9 with Evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341-50.

Raal FJ, Stein EA. RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG145) in heterozygous familial hypercholesterolemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331-40.

Sabatine MS, Giugliano RP. Investigators. Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med. 2015;372:1500-9.

Clinical Trials.gov. NCT01849497: a multi-center, randomized study in subjects with primary hypercholesterolemia or mixed dyslipidemia Available from: http://ClinicalTrials.gov/show/NCT01849497).

Clinical Trials.gov. NCT01879319: a randomized, multi-center clinical study in subjects with hypercholesterolemia or mixed dyslipidemia Available from: http://ClinicalTrials.gov/show/NCT01879319

Kiyosue A, Honarpour N. A Phase 3 Study of Evolocumab (AMG 145) in Statin-Treated Japanese Patients at High Cardiovascular Risk (YUKAWA-2): Am J Cardiol. 2016;117:40e47.

Dent. Evolocumab lowers LDL-C safely and effectively when self-administered in the at-home setting (THOMAS 1 and THOMAS 2): Springer Plus 2016;5:300.

Sabatine MS. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (FOURIER): N Engl J Med. 2017.

Nissen SE. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients with Muscle-Related Statin Intolerance The (GAUSS-3): JAMA. 2016;315(15):1580-90.

Nicolls SJ, Puri S, Anderson, T. Effect of evolocumab on progression of coronary disease in statin-treated patients. The GLAGOV randomized clinical trial. JAMA. 2016;316:2372-84.

Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat. Rev. Cardiol. 2014;11(10):563-75.