==== Front Int J Appl Basic Med ResInt J Appl Basic Med ResIJABMRInternational Journal of Applied and Basic Medical Research2229-516X2248-9606Medknow Publications & Media Pvt Ltd India 30123740IJABMR-8-13510.4103/ijabmr.IJABMR_217_18EditorialNovel Lipid-Lowering Agents Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors: Do They Show Mortality Benefits? Mahajan Rajiv Department of Pharmacology, Adesh Institute of Medical Sciences and Research, Bathinda, Punjab, IndiaAddress for correspondence: Dr. Rajiv Mahajan, Department of Pharmacology, Adesh Institute of Medical Sciences and Research, Bathinda - 151 101, Punjab, India. E-mail: drrajivmahajan01@gmail.comJul-Sep 2018 8 3 135 136 Copyright: © 2018 International Journal of Applied and Basic Medical Research2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ==== Body Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a hepatic protease that binds to low-density lipoprotein receptors (LDLRs) and causes their internalization into the lysosomes thus promoting destruction of LDLR.[1] Seidah et al. discovered that PCSK9 regulates LDLR degradation and could potentially be a target for modulating LDLR expression and consequently LDL-cholesterol (LDL-C) levels.[2] Destruction of LDLR, in a way stops removal of LDL-C from the blood, leading to an increase in blood LDL levels. Drugs which inhibit PCSK9 will act to increase LDL receptors levels thus lowering the levels of LDL-C. Hyperlipidemia is one of the most common and best-established risk factors for cardiovascular disease (CVD). Although guidelines recommend the use of statins for treatment of individuals at increased risk for developing CVD events; there are limited options for patients who either develop intolerable side effects to statins or develop CVD despite being on maximally tolerated statin therapy. In these patients, a new modality of treatment, PCSK9 inhibitors will definitely prove useful.[3] The Food and Drug Administration (FDA) has already approved PCSK9 inhibitors for lipid lowering.[3] Alirocumab was approved by the FDA in July 2015. The approved indications for alirocumab are as follows: For adult patients with heterozygous familial hypercholesterolemia In patients with clinically significant atherosclerotic CVD requiring additional LDL lowering after being on diet control and maximally tolerated statin therapy. Evolocumab was also approved by the FDA in August 2015, with indications as: For the use in adult patients with heterozygous familial hypercholesterolemia For the use in adult patients with homozygous familial hypercholesterolemia For the use in adult patients with clinical atherosclerotic CVD requiring additional lowering of LDL cholesterol after being on a controlled diet and maximally tolerated statin therapy. Earlier in clinical trials, Alirocumab has been found to reduce LDL-C in a dose-dependent manner by up to 43% with a maximum dose of 300 mg every 4 weeks; and even a greater reduction of up to 70% was seen at a dosage regimen of 150 mg every 2 weeks.[4] Evolocumab, when added to maximally tolerated dose of statins, showed LDL reduction up to 65% with 70–140 mg of drug every 2-week regimen and approximately 50% LDL reduction with 280–420 mg drug every 4-week regimen.[5] As monotherapy, evolocumab has shown a reduction in LDL values by 40%–50% at doses of 420 mg every 4 weeks.[6] Nasopharyngitis, upper respiratory tract infection, back pain, and nausea are commonly seen adverse effects with PCSK9 inhibitors. The most common adverse events leading to drug discontinuation include myalgia, nausea, and dizziness. Notable serious adverse events are cardiac disorders including palpitations, angina pectoris, and ventricular extrasystoles.[3] Although no major life-threatening adverse effect has been reported, the development of one of PCSK9 inhibitor bococizumab has been shelved off by Pfizer in 2016.[7] Although in trials, bococizumab met all the trial-related endpoints, a press release by company briefed that it observed a set of patients with an unanticipated attenuation of LDL-C lowering over time, as well as a higher level of immunogenicity and higher rate of injection-site reactions with bococizumab than shown with the other agents in this class.[7] This event should be read along with the results of meta-analysis which concluded that despite favorable early indications from lipid-lowering trials, the available clinical data do not demonstrate a mortality benefit with PCSK9 inhibitors, though significant reduction in myocardial infarction, stroke, and coronary revascularization incidences were seen with a PCSK9 inhibitor treatment.[8] Thirty-five randomized controlled trials (RCTs) were included in the analysis of all-cause mortality in the meta-analysis. Compared with no treatment with a PCSK9 inhibitor, treatment with a PCSK9 inhibitor was not associated with a statistically significant change in all-cause mortality (crude rate 1.9% vs. 2.2%; odd ratio: 0.71 [95% confidence interval, 0.47–1.09]; P = 0.12, I2 = 18%, heterogeneity P = 0.26).[8] Similarly, 34 RCTs were included in the analysis of cardiovascular mortality in this meta-analysis. Compared with no treatment with a PCSK9 inhibitor, treatment with a PCSK9 inhibitor was not associated with a statistically significant change in cardiovascular mortality (crude rate 1.1% vs. 1.3%; odd ratio: 1.01 [95% CI, 0.85–1.19]; P = 0.95, I2 = 0%, heterogeneity P = 0.74).[8] As such, PCSK9 inhibitors have no effect on all-cause mortality and cardiovascular mortality. Due to these obvious reasons coupled with cost factors, though PCSK9 inhibitors are welcome innovation in controlling hyperlipidemia in patients intolerant to statins, they should be used cautiously, and efforts should be made to identify more subset of patients where they can prove useful. ==== Refs References 1 Lambert G Sjouke B Choque B Kastelein JJ Hovingh GK The PCSK9 decade J Lipid Res 2012 53 2515 24 22811413 2 Seidah NG Benjannet S Wickham L Marcinkiewicz J Jasmin SB Stifani S The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation Proc Natl Acad Sci U S A 2003 100 928 33 12552133 3 Chaudhary R Garg J Shah N Sumner A PCSK9 inhibitors: A new era of lipid lowering therapy World J Cardiol 2017 9 76 91 28289523 4 Stein EA Gipe D Bergeron J Gaudet D Weiss R Dufour R 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 22633824 5 Giugliano RP Desai NR Kohli P Rogers WJ Somaratne R Huang F 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 study Lancet 2012 380 2007 17 23141813 6 Sullivan D Olsson AG Scott R Kim JB Xue A Gebski V 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 23128163 7 Adams B Pfizer Dumps PCSK Inhibitor Bococizumab after Finding ‘No Value’ in Med FiereceBiotech 2016 11 01 Last accessed on 2018 May 28 Available from: https://www.fiercebiotech.com/biotech/pfizer-dumps-pcsk9i-inhibitor-bococizumab-after-finding-no-value-med 8 Karatasakis A Danek BA Karacsonyi J Rangan BV Roesle MK Knickelbine T Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: A Meta-analysis of 35 randomized controlled trials J Am Heart Assoc 2017 6 pii: e006910