{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:17:53Z","timestamp":1789834673315,"version":"4.0.1"},"reference-count":22,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"crossref","award":["Project number: 5P20GM103652-10, Sub-Project ID: 9499"],"award-info":[{"award-number":["Project number: 5P20GM103652-10, Sub-Project ID: 9499"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Atherosclerosis occurs due to accumulation of low-density lipoprotein cholesterol (LDL-c) in the arterial system. Thus, lipid lowering therapy is essential for both primary and secondary prevention. Proprotein convertase subtilisn\/kexin type 9 (PCSK9) inhibitors (Evolocumab, Alirocumab) and small interfering RNA (siRNA) therapy (Inclisiran) have been demonstrated to lower LDL-c and ASCVD events in conjunction with maximally tolerated statin therapy. However, the degree of LDL-c reduction and the impact on reducing major adverse cardiac events, including their impact on mortality, remains unclear.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objective<\/jats:title>\n<jats:p>The purpose of this study is to examine the effects of PCSK9 inhibitors and small interfering RNA (siRNA) therapy on LDL-c reduction and major adverse cardiac events (MACE) and mortality by conducting a meta-analysis of randomized controlled trials.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Using Pubmed, Embase, Cochrane Library and clinicaltrials.gov until April 2023, we extracted randomized controlled trials (RCTs) of PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) for lipid lowering and risk of MACE. Using random-effects models, we pooled the relative risks and 95% CIs and weighted least-squares mean difference in LDL-c levels. We estimated odds ratios with 95% CIs among MACE subtypes and all-cause mortality. Fixed-effect model was used, and heterogeneity was assessed using the I<jats:sup>2<\/jats:sup> statistic.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>In all, 54 studies with 87,669 participants (142,262 person-years) met criteria for inclusion. LDL-c percent change was reported in 47 studies (n = 62,634) evaluating two PCSK9 inhibitors and siRNA therapy. Of those, 21 studies (n = 41,361) included treatment with Evolocumab (140mg), 22 (n = 11,751) included Alirocumab (75mg), and 4 studies (n = 9,522) included Inclisiran (284mg and 300mg). Compared with placebo, after a median of 24 weeks (IQR 12\u201352), Evolocumab reduced LDL-c by -61.09% (95% CI: -64.81, -57.38, p&lt;0.01) and Alirocumab reduced LDL-c by -46.35% (95% CI: -51.75, -41.13, p&lt;0.01). Inclisiran 284mg reduced LDL-c by -54.83% (95% CI: -59.04, -50.62, p = 0.05) and Inclisiran 300mg reduced LDL-c by -43.11% (95% CI: -52.42, -33.80, p = 0.01). After a median of 8 months (IQR 6\u201315), Evolocumab reduced the risk of myocardial infarction (MI), OR 0.72 (95% CI: 0.64, 0.81, p&lt;0.01), coronary revascularization, 0.77 (95% CI: 0.70, 0.84, p&lt;0.01), stroke, 0.79 (95% CI: 0.66, 0.94, p = 0.01) and overall MACE 0.85 (95% CI: 0.80, 0.89, p&lt;0.01). Alirocumab reduced MI, 0.57 (0.38, 0.86, p = 0.01), cardiovascular mortality 0.35 (95% CI: 0.16, 0.77, p = 0.01), all-cause mortality 0.60 (95% CI: 0.43, 0.84, p&lt;0.01), and overall MACE 0.35 (0.16, 0.77, p = 0.01).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) significantly reduced LDL-c by &gt;40% in high-risk individuals. Additionally, both Alirocumab and Evolocumab reduced the risk of MACE, and Alirocumab reduced cardiovascular and all-cause mortality.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0295359","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T18:35:41Z","timestamp":1701887741000},"page":"e0295359","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":35,"title":["Proprotein convertase subtilisn\/kexin type 9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: A systematic review and meta-analysis"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2089-8244","authenticated-orcid":true,"given":"Tasnim F.","family":"Imran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4250-8828","authenticated-orcid":true,"given":"Ali A.","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phinnara","family":"Has","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Bogin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahnoor","family":"Khalid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asim","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebhat","family":"Erqou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Choudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Aspry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2834-2024","authenticated-orcid":true,"given":"Wen-Chih","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"issue":"19","key":"pone.0295359.ref001","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1001\/jama.285.19.2486","article-title":"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)","volume":"285","author":"Expert Panel on Detection E","year":"2001","journal-title":"JAMA"},{"key":"pone.0295359.ref002","unstructured":"Organization WH. Cardiovascular diseases (CVDs). World Health Organization. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/cardiovascular-diseases-(cvds)"},{"issue":"1","key":"pone.0295359.ref003","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2015.01.036","article-title":"A century of cholesterol and coronaries: from plaques to genes to statins","volume":"161","author":"JL Goldstein","year":"2015","journal-title":"Cell"},{"issue":"5","key":"pone.0295359.ref004","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.jacl.2016.06.011","article-title":"Prevalence of the American College of Cardiology\/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011\u20132012","volume":"10","author":"ND Wong","year":"2016","journal-title":"J Clin Lipidol"},{"issue":"25","key":"pone.0295359.ref005","first-page":"e1082","article-title":"2018 AHA\/ACC\/AACVPR\/AAPA\/ABC\/ACPM\/ADA\/AGS\/APhA\/ASPC\/NLA\/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines","volume":"139","author":"SM Grundy","year":"2019","journal-title":"Circulation"},{"issue":"1","key":"pone.0295359.ref006","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/eurheartj\/ehz455","article-title":"2019 ESC\/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk","volume":"41","author":"F Mach","year":"2020","journal-title":"Eur Heart J"},{"issue":"34","key":"pone.0295359.ref007","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1093\/eurheartj\/ehab484","article-title":"2021 ESC Guidelines on cardiovascular disease prevention in clinical practice","volume":"42","author":"FLJ Visseren","year":"2021","journal-title":"Eur Heart J"},{"issue":"4","key":"pone.0295359.ref008","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.jacl.2017.05.001","article-title":"Update on the use of PCSK9 inhibitors in adults: Recommendations from an Expert Panel of the National Lipid Association","volume":"11","author":"CE Orringer","year":"2017","journal-title":"J Clin Lipidol"},{"issue":"2","key":"pone.0295359.ref009","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.cct.2006.04.004","article-title":"Random-effects model for meta-analysis of clinical trials: an update","volume":"28","author":"R DerSimonian","year":"2007","journal-title":"Contemp Clin Trials"},{"key":"pone.0295359.ref010","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"JAC Sterne","year":"2019","journal-title":"BMJ"},{"issue":"7650","key":"pone.0295359.ref011","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: an emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"GH Guyatt","year":"2008","journal-title":"BMJ"},{"key":"pone.0295359.ref012","doi-asserted-by":"crossref","first-page":"1016802","DOI":"10.3389\/fcvm.2022.1016802","article-title":"Effect of alirocumab and evolocumab on all-cause mortality and major cardiovascular events: A meta-analysis focusing on the number needed to treat","volume":"9","author":"HF Wang","year":"2022","journal-title":"Front Cardiovasc Med"},{"issue":"12","key":"pone.0295359.ref013","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/phar.2635","article-title":"Meta-analysis of clinical outcomes of PCSK9 modulators in patients with established ASCVD","volume":"41","author":"AH Talasaz","year":"2021","journal-title":"Pharmacotherapy"},{"key":"pone.0295359.ref014","article-title":"Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials","author":"P Guedeney","year":"2019","journal-title":"Eur Heart J"},{"issue":"3","key":"pone.0295359.ref015","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1093\/ehjcvp\/pvaa024","article-title":"Indirect comparison of the efficacy and safety of alirocumab and evolocumab: a systematic review and network meta-analysis","volume":"7","author":"P Guedeney","year":"2021","journal-title":"Eur Heart J Cardiovasc Pharmacother"},{"key":"pone.0295359.ref016","article-title":"L. Ldl-cholesterol reduction with PCSK9 inhibitors: A meta-analysis of randomised controlled trials","volume":"263","author":"M SL Casula","year":"2017","journal-title":"Atherosclerosis"},{"key":"pone.0295359.ref017","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.atherosclerosis.2022.06.128","article-title":"Efficacy & safety of PCSK9-inhibitors: A systematic review and meta-analysis of real-world data","volume":"355","author":"J Mulder","year":"2022","journal-title":"Atherosclerosis"},{"issue":"1","key":"pone.0295359.ref018","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s12933-022-01542-4","article-title":"PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: a bayesian network meta-analysis","volume":"21","author":"X Wang","year":"2022","journal-title":"Cardiovasc Diabetol"},{"key":"pone.0295359.ref019","doi-asserted-by":"crossref","first-page":"173114","DOI":"10.1016\/j.ejphar.2020.173114","article-title":"Statins and PCSK9 inhibitors: A new lipid-lowering therapy","volume":"878","author":"E Gallego-Colon","year":"2020","journal-title":"Eur J Pharmacol"},{"issue":"12","key":"pone.0295359.ref020","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1001\/archinternmed.2012.2145","article-title":"Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis","volume":"172","author":"J Gutierrez","year":"2012","journal-title":"Arch Intern Med"},{"issue":"2","key":"pone.0295359.ref021","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1001\/jamacardio.2020.3151","article-title":"Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial","volume":"6","author":"P Deedwania","year":"2021","journal-title":"JAMA Cardiol"},{"issue":"3","key":"pone.0295359.ref022","doi-asserted-by":"crossref","DOI":"10.3390\/metabo12030256","article-title":"Insight into the Evolving Role of PCSK9","volume":"12","author":"M Maliglowka","year":"2022","journal-title":"Metabolites"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0295359","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T18:36:12Z","timestamp":1701887772000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0295359"}},"subtitle":[],"editor":[{"given":"Luiz S\u00e9rgio Fernandes","family":"de Carvalho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,12,6]]},"references-count":22,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0295359","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,6]]}}}