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The first two antibodies targeting PCSK9 (evolocumab, alirocumab) approved by the United States Food and Drug Administration (FDA) provided significant and sustained reductions in atherogenic lipids and a reduced risk of atherosclerotic cardiovascular disease (ASCVD) events. More recently, phase 3 trials of inclisiran\u2014a small interfering RNA\u2010based agent targeting PCSK9\u2014reported similar lipid\u2010lowering effects and preliminary evidence of ASCVD risk reduction, although significant questions remain regarding the extent of benefits across cardiovascular outcomes. We conducted a systematic review and meta\u2010analysis (random\u2010effects model) of the available data on lipid lowering, incidence of atherosclerotic cardiovascular disease (ASCVD) events, and safety of pharmacologic agents targeting PCSK9. A significant and consistent reduction in low\u2010density lipoprotein cholesterol (LDL\u2010C) was observed across all agents (\u221251% [95% confidence interval {CI}: \u221261%, \u221241%]). Despite the impressive reduction in LDL\u2010C, the individual effects on mortality, cardiovascular death, myocardial infarction (MI), and stroke remained nonsignificant. However, a consistent reduction was observed in the composite outcomes of MI, stroke, and cardiovascular death [relative risk {RR} (95% CI): 0.80 (0.73\u20130.87)] and MI, stroke, unstable angina (requiring revascularization), and cardiovascular death [RR (95% CI): 0.85 (0.74\u20130.97)]. In terms of safety outcomes, there was no significant difference in severe adverse events, new onset diabetes, neurocognitive disorders, or myalgia. Meanwhile, injection site reaction was more frequent in patients receiving these agents compared to placebo [RR 2.11 (95% CI): 1.26\u20133.54]. These findings suggest a class effect for favorable lipid changes and a low risk of serious adverse events among pharmacologic agents targeting PCSK9. Although there is compelling evidence that PCSK9\u2010targeting agents reduce the risk of some cardiovascular outcomes, adequately powered studies with longer follow\u2010up may be needed to fully characterize the magnitude of benefits across the cardiovascular spectrum.<\/jats:p>","DOI":"10.1002\/phar.2635","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T05:45:31Z","timestamp":1634449531000},"page":"1009-1023","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Meta\u2010analysis of clinical outcomes of PCSK9 modulators in patients with established ASCVD"],"prefix":"10.1002","volume":"41","author":[{"given":"Azita H.","family":"Talasaz","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy &amp; Outcomes Science Virginia Commonwealth University School of Pharmacy Richmond Virginia 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