Comparative efficacy and safety of PCSK9 inhibitors for lipoprotein(a) reduction: a systematic review and network meta−analysis

Abstract Introduction Lipoprotein(a) [Lp(a)] is a genetically determined cardiovascular risk factor that is largely unaffected by statins. Although PCSK9 inhibitors can lower Lp(a), comparative evidence among agents is limited. Methods We conducted a systematic review and frequentist random−effects network meta−analysis of randomized controlled trials from database inception to February 2026 (PROSPERO: CRD420251208404). The primary outcome was the percentage change in Lp(a) from baseline. Secondary outcomes included changes in low−density lipoprotein cholesterol (LDL − C), non−high−density lipoprotein cholesterol (non − HDL−C), triglyceride (TG), total cholesterol (TC), high−density lipoprotein cholesterol (HDL − C), and apolipoprotein B (ApoB). Safety outcomes were adverse events (AEs) and serious adverse events (SAEs). Certainty of evidence was assessed using CINeMA. Sensitivity analyses were conducted according to the reported Lp(a) unit and by restricting the analysis to label−approved dose regimens. Results Sixty − two trials involving 73,240 participants and six PCSK9 inhibitors were included. All evaluated agents were associated with reductions in Lp(a) versus placebo. The largest point estimates were observed for ongericimab (MD = − 46.36%, 95% CI − 55.96 to − 36.77) and tafolecimab (MD = − 41.12%, 95% CI − 50.73 to − 31.51), although certainty was low and comparisons were predominantly indirect. Sensitivity analyses yielded broadly similar results. No statistically significant differences in overall AEs or SAEs were detected versus placebo. Conclusions PCSK9 inhibitors may reduce Lp(a) and improve atherogenic lipid profiles. Comparative effects among individual agents remain uncertain because the evidence was mainly indirect and of low certainty. Whether Lp(a) lowering itself improves cardiovascular outcomes remains unknown.