EFFICACY AND SAFETY OF PCSK9 INHIBITORS IN REDUCING MAJOR ADVERSE CARDIOVASCULAR EVENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract

Background: Despite optimal statin therapy, many patients with atherosclerotic cardiovascular disease (ASCVD) remain at high residual risk due to persistently elevated low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as potent lipid-lowering agents; however, comparative evidence on their impact on LDL-C reduction and major adverse cardiovascular events (MACE) across clinical settings remains evolving.

Methods: We conducted a systematic review and meta-analysis of studies evaluating the efficacy of PCSK9 inhibitors compared with control therapy. Electronic databases were searched for eligible randomized and observational studies reporting LDL-C outcomes and/or MACE. Pooled effect estimates were calculated using random-effects models (REML). LDL-C outcomes were expressed as mean differences with 95% confidence intervals (CIs), while cardiovascular outcomes were expressed as odds ratios with 95% CIs. Subgroup analyses were performed according to individual PCSK9 inhibitors (alirocumab and evolocumab). Heterogeneity was assessed using the I² statistic.

Results: A total of eligible studies encompassing high-risk patients with acute coronary syndromes or stable coronary artery disease were included. PCSK9 inhibitor therapy resulted in a significant reduction in LDL-C compared with control therapy (overall mean difference −1.13, 95% CI −1.40 to −0.86). Both alirocumab and evolocumab demonstrated substantial and comparable LDL-C lowering, with no significant subgroup differences. PCSK9 inhibitors were also associated with a significant reduction in MACE (overall effect estimate 0.83, 95% CI 0.77–0.90), corresponding to a 17% relative risk reduction. No significant difference in cardiovascular outcomes was observed between individual agents.

Conclusions: PCSK9 inhibitors provide profound LDL-C reduction and significantly lower the risk of major adverse cardiovascular events. These findings support their use as effective adjunctive therapies for cardiovascular risk reduction in patients with ASCVD who remain at high residual risk despite standard lipid-lowering treatment.