Comparative LDL-C Reduction and Cardiovascular Outcomes With PCSK9-Pathway Therapies: A Systemic Review and Network Meta-Analysis
H Ramteke, R Khan, N Shafi, A AsifAbstract
Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9)–targeted therapies substantially reduce low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. While monoclonal antibodies have demonstrated outcome benefits, newer agents including siRNA and small-protein inhibitors lack mature event-driven data. A comparative network meta-analysis is needed to define relative efficacy, cardiovascular outcomes, and safety across agents.
Purpose
To compare the efficacy, cardiovascular outcomes, and safety of PCSK9-pathway therapies using a comprehensive Bayesian network meta-analysis.
Methods
We systematically searched PubMed, Embase, and Cochrane CENTRAL for randomized controlled trials evaluating PCSK9-pathway therapies in adults with hypercholesterolemia. Risk of bias was assessed using Cochrane RoB 2.0, and statistical analyses were performed using the R package netmeta, applying frequentist network meta-analysis models to estimate pooled effects with 95% confidence intervals and treatment rankings.
Results
A total of 31 randomized controlled trials (n=94,276) were included, comprising 62,184 men (66.0%) and 32,092 women (34.0%). Treatment allocation was: Evolocumab (n=27,842), Alirocumab (n=21,516), Inclisiran (n=18,404), Lerodalcibep (n=6,112), and control (n=20,402). For the primary endpoint, all therapies significantly reduced LDL-C versus control. Lerodalcibep achieved the greatest reduction (MD −2.30 mmol/L, 95% CrI −2.42 to −2.18), followed closely by evolocumab (−2.25, −2.36 to −2.14), then alirocumab (−2.05, −2.19 to −1.91), while inclisiran demonstrated the smallest but still substantial reduction (−1.88, −1.98 to −1.78). SUCRA rankings for LDL-C reduction were highest for lerodalcibep, followed by evolocumab, alirocumab, and inclisiran. For MACE, evolocumab (OR 0.85, 95% CrI 0.79–0.92) and alirocumab (0.87, 0.80–0.95) significantly reduced cardiovascular events, whereas inclisiran showed a non-significant trend (0.81, 0.64–1.02) and lerodalcibep demonstrated the most imprecise estimate (0.92, 0.64–1.31). SUCRA rankings for MACE were highest for evolocumab, followed by alirocumab, inclisiran, and lerodalcibep. Safety outcomes were comparable across agents: serious adverse events were neutral (lerodalcibep RR 0.95, 0.82–1.10; evolocumab/alirocumab RR 1.01, 0.94–1.08; inclisiran RR 1.00, 0.91–1.10). SUCRA rankings for serious adverse events favored lerodalcibep, followed by inclisiran, alirocumab, and evolocumab. Injection-site reactions were lowest with lerodalcibep and highest with inclisiran. SUCRA rankings for injection-site reactions favored lerodalcibep, followed by alirocumab/evolocumab, with inclisiran ranking lowest.
Conclusion
PCSK9-pathway therapies significantly reduce LDL-C, with lerodalcibep demonstrating the greatest lipid-lowering effect, while only evolocumab and alirocumab show definitive MACE reduction; overall safety profiles were comparable across agents.