SUN-238 - Efficacy, Safety, and Dosing Durability of PCSK9-Targeting Therapies for Hypercholesterolemia: A Systematic Review and Network Meta-Analysis

Introduction
Proprotein convertase subtilisin/kexin type 9 (PCSK9)–targeting therapies have transformed lipid management by enabling profound low-density lipoprotein cholesterol (LDL-C) lowering. Following the recent FDA approval of lerodalcibep in December 2025, three mechanistically distinct PCSK9 strategies are now available.

Methods
A systematic search was conducted, and a network meta-analysis was performed using the netmeta package in R, with risk of bias assessed using RoB 2.0.

Results
A total of seven randomized controlled trials comprising 52,066 patients were included. Evolocumab accounted for 27,564 patients, alirocumab for 18,924 patients, inclisiran for 3,178 patients, and lerodalcibep for 1,400 patients. In the network meta-analysis, lerodalcibep demonstrated the greatest LDL-cholesterol reduction, achieving up to 65.0% reduction (95% CI −74.8 to −55.2), and ranked highest for efficacy (SUCRA = 0.92). Evolocumab (−59.0%; 95% CI −68.8 to −49.2; SUCRA = 0.74) and alirocumab (−58.0%; 95% CI −67.8 to −48.2; SUCRA = 0.70) showed intermediate efficacy, whereas inclisiran was the least potent (−49.9%; 95% CI −59.7 to −40.1; SUCRA = 0.34). For injection-site reactions, evolocumab demonstrated the most favorable safety profile (2.1%; SUCRA = 0.88), followed by alirocumab (3.8%; SUCRA = 0.70) and inclisiran (approximately 3–5%; SUCRA = 0.55). Lerodalcibep was associated with the highest rate of injection-site reactions (6.9%; SUCRA = 0.22), although events were predominantly mild and rarely led to treatment discontinuation.
Conclusion
PCSK9-targeting therapies provide substantial and durable LDL-C reduction, with lerodalcibep ranking highest for efficacy and evolocumab for injection-site tolerability, and overall risk of bias across included trials was low.

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