Abstract
PURPOSE: The comparative efficacy and safety profiles of PCSK9 inhibitors in familial hypercholesterolemia (FH), including genotype-dependent treatment responses, remain unclear. METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Meta-Analyses guidelines. A network meta-analysis of randomized clinical trials evaluating the use of PCSK9 inhibitors for the treatment of FH patients, including subgroup analyses of efficacy, was performed. RESULTS: Fifteen randomized clinical trials (n = 2954 patients) were included. All PCSK9 inhibitors significantly improved lipid parameters compared to control. In heterozygous FH (HeFH) populations, ongericimab showed the greatest reductions in LDL-C (mean difference [MD]: -74.98 %), ApoB (MD: -64.64 %), and Lp(a) (MD: -59.66 %), with SUCRA rankings of 68.7 %, 63.6 %, and 95.0 %, respectively. However, these results are based on a single trial and require further validation. No significant lipid-lowering effects were observed in HoFH patients. In terms of safety, lerodalcibep showed the most favorable profile for injection-site reactions and ALT >3 × ULN, with SUCRA values of 98.5 % and 96.7 %, respectively. Inclisiran was associated with a significantly higher risk of injection-site reactions. CONCLUSION: PCSK9 inhibitors generally show favorable efficacy and safety in FH patients. However, comparative rankings and point estimates should be interpreted with caution due to funnel plot asymmetry for LDL-C and imbalances in trial data. Ongericimab demonstrated promising results in HeFH, but further validation is required. Inclisiran's efficacy may be underestimated due to short-term follow-up. Monotherapy with PCSK9 inhibitors has limited efficacy in HoFH patients, highlighting the need for combination therapies.