Lipoprotein(a) reduction with inclisiran, alirocumab, evolocumab, enlicitide, and lerodalcibep: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is a causal contributor to atherosclerotic cardiovascular disease (ASCVD). While no therapies are currently approved solely for lowering Lp(a), subgroup analyses suggest that individuals with elevated Lp(a) may gain added benefit from intensive lipid-lowering strategies. No prior meta-analysis has compared evolocumab, alirocumab, inclisiran, lerodalcibep, and enlicitide in their Lp(a)-lowering efficacy. We aimed to determine whether proprotein convertase subtilisin/kexin type 9 (PCSK9) targeted therapies differ significantly in Lp(a) reduction, or whether agent selection can be guided primarily by other factors such as dosing frequency, cost, and patient preference.

SOURCES OF MATERIAL: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) reporting percent change in Lp(a) following treatment with the 5 PCSK9-targeted agents. A random-effects model calculated pooled estimates of percentage Lp(a) change, and mixed-effects meta-regression assessed differences between agents.

ABSTRACT OF FINDINGS: Thirty-one RCTs were included. PCSK9 inhibitors and inclisiran reduced Lp(a) by a pooled mean of -25.76% vs control (95% CI -29.54 to -21.99; P < .0001). Meta-regression revealed no significant differences between agents (alirocumab vs evolocumab: +3.3%, 95% CI -1.40 to 8.07, P = .16; inclisiran vs evolocumab: +4.9%, 95% CI -2.31 to 12.16, P = .18; inclisiran vs alirocumab: +1.6%, 95% CI -5.38 to 8.55, P = .65). Lerodalcibep and enlicitide demonstrated similar approximate 25% reductions; however, insufficient trial numbers precluded a powered head-to-head comparison.

CONCLUSIONS

No statistically significant differences in Lp(a) reduction were observed between currently available PCSK9-targeting medications. Agent selection may reasonably be based on non-efficacy factors, including administration frequency, cost, and patient preference.