A systematic review, meta-analysis and meta-regression of the impact of PCSK9 inhibitors on carotid intima-media thickness and the association with lipid parameters

AbstractObjective We assessed the impact of PCSK9 inhibitors (PCSK9i) on carotid intima-media thickness (cIMT) and their interplay with lipid profile parameters. Methods A systematic review was conducted in accordance with the PRISMA 2020 guidelines. The primary endpoint was cIMT reduction in millimeters by the end of treatment. A meta-regression analysis was performed, examining the influence of demographic, imaging, and biochemical parameters on cIMT outcomes. Heterogeneity exploration was conducted via leave-one-out and Baujat plot analysis. Results Four randomized controlled trials comparing PCSK9i plus statin versus placebo plus statin, and two single-arm studies were included, enrolling 607 patients and 2175 carotid segments. Pooled analysis demonstrated a significant reduction in cIMT from baseline to completion of PCSK9i therapy; mean difference (MD) -0.03 (95% CI: -0.05 to -0.01) (I2=95.4%, p2=0%, p=0.59). Initially, the comparison between PCSK9i and placebo yielded a non-significant reduction in cIMT by the end of follow-up, favouring PCSK9i; MD -0.04 (95% CI: -0.10 to 0.03) (I2=98.6%, p2=52%, p=0.12). Meta-regression analysis displayed associations between baseline cIMT (β=-0.45, pConclusions This review provides evidence supporting a potential association between PCSK9i treatment and cIMT reduction, with observed correlations involving total and LDL cholesterol indicating a lipid-mediated vascular response. Nonetheless, these findings warrant cautious interpretation given the substantial heterogeneity, partly driven by baseline differences in cIMT and lipid profiles. Future studies should ensure baseline comparability in vascular and biochemical parameters to strengthen causal inferences.