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

Objective We assessed the impact of proprotein convertase subtilisin-kexin type 9 inhibitor (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 end point was cIMT reduction in millimeters by the end of treatment. A metaregression 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 vs 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% confidence interval [CI], −0.05 to −0.01; I 2 = 95.4%; P < .01). After exploration and mitigation of heterogeneity, this decrease persisted (MD, −0.01; 95% CI, −0.02 to −0.01; I 2 = 0%; P = .59). Initially, the comparison between PCSK9i and placebo yielded a nonsignificant reduction in cIMT by the end of follow-up, favoring PCSK9i (MD, −0.04; 95% CI, −0.10 to 0.03; I 2 = 98.6%; P < .01). However, after heterogeneity adjustment, the effect estimate reached statistical significance, demonstrating a consistent cIMT reduction with PCSK9i (MD, −0.01; 95% CI, −0.02 to −0.01; I 2 = 52%; P = .12). Metaregression analysis displayed associations between baseline cIMT (β = −0.45; P < .01), high-density lipoprotein cholesterol (β = 1.92; P < .01), and cIMT outcomes. Pooled between-group cIMT differences showed moderate correlations with the respective differences in total (r = 0.69) and low-density lipoprotein cholesterol (r = 0.59) across the included studies. Conclusions This review provides evidence supporting a potential association between PCSK9i treatment and cIMT reduction, with observed correlations involving total and low-density lipoprotein 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.