Systematic review and network meta-analysis: Comparison and selection of lipid-lowering strategies for improving atherosclerotic plaque vulnerability

Background Cholesterol is a causal pathogenic risk factor for atherosclerosis. Effective management of low-density lipoprotein cholesterol (LDL-C) stabilizes or regresses plaques and reduces cardiovascular events. Fibrous cap thickness (FCT), percent atheroma volume (PAV), and carotid intima-media thickness (CIMT) are core imaging markers for plaque evaluation, yet head-to-head comparisons of different lipid-lowering regimens on these endpoints are lacking. Objective To systematically compare, via network meta-analysis (NMA), the efficacy of statin monotherapies, ezetimibe monotherapy, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monotherapy, and their combinations on FCT, PAV, and CIMT. Methods We searched PubMed, Web of Science, Embase, and Cochrane for randomized controlled trials (RCTs) published up to October 4, 2026. Eligible interventions included seven statins, ezetimibe, PCSK9 inhibitors, and other agents. Primary endpoints were FCT and PAV. Secondary endpoint was CIMT. Standardized procedures were used for screening, data extraction, and NMA. Results A total of 78 RCTs were included. Significant heterogeneity was observed across regimens. Combination therapies showed superior comprehensive plaque-modulating effects versus monotherapies. Each statin exhibited unique strengths across the three endpoints; no single agent performed best on all markers. Conclusions Combination lipid-lowering provides stronger plaque stabilization and regression, while statin monotherapies offer definite but heterogeneous benefits, supporting personalized choices based on plaque characteristics, comorbidities, financial constraints, and adherence. This NMA yields high-reliability evidence for stratified clinical decisions. Extended long-term trials are needed to confirm durable benefits. This systematic review was conducted in strict accordance with the PRISMA 2020 guidelines.