Cardiovascular Outcomes with Non-Statin LDL-C-Lowering Therapies: A Meta-Analysis

Background: Non-statin low-density lipoprotein cholesterol (LDL-C)-lowering therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, ezetimibe, and bempedoic acid, demonstrated cardiovascular benefit in randomized trials. The recent VESALIUS-CV trial expanded evidence for LDL-C lowering into primary prevention populations. Research Question: Do non-statin LDL-C-lowering therapies reduce cardiovascular events and mortality compared with placebo, usual care, or background statin therapy in adults at cardiovascular risk, and do treatment effects differ between primary- and secondary-prevention populations? Methods: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception through May 2026 for randomized controlled trials (RCTs) evaluating PCSK9 monoclonal antibodies, ezetimibe, or bempedoic acid. Adults undergoing primary or secondary cardiovascular prevention were eligible. The primary outcome was adjudicated 3-point major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke). Secondary outcomes included trial-defined MACE, myocardial infarction (MI), stroke, coronary revascularization, cardiovascular mortality, all-cause mortality, serious adverse events (SAE), and discontinuation due to adverse events. Risk ratios (RRs) or Peto odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using random-effects models. A pre-specified subgroup analysis compared primary- versus secondary-prevention populations. Statistical heterogeneity was assessed using I 2 . Results: Seven RCTs comprising 103,540 participants were included. Non-statin LDL-C-lowering therapy significantly reduced 3-point MACE (RR 0.84, 95% CI 0.78-0.91; p<0.0001; I 2 =63%), trial-defined MACE (RR 0.86, 95% CI 0.82-0.91; p<0.00001; I 2 =62%), MI (RR 0.79, 95% CI 0.73-0.87; p<0.00001; I 2 =57%), stroke (RR 0.81, 95% CI 0.75-0.88; p<0.00001; I 2 =0%), and coronary revascularization (RR 0.83, 95% CI 0.76-0.90; p<0.0001; I 2 =74%). No significant reductions were observed in mortality or SAE. Discontinuation due to adverse events was also comparable between groups. For 3-point MACE, benefits were consistent across primary- and secondary-prevention populations (p=0.18). Similar findings were observed for trial-defined MACE (interaction p=0.11). Sensitivity analyses confirmed the robustness of the findings. Conclusion: Non-statin LDL-C-lowering therapies significantly reduce MACE, MI, stroke, and coronary revascularization in adults at cardiovascular risk, with consistent benefits across primary- and secondary-prevention settings. No significant effects on mortality were observed, and overall safety remained comparable to control.