Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials

Background: Injectable proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an established strategy to lower low-density lipoprotein cholesterol (LDL-C) and reduce atherosclerotic cardiovascular disease risk. Recently developed oral PCSK9 inhibitors may be a user-friendly alternative. Methods: A systematic search from inception through March 6, 2026, identified randomized controlled trials comparing oral PCSK9 inhibitors with placebo in adults with established atherosclerotic cardiovascular disease or at high risk of atherosclerotic cardiovascular disease, receiving background lipid-lowering therapy, or with statin intolerance. The efficacy endpoint was percentage change in lipid levels including LDL-C, apolipoprotein-B, lipoprotein(a), triglycerides, and non-HDL-C. Safety outcomes included any adverse event, serious adverse events, discontinuation due to adverse events, and new-onset or worsening of diabetes attributed to intervention. Random-effects meta-analysis was performed using restricted-maximum-likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment. Heterogeneity was assessed using I² statistic. Results: Across five randomized phase 2 and 3 trials (n = 4226), oral PCSK9 inhibitors were associated with a significant reduction in LDL-C versus placebo (mean difference -49.92%; 95% CI -56.41 to -43.43; I² = 86%; PI, -72.30 to -27.54). Significant reductions were also observed in ApoB, Lp(a), triglycerides, and non-HDL-C. Safety outcomes were similar between both groups. In dose-matched analyses of MK-0616 at comparable dosing across trials, reductions in lipid markers remained significant with minimal heterogeneity. Conclusions: Oral PCSK9 inhibitors were associated with reductions in LDL-C, ApoB, non-HDL-C, and lipoprotein(a), with safety profile comparable to placebo. Longer-term studies evaluating cardiovascular outcomes and comparisons with injectable PCSK9 inhibitors are required to define their clinical role.