Efficacy and Safety of Oral PCSK9 Inhibitors in Adults with Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Injectable PCSK9 inhibitors effectively lower LDL-C levels in patients with hypercholesterolemia; however, their high cost and requirement for parenteral administration limit their widespread use. Oral PCSK9 inhibitors have emerged as a convenient alternative. This review and meta-analysis of the literature evaluate the effectiveness and safety of oral PCSK9 inhibitor treatment for adults with hypercholesterolemia. PubMed, Embase, Cochrane CENTRAL, and Scopus were searched through September 2025 for randomized controlled trials comparing oral PCSK9 inhibitors with placebo. The primary outcome was percentage change in LDL-C, with secondary lipid and safety outcomes. We used Cochrane RoB 2.0 tool to assess risk of bias, and pooled estimates were calculated using a random-effects model. Certainty of evidence was evaluated with GRADE. From 1,253 records, three trials were included. Participants were mostly male, aged 61-65 years, with elevated baseline LDL-C. Oral PCSK9 inhibitors significantly reduced LDL-C and ApoB in a dose-dependent manner and achieved modest reductions in triglycerides (MD -6.56 mg/dL; 95% CI: -12.30 to -0.83) and total cholesterol (MD -25.25 mg/dL; 95% CI: -30.67 to -19.83). Effects on lipoprotein(a) were inconsistent. Adverse events (RR 1.06; 95% CI: 0.91-1.23) and serious adverse events (RR 1.32; 95% CI: 0.41-4.26) were comparable to placebo. According to our review, oral PCSK9 inhibitors are a promising therapeutic option for treating hypercholesterolemia due to their potent lipid-lowering effects and an overall favorable safety profile. However, more trials are needed to confirm their impact on cardiovascular outcomes.