Efficacy and Safety of Oral PCSK9 Inhibitors in Adults With Hypercholesterolemia: An Updated Systematic Review and Meta-Analysis of RCTs

OBJECTIVE: To evaluate the efficacy and safety of oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with hypercholesterolemia and assess their potential as a convenient alternative to injectable therapies. DATA SOURCES: PubMed, Embase, Scopus, and CENTRAL were searched from inception to May 10th, 2026, using terms related to oral PCSK9 inhibitors and hypercholesterolemia. The study was registered with PROSPERO (CRD420261329028). STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials (RCTs) comparing oral PCSK9 inhibitors with placebo in adults receiving background lipid-lowering therapy were included. Two reviewers independently screened studies and extracted data on an Excel sheet. DATA SYNTHESIS: Five RCTs were analyzed. Oral PCSK9 inhibitors significantly reduced LDL cholesterol (mean difference [MD] -52.15 mg/dL; 95% CI -59.42 to -44.87), apolipoprotein B (MD -42.85 mg/dL; 95% CI -49.52 to -36.18), and lipoprotein(a) (MD -35.11 mg/dL; 95% CI -52.86 to -17.36) compared with placebo. Significant reductions were also observed in triglycerides and total cholesterol. Safety outcomes were comparable to placebo, with no increased risk of adverse events (risk ratio [RR] 1.04; 95% CI 0.98-1.09) or serious adverse events. Subgroup analyses indicated enhanced efficacy with enlicitide and specific dosing regimens. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Oral PCSK9 inhibitors address major barriers inherent to injectable biologics. By eliminating needle-related anxiety, injection-site reactions, and the logistical burdens of cold-chain storage, these agents may significantly improve patient adherence and satisfaction. This transition to a convenient oral regimen facilitates integration into standard care, potentially expanding access for patients reluctant to maintain long-term injectable therapy. CONCLUSIONS: Oral PCSK9 inhibitors significantly improve atherogenic lipid profiles and are well tolerated. They represent a promising and convenient alternative to injectable PCSK9 inhibitors for managing hypercholesterolemia.