Dose–specific Efficacy, Safety of Oral Pcsk9 Inhibitors: A Systematic Review and Meta–analysis of Randomized Trials

Background Oral inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) represent a novel lipid–lowering strategy that may overcome limitations related to injectable therapies. However, the dose–specific efficacy and safety of this emerging drug class have not been comprehensively evaluated. Methods We performed a systematic review and dose–stratified meta–analysis of randomized, placebo–controlled trials evaluating oral PCSK9 inhibitors. PubMed, Embase, and CENTRAL were searched from inception to November 2025. Primary efficacy outcomes were percentage changes in LDL cholesterol (Table LDL–C) at the lowest and highest tested doses. Secondary endpoints included apolipoprotein B (Table ApoB), non–HDL cholesterol, and lipoprotein(a) [Lp(a)]. Safety outcomes comprised overall adverse events (AEs), serious AEs, and selected individual AEs. Random–effects models were applied, and interaction testing was used to assess dose–response relationships. Results Four trials encompassing 859 participants were included. Oral PCSK9 inhibitors significantly reduced LDL–C at both dose levels, with greater reductions observed at the highest dose (–58.5%) compared with the lowest dose (–42.3%; p for interaction = 0.02). Similar dose–dependent effects were observed for ApoB (–49.7% vs –33.9%) and non–HDL cholesterol, while reductions in Lp(a) were consistent but not significantly dose–dependent. Safety outcomes were comparable to placebo across doses, with no increase in overall or serious AEs. Rates of gastrointestinal, musculoskeletal, and infectious events were low, and no dose–related safety signals were identified (Table 2). Conclusions Oral PCSK9 inhibitors provide substantial, dose–dependent reductions in atherogenic lipoproteins with a favorable short–term safety profile. These findings support continued clinical development and highlight the potential role of oral PCSK9 inhibition as an effective and patient–friendly option for intensive LDL–C lowering.