Efficacy and Safety of Oral PCSK9 Inhibitors: Insights from a Meta-analysis of RCTS

AIM: Current proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (the monoclonal antibodies evolocumab and alirocumab, and the siRNA inclisiran) require parenteral administration, which may limit long-term adherence. Orally active PCSK9 inhibitors could improve convenience and treatment accessibility. This meta-analysis evaluates LDL-C reduction and other lipid changes reported in randomized controlled trials (RCTs) of oral PCSK9 inhibitors. METHODS: RCTs comparing oral PCSK9 inhibitors with placebo and reporting LDL-C changes were identified through PubMed, EMBASE, Web of Science, CENTRAL, and ClinicalTrials.gov up to November 2025. Pooled mean percentage changes in lipid parameters were calculated using random- and fixed-effects models. Serious adverse events (SAEs) were analysed using risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Five RCTs on three different molecules (enlicitide, NNC0385-0434, and laroprovstat), including a total of 3,295 participants with hypercholesterolemia receiving stable doses of background lipid-lowering therapy prior to study initiation, met the inclusion criteria. Treatment durations ranged from 8 to 24 weeks. Pooled analysis showed a significant LDL-C reduction of -59.31% (95% CI -62.33 to -56.28) compared with placebo. Additional lipid parameters also improved: apolipoprotein B (-49.53%, 95% CI -54.19 to -44.79), non-HDL cholesterol (-55.41%, 95% CI -57.35 to -53.48), and Lipoprotein(a) (-22.74%, 95% CI -26.67 to -18.81). The pooled RR for SAEs was 0.84 (95% CI 0.68-1.03; p = 0.41), indicating no increased risk versus placebo. CONCLUSIONS: Oral PCSK9 inhibitors demonstrate potent LDL-C-lowering efficacy, comparable to parenteral PCSK9i, with favourable effects on other atherogenic lipids and a reassuring short-term safety profile.