Orally active proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are being developed as alternatives to injectable PCSK9 therapies for patients requiring intensive lipid lowering. A meta-analysis of randomized controlled trials published in the European Journal of Preventive Cardiology evaluated the lipid-lowering efficacy and short-term safety of oral PCSK9 inhibitors in patients with hypercholesterolemia receiving background lipid-lowering therapy.

The analysis identified placebo-controlled trials through PubMed, EMBASE, Web of Science, CENTRAL, and ClinicalTrials.gov through November 2025. Five randomized controlled trials involving 3,295 participants evaluated enlicitide, NNC0385-0434, and laroprovstat over treatment durations ranging from 8 to 24 weeks. Pooled lipid changes were assessed using random- and fixed-effects models, while serious adverse events were evaluated using risk ratios with 95% confidence intervals.

Findings

• Oral PCSK9 inhibitors reduced LDL-C by –59.31% compared with placebo (95% CI –62.33 to –56.28).
• Apolipoprotein B decreased by –49.53% (95% CI –54.19 to –44.79), non-HDL cholesterol by –55.41% (95% CI –57.35 to –53.48), and lipoprotein(a) by –22.74% (95% CI –26.67 to –18.81).
• Serious adverse event rates were comparable between oral PCSK9 inhibitors and placebo (RR 0.84; 95% CI 0.68-1.03; P=0.41).

Oral PCSK9 inhibitors demonstrated substantial LDL-C lowering in short-term randomized trials, along with favorable effects on other atherogenic lipid parameters. Serious adverse event rates were similar to placebo, supporting a reassuring short-term safety profile.