Meta-Analysis of Oral PCSK9 Inhibitors for Hypercholesterolemia in Adults: A Systematic Review and GRADE Assessment

Abstract

Oral PCSK9 inhibitors are emerging once-daily therapies intended to simplify PCSK9 pathway inhibition, but trial-level evidence varies across agents, populations, and follow-up. We searched PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials from inception to February 5, 2026 for double-blind randomized trials comparing oral PCSK9 inhibitors with placebo on background lipid-lowering therapy. Five trials (n = 4232) evaluating AZD0780, NNC0385-0434, MK-0616, and enlicitide were included. Compared with placebo, oral PCSK9 inhibitors significantly reduced low-density lipoprotein cholesterol (mean difference, -52.42 percentage points; 95% confidence interval, -62.84 to -42.00) and ApoB (mean difference, -43.03 percentage points; 95% confidence interval, -52.12 to -33.94), with consistent reductions in nonhigh-density lipoprotein cholesterol and total cholesterol. High-density lipoprotein cholesterol was not significantly changed. No significant differences were observed in discontinuation due to adverse events, any adverse events, serious adverse events, or treatment-related adverse events. Oral PCSK9 inhibitors provide substantial short-term reductions in atherogenic lipoproteins without an apparent excess of short-term adverse events; longer-term cardiovascular outcome trials are needed.