Abstract 4341793: Oral PCSK9 Inhibitors for Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Trials

Introduction: Despite advances with injectable PCSK9 inhibitors, many patients with hypercholesterolemia remain unable to achieve LDL-C goals due to barriers such as cost, access, and adherence. Oral PCSK9 inhibitors represent a promising alternative, but their lipid-lowering efficacy and safety profile have not been systematically evaluated. Methods: We searched PubMed, Embase, and ClinicalTrials.gov through April 2025 and identified four randomized trials of oral PCSK9 inhibitors in hypercholesterolemia, including one Phase 1 and three Phase 2 trials (1,114 participants). The primary outcome was the percent change in LDL-C compared to placebo. Secondary outcomes included changes in lipoprotein(a), apolipoprotein B, total cholesterol, triglycerides, and adverse events. Results were pooled using a random effects model with mean differences and 95% confidence intervals. Results: Oral PCSK9 inhibitors significantly reduced LDL-C compared to placebo (MD –47.09%; 95% CI, –53.22% to –40.96%; p < 0.001). MK-0616 achieved the greatest LDL-C reduction (–53.69%; 95% CI, –61.05% to –46.34%), followed by NNC0385-0434 (–46.23%; 95% CI, –63.15% to –29.31%) and AZD0780 (–38.18%; 95% CI, –45.06% to –31.29%). Lipoprotein(a) (–19.87%; 95% CI, –25.59% to –14.14%; p < 0.001), apolipoprotein B (–37.70%; 95% CI, –43.69% to –31.71%; p < 0.001), and total cholesterol (–24.29%; 95% CI, –27.88% to –20.70%; p < 0.001) were also significantly reduced. Triglyceride reduction was not significant (–3.58%; 95% CI, –7.63% to 0.47%; p = 0.08). Adverse events were similar between groups (RR 1.06; 95% CI, 0.95–1.17; p = 0.32). Conclusions: Oral PCSK9 inhibitors significantly reduced LDL-C, lipoprotein(a), apolipoprotein B, and total cholesterol compared to placebo, with no significant reduction in triglycerides. Among the agents studied, MK-0616 demonstrated the greatest overall LDL-C lowering effect.