Lipid-Lowering Efficacy and Safety of Oral Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Systematic...

Pharmacological inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a well-established strategy for achieving substantial reductions in low-density lipoprotein cholesterol (LDL-C). Recently, novel oral PCSK9 inhibitors have emerged, providing new evidence regarding their lipid-lowering efficacy and safety.

This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. Randomized clinical trials evaluating oral PCSK9 inhibitors and reporting percentage changes in lipid parameters and/or adverse events were included. A qualitative synthesis was performed for all studies meeting predefined eligibility criteria, followed by a quantitative synthesis of studies with sufficient data for statistical pooling.

Seven randomized clinical trials were included in the qualitative analysis, of which four were eligible for meta-analysis. Five oral PCSK9 inhibitors were identified. Three agents (MK-0616, AZD0780, and NNC0385-0434) contributed to the quantitative analysis, while two (DC371739 and CVI-LM001) were assessed descriptively. Compared with placebo, oral PCSK9 inhibitors significantly reduced LDL-C [mean difference (MD) - 55.7; 95% confidence interval (CI) - 59.3 to - 52.1; I² = 14%)] and apolipoprotein B (MD - 46.9; 95% CI - 54.6 to - 39.2; I² = 72.9%). They also lowered non-high-density lipoprotein cholestero (MD - 49.4; 95% CI - 57.4 to - 41.5; I² = 50.3%), triglycerides (MD - 13.2; 95% CI - 21.4 to - 5.0; I² = 0%), and lipoprotein(a) (MD - 24.9; 95% CI - 34.9 to - 15.0; I² = 77.6%). Across trials, no differences in safety outcomes were observed between oral PCSK9 inhibitors and placebo.

Oral PCSK9 inhibitors demonstrate lipid-lowering efficacy and safety comparable to that of currently approved injectable PCSK9 therapies. These findings support their potential as a convenient and effective alternative, although current evidence remains limited to early-phase studies.