Current Evidence on the Lipid-Lowering Efficacy and Safety of Oral PCSK9 Inhibitors: A Systematic Review and Meta-analysis

Abstract

Background: Inhibition of the proprotein convertase subtilisin/kexin type 9 (PCSK9) is a well-established therapeutic strategy for significantly reducing low-density lipoprotein cholesterol (LDL-C) levels. In recent years, new oral PCSK9 inhibitors have been developed, providing emerging evidence regarding their lipid-lowering efficacy and safety profile. Objective: The aim of this study was to update the available evidence on the efficacy and safety of oral PCSK9 inhibitors. Methods: A systematic review and meta-analysis was conducted following the PRISMA statement guidelines. Randomized clinical trials evaluating oral PCSK9 inhibitors versus placebo or other lipid-lowering drugs were included. Percent changes in lipid parameters and the occurrence of adverse events were analyzed. Studies that could not be included in the quantitative analysis were described qualitatively. Results: Ten randomized clinical trials were included in the qualitative analysis, of which six met the criteria for inclusion in the meta-analysis. Five oral PCSK9 inhibitors were identified. Three of them (enlicitide, laroprovstat and NNC0385-0434) provided data for the quantitative analysis, while the other two (DC371739 and CVI-LM001) were evaluated descriptively. Compared with placebo, oral PCSK9 inhibitors were associated with significant reductions in LDL-C [mean difference (MD) -57.83%; 95% confidence interval (CI) -60.48% to -5.18%; I² = 23%] and apolipoprotein B (MD -49.02%; 95% CI -53.61 to -44.42%; I² = 76.3%). Similarly, decreases were observed in non-HDL cholesterol (MD -53.48%; 95% CI -57.61% to -49.36; I² = 56.5%), triglycerides (MD -15.44%; 95% CI -15.96% to -14.92%; I² = 0.0%) and lipoprotein(a) (MD -24.86%; 95% CI -29.50% to -20.21; I² = 99.2%). No significant differences in the incidence of adverse events were observed between oral PCSK9 inhibitors and placebo in the included studies. Conclusion: Oral PCSK9 inhibitors appear to offer lipid-lowering efficacy comparable to that achieved with currently approved subcutaneous therapies, without any relevant safety concerns.