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Introduction <p>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.</p> Methods <p>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.</p> Results <p>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)&#xa0;−&#xa0;55.7; 95% confidence interval (CI)&#xa0;−&#xa0;59.3 to&#xa0;−&#xa0;52.1; <i>I</i><sup>2</sup>&#xa0;=&#xa0;14%)] and apolipoprotein B (MD&#xa0;−&#xa0;46.9; 95% CI&#xa0;−&#xa0;54.6 to&#xa0;−&#xa0;39.2; <i>I</i><sup>2</sup>&#xa0;=&#xa0;72.9%). They also lowered non–high-density lipoprotein cholestero (MD&#xa0;−&#xa0;49.4; 95% CI&#xa0;−&#xa0;57.4 to&#xa0;−&#xa0;41.5; <i>I</i><sup>2</sup>&#xa0;=&#xa0;50.3%), triglycerides (MD&#xa0;−&#xa0;13.2; 95% CI&#xa0;−&#xa0;21.4 to&#xa0;−&#xa0;5.0; <i>I</i><sup>2</sup>&#xa0;=&#xa0;0%), and lipoprotein(a) (MD&#xa0;−&#xa0;24.9; 95% CI&#xa0;−&#xa0;34.9 to&#xa0;−&#xa0;15.0; <i>I</i><sup>2</sup>&#xa0;=&#xa0;77.6%). Across trials, no differences in safety outcomes were observed between oral PCSK9 inhibitors and placebo.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Walter Masson,
  • Martín Lobo,
  • Gustavo Giunta,
  • Leandro Barbagelata,
  • Juan P. Nogueira

摘要

Introduction

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.

Methods

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.

Results

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.

Conclusion

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.