A narrative review of PCSK9 inhibitors: from evolocumab to novel discoveries

The application of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represents a crucial milestone in the field of lipid-lowering therapy. As the first PCSK9 inhibitor to be approved globally, evolocumab has not only offered an entirely novel therapeutic option for patients with familial hypercholesterolemia but also established a paradigm for the development of subsequent anti-PCSK9 monoclonal antibodies. This narrative review provides an overview of the discovery of PCSK9 and its role in low-density lipoprotein cholesterol metabolism, detailing the developmental trajectory and key clinical trials of evolocumab, and underscoring its central importance and transformative impact on lipid-lowering therapeutics. On this basis, we conduct a comparative analysis of the differences in mechanism of action, clinical efficacy and safety among the marketed PCSK9 inhibitors, and dissect the limitations and unmet needs in current clinical practice. Furthermore, this review explores the pleiotropic effects of PCSK9 beyond lipid metabolism, and comments on its potential application value and latest research advances in diseases such as infection, liver disease, and malignancy. Finally, we prospect the future development directions of PCSK9-targeted therapy, aiming to provide an integrated reference perspective for basic research and clinical practice in this field.