Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) represent a major advancement in lipid-lowering therapy, offering robust reductions in low-density lipoprotein cholesterol (LDL-C), and now play a pivotal role in lipid management, especially for patients with atherosclerotic cardiovascular disease at high or very high risk. Despite their proven efficacy in clinical trials, a subset of patients exhibits a suboptimal LDL-C response, especially in real-world settings. Under-response may result from insufficient drug exposure due to non-adherence, suboptimal injection technique, or discontinuation of background lipid-lowering therapy, and biological factors that limit drug efficacy despite adequate exposure. This review explores the frequency and mechanisms of under-response to PCSK9-i, and provide a practical guide for clinicians to identify and address causes of PCSK9-i under-response, ensuring appropriate intervention for a sustained cardiovascular risk reduction.
