Mechanisms of unusual response to lipid-lowering therapy: PCSK9 inhibition

The efficacy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has broadened lipid-lowering therapy thus providing decreased risk in atherosclerotic cardiovascular disease. Unfortunately, the widespread use of PCSK9 inhibitors (PCSK9i), ie, monoclonal antibodies, has led to the findings of unusual responsiveness, ie, a phenomenon defined as an LDL-C reduction of <30% vs the average LDL-C reduction efficacy of 50-60%. This unusual responsiveness to PCSK9i is attributable to several factors, ie, lack of adherence, impaired absorption, poor distribution or early elimination as well as abnormal effects of PCSK9i in the presence of anti-antibodies or mutations in PCSK9 and LDLR. Unexpectedly increased lipoprotein (Lp)(a) also appear to contribute to the unusual responsiveness scenario. Identification of these responses and mechanisms underlying them are essential for effective management of LDL-C and cardiovascular risk. In this review, we describe plausible reasons un-derlying this phenomenon supported by findings of clinical trials. We also elaborate on the need for education and regular follow-up to improve adherence. Collectively, the review provides a summary of the past, present, and future of mechanisms and countermeasures revolving around unusual responses to PCSK9i therapy.

Automated summary

The use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has shown efficacy in lowering the risk of atherosclerotic cardiovascular disease. However, a phenomenon of unusual responsiveness, with lower LDL-C reduction than average, has been observed. Several factors, including lack of adherence and abnormal effects of PCSK9 inhibitors, contribute to this unusual responsiveness. Understanding these mechanisms is crucial for effective management of LDL-C and cardiovascular risk.