Lipoprotein(a) in the advent of a PCSK9 world

To the Editor,

The review article recently written by Malo et al. ¹ is a thorough overview of the currently available knowledge concerning proprotein convertase subtilisin/kexin type 9 (PCSK9), including descriptions of its molecular, physicochemical and clinical aspects. Research on PCSK9 has promoted our understanding of low-density lipoprotein (LDL) regulation, and reduced cardiovascular disease (CVD) event rates have been observed in studies using PCSK9 inhibitors. ¹ Malo et al. noted that important questions remain regarding PCSK9, without specifying its relation to lipoprotein(a) (Lp(a)). We would like to address some of the questions pertaining to PCSK9 and Lp(a).

Of note, PCSK9 inhibitors reduce not only LDL-cholesterol but also Lp(a) concentrations (by approximately 20%–25%) in the circulation.^1,2 Thus far, no drugs have been clinically used to reduce Lp(a), which is recognized as a CVD risk factor. ³ Whether or not the suppressive effect of treatment with PCSK9 inhibitors on CVD events stems from a simple reduction in LDL-cholesterol concentrations or a synergistic reduction in Lp(a) (and to what extent does Lp(a) contribute to the effect, if so) remains unclear at present. ³ Additional studies using PCSK9 inhibitors comparing patients with high and low Lp(a) concentrations may help determine the answer to such a question.

Furthermore, the route of Lp(a) metabolism and its related pathophysiological role is incompletely known. ⁴ Research on the mechanisms underlying the behaviour of Lp(a) as influenced by PCSK9 and its inhibitors may help clarify both the metabolism and role of Lp(a). ⁴

Other aspects include the establishment of a standardized method to measure Lp(a); there is a lack of rigorous validation of immunoassays for Lp(a). ⁵ It also remains necessary to establish common units for Lp(a) concentrations. ⁵ New guidelines on measurement of Lp(a) in routine practice will emerge. The advent of the ‘PCSK9 world’ has had a substantial impact on our understanding of the clinical biochemistry of Lp(a).