Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors

Abstract

Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Details about its synthesis, many aspects of composition and clearance from the bloodstream are still unknown. LDL receptor (LDLR) (and probably other receptors) play a role in the elimination of Lp(a) particles. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors increase the number of available LDLRs and in this way very effectively reduce the LDL cholesterol (LDL-C) concentrations. As shown in controlled studies using PCSK9 inhibitors, Lp(a) levels are decreased by 20 to 30%, though in some patients no effect was observed. So far, it has not been clarified whether this decrease is associated with an effect on the incidence of cardiovascular events (CVEs). In two recently published well-performed secondary prevention studies (FOURIER with evolocumab, ODYSSEY OUTCOMES with alirocumab) baseline Lp(a) levels were shown to have an impact on CVEs independently of baseline LDL-C concentrations. The rather modest PCSK9 inhibitor-induced decrease of Lp(a) was associated with a reduction of CVEs in both studies, even after adjusting (ODYSSEY OUTCOMES) for demographic variables (age, sex, race, region), baseline Lp(a), baseline LDL-C, change in LDL-C, and clinical variables (time from acute coronary syndrome, body mass index, diabetes, smoking history). The largest decrease of CVEs was seen in patients with relatively low concentrations of both LDL-C and Lp(a) (FOURIER). These findings will probably have an influence on the use of PCSK9 inhibitors in patients with high Lp(a) concentrations. Keywords Lipoprotein(a) · LDL cholesterol · PCSK9 inhibitors · Cardiovascular events · Lipoprotein apheresis Lipoprotein(a)-synthesis, composition, metabolism, and clinical significanceLipoprotein(a) (Lp(a)) consists of an LDL particle to which an apolipoprotein(a) (apo(a)) is linked with a single disulfide bond. The binding between apolipoprotein (B) (apoB), the major apolipoprotein of the LDL, and apo(a) takes place either in the hepatic cells, in the space of Disse, or in the vascular lumen [1]. The cholesterol content of the LDL in Lp(a) varies between 30 and 45%. The Lp(a) concentration is genetically determined. Mutations in the Lp(a) gene (LPA) and especially a variable number of LPA kringles IV type 2 in the apo(a) have an effect. A low number of these kringles is associated with higher Lp(a) levels.

Lipoprotein(a)—an interdisciplinary challenge

“…PCSK9 inhibitors-decrease Lp(a) by a mean of about 20% (ranging between 0 and 44%); in some patients a reduction cannot be achieved. In two prospective controlled large studies, both evolocumab and alirocomab induced a modest reduction of cardiovascular events which was the consequence of decreasing Lp(a) levels-independently of the effects on LDL-C [20]. Up to now, an elevation of Lp(a) is no accepted indication for this injection therapy.…”

Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy

“…Therefore, in the ODYSSEY OUTCOMES trial, patients treated with alirocumab for a median of 33 months showed 1.1 mmol/L reduction in LDL-C level that it can be considered up to 22% reduction in risk for cardiovascular events [83]. Moreover, a 25% lipoprotein little (a) (Lp(a)) reduction has been observed in alirocumab and evolocumab treated patients at long term follow up [84]; probably due to the similarities between LDL and Lp(a), it can be catabolized using LDLR-mediated pathway, this possibility, however, remains to be addressed. Further follow-up is essential to clarify mAbs' long-term safety and efficacy.…”

Einfluss erhöhter Lipoprotein-konzentrationen auf die Prognose von Patienten mit Diabetes mellitus

“…Sowohl in Statinstudien als auch in PCSK9-Inhibitorstudien hat sich trotz der erzielten Absenkungen von LDL-Cholesterin Lp(a) als ein eigenständiger atherogener Risikofaktor etabliert [32,33]. PCSK9-Hemmer reduzieren den Lp(a)-Spiegel um ca.…”

“…PCSK9-Hemmer reduzieren den Lp(a)-Spiegel um ca. 20 % und haben sowohl in der FOURIER-Studie (mit Evolocumab) als auch in der ODYSSEY-OUTCOMES-Studie (mit Alirocumab) auf diese Weise zu einer signifikanten Reduktion der kardiovaskulären Morbidität beigetragen [33].…”