The roles of apo(a) size, phenotype, and dominance pattern in PCSK9-inhibition-induced reduction in Lp(a) with alirocumab

Abstract

An elevated level of lipoprotein (a) [Lp(a)] is a risk factor for CVD. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is reported to reduce Lp(a) levels. The relationship of Lp(a) reduction with apo(a) size polymorphism, phenotype, and dominance pattern and LDL cholesterol (LDL-C) reduction was evaluated in a pooled analysis of 155 hypercholesterolemic patients (75 with heterozygous familial hypercholesterolemia) from two clinical trials. Alirocumab significantly reduced total Lp(a) (pooled median: -21%, = 0.0001) and allele-specific apo(a), an Lp(a) level carried by the smaller (median: -18%, = 0.002) or the larger (median: -37%, = 0.0005) apo(a) isoform, at week 8 versus baseline. The percent reduction in Lp(a) level with alirocumab was similar across apo(a) phenotypes (single vs. double bands) and carriers and noncarriers of a small size apo(a) (≤22 kringles). The percent reduction in LDL-C correlated significantly with the percent reduction in Lp(a) level ( = 0.407, < 0.0001) and allele-specific apo(a) level associated with the smaller ( = 0.390, < 0.0001) or larger ( = 0.270, = 0.0183) apo(a) sizes. In conclusion, alirocumab-induced Lp(a) reduction was independent of apo(a) phenotypes and the presence or absence of a small size apo(a).

Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies

“…Furthermore, there is evidence that alirocumab may reduce Lp(a) independent of apo(a) isoform size. 34 More patients in the evolocumab analysis achieved LDL-C reduction >35% compared with our study (93.7% vs. our 84.6%). This may be due to the fact that many patients in our analysis (i.e.…”

Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease

“…Different apo(a) isoforms were not assessed in these trials; however, an independent study did not find an association between apo(a) isoforms and the reduction of Lp(a) with alirocumab. 26 In our analysis, alirocumab was generally well tolerated and had no effect on renal function over the study period compared with control, regardless of baseline renal function status. Individuals with diabetes often develop CKD and are at high risk of CVD.…”

Heritability of apolipoprotein (a) traits in two-generational African-American and Caucasian families

“…The results were related to human apo(a) isoform standard with known apo(a) isoforms (Technoclone GmbH, Austria) taking into account the inverse relation between the number of K4 repeats (i.e., apparent molecular mass) and isoform mobility during agarose gel electrophoresis. The protein isoform dominance pattern was assessed by optical analyses of the apo(a) protein expression on the Western blots, followed by a computerized analysis of scans as described previously (12,24). To determine ISLs, Lp(a) levels were apportioned according to the degree of intensity of the bands on the Western blot as described in detail elsewhere (11,24,25).…”

“…The protein isoform dominance pattern was assessed by optical analyses of the apo(a) protein expression on the Western blots, followed by a computerized analysis of scans as described previously (12,24). To determine ISLs, Lp(a) levels were apportioned according to the degree of intensity of the bands on the Western blot as described in detail elsewhere (11,24,25).…”