Relationship between LDL-C, estimated true LDL-C, apolipoprotein B-100, and PCSK9 levels following lipoprotein(a) lowering with an antisense oligonucleotide

BACKGROUND: The laboratory measurement of low-density lipoprotein cholesterol (LDL-C) includes the cholesterol content of lipoprotein(a) (Lp(a)-C). OBJECTIVE: To estimate the true LDL-C in relation to changes in apolipoprotein B-100 (apoB-100) and assess changes in proprotein convertase subtilisin/kexin 9 (PCSK9) levels in patients with elevated Lp(a) treated with IONIS-APO(a)(Rx). METHODS: A pooled placebo group (n = 29), and cohort A (n = 24, baseline Lp(a) 50-175 mg/dL) and cohort B (n = 8, baseline Lp(a) > 175 mg/dL) treated with IONIS-APO(a)(Rx) were studied. Lp(a) particle number, ultracentrifugation-measured LDL-C, apoB-100, total PCSK9, and lipoprotein-associated PCSK9 (PCSK9-Lp(a), PCSK9-apoB, PCSK9-apoAI) were measured. Lp(a)-cholesterol (Lp(a)-C) and LDL-C corrected for Lp(a)-C (LDL-C-corr) were calculated. RESULTS: Baseline mean (standard deviation) LDL-C was 120 (42), 128 (45), and 112 (39) mg/dL in placebo, cohorts A and B, respectively, whereas LDL-C-corr was 86 (48), 96 (43), and 57 (37) mg/dL (P < .001 compared with placebo), representing 28%, 25%, and 50% lower levels than LDL-C. Following IONIS-APO(a)(Rx) treatment at day 85/99, Lp(a) particle number and Lp(a)-C decreased -66.8% and -71.6%, apoB-100 -10.3% and -17.5%, LDL-C -11.8% and -22.7%, (P < .001 for all vs placebo), whereas LDL-C-corr increased +10.4% (P = .66) and +49.9% (P < .001) in cohorts A and B, respectively. Total PCSK9 did not change but PCSK9-Lp(a) decreased with IONIS-APO(a)(Rx) vs placebo (-39.0% vs +8.4%, P < .001). CONCLUSION: LDL-C-corr is lower than laboratory LDL-C in patients with elevated Lp(a). Following apolipoprotein(a) inhibition and decline in Lp(a) and Lp(a)-C, the decline in apoB-100 is consistent with the notion that LDL devoid of apo(a) is cleared faster than Lp(a). These types of analyses may provide insights into the mechanisms of drugs affecting Lp(a) levels in clinical trials. (C) 2018 National Lipid Association. All rights reserved.