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 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 corr increased +10.4% ( P  = .66) and +49.9% ( P Rx vs placebo (–39.0% vs +8.4%, P 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.