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

Abstract

The laboratory measurement of "low-density lipoprotein cholesterol (LDL-C)" includes the cholesterol content of lipoprotein(a) (Lp(a)-C). 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) 50-175mg/dL) and cohort B (n=8, baseline Lp(a)>175mg/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-Ccorr) were calculated. 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-Ccorr 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-Ccorr 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). LDL-Ccorr 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.