Antisense drug IONIS-APO(a)Rx reveals standard LDL-C tests overestimate true LDL-C by up to 50% in high-Lp(a) patients, a phase 2 trial (J Clin Lipidol 2018)

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

J Clin Lipidol · 1 January 2018 · 8

Viney NJ, Yeang C, Yang X, Xia S, Witztum JL, Tsimikas S

This analysis of a placebo-controlled phase 2 trial of the antisense oligonucleotide IONIS-APO(a)Rx examined how conventional LDL cholesterol measurements, which include Lp(a) cholesterol content, relate to apolipoprotein B-100 and PCSK9 changes, in a pooled placebo group (n=29), cohort A (n=24, baseline Lp(a) 50-175 mg/dL), and cohort B (n=8, baseline Lp(a) above 175 mg/dL). Baseline Lp(a)-corrected LDL-C was 28%, 25% and 50% lower than standard laboratory LDL-C in placebo, cohort A and cohort B, respectively. Following treatment, Lp(a) particle number and Lp(a)-cholesterol fell -66.8% and -71.6%, apoB-100 fell -10.3% and -17.5%, and standard LDL-C fell -11.8% and -22.7% in cohorts A and B (all P<.001 versus placebo), while Lp(a)-corrected LDL-C rose +10.4% (P=.66) and +49.9% (P<.001). Total PCSK9 was unchanged, but Lp(a)-associated PCSK9 fell with treatment versus placebo (-39.0% vs +8.4%, P<.001). The findings show standard LDL-C tests overestimate true LDL-C in patients with elevated Lp(a), and that apoB-100 decline after apo(a) inhibition is consistent with Lp(a)-free LDL being cleared faster than Lp(a).

Original abstract

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-Ccorr) 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-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).

Conclusion: 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.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.