Lowering of Lp(a)-c results in lower LDL-c measurements, but constant true LDL-c levels
In a phase 2 study in patients with elevated Lp(a), measured LDL-c included circulating Lp(a)-c and lowering of Lp(a)-c led to lower LDL-c measurements and constant ‘true’ LDL-c levels.
Relationship between “LDL-C”, estimated true LDL-C, apolipoprotein B-100 and PCSK9 levels following lipoprotein(a) lowering with an antisense oligonucleotideLiterature - Viney NJ, Yeang C, Yang X, et al. - J Clin Lipidol 2018; published online ahead of print
Introduction and methods
Assays that measure LDL-c cannot separate LDL-c from lipoprotein(a) cholesterol (Lp(a)-c), because their densities overlap [1]. Therefore, approximately 30-45% of measured ‘LDL-c’ is actually Lp(a)-c [2]. LDL-ccorr is the estimated true LDL-c that is corrected for Lp(a)-c. Lipid-lowering therapies that reduce LDL-c can increase Lp(a) mass and Lp(a)-c, meaning that the achieved “LDL-c” is the sum of true LDL-c reduction and Lp(a)-c elevation that reaches an equilibrium in plasma [3].
In the present analysis, the changes in "LDL-c", LDL-ccorr, Lp(a)-c, apolipoprotein B-100 (apoB-100), PCSK9 and lipoprotein-associated PCSK9 levels were assessed in a phase 2 clinical trial of Lp(a) lowering with the antisense oligonucleotide IONIS-APO(a)Rx.
In this randomized, placebo-controlled, double-blind, dose titration, phase 2 study, patients were randomized to placebo (n=29) or IONIS-APO(a)Rx (n=32) subcutaneously with a dose regimen of 100 mg weekly for 4 weeks, 200 mg weekly for another 4 weeks, and 300 mg weekly for another 4 weeks, and a follow-up of 112 days [4]. Patients receiving IONIS-APO(a)Rx had baseline Lp(a) of either 50-175 mg/dL in cohort A (n=24), or >175 mg/dL in cohort B (n=8), whereas 70% of patients were treated with lipid modifying therapies including statins/ezetimibe.
Main results
- Baseline mean “LDL-c” was 120 (SD: 42) in the placebo group, 128 (SD: 45) in cohort A, and 112 (SD: 39) mg/dL in cohort B.
- Baseline LDL-ccorr was 86 (SD: 48) in the placebo group, 96 (SD: 43) in cohort A, and 57 (SD: 37) mg/dL in cohort B, representing respectively 28%, 25% and 49% lower levels than “LDL-c”.
- In cohort A and B, significant reductions at day 85/99 were seen in Lp(a) particle number, Lp(a)-c, “LDL-c and apoB100 with IONIS-APO(a)Rx compared to placebo.
- In cohort B, also a significant increase in LDL-ccorr was observed with IONIS-APO(a)Rx compared to placebo.
- There were no significant changes in any parameter in the placebo group.
- Total PCSK9 did not change throughout the study, but PCSK9-Lp(a) decreased with IONIS-APO(a)Rx versus placebo (-39.0% vs. +8.4%; P<0.001).
Conclusion
The true LDL-c values are lower than the measured LDL-c at the laboratory, due to the contribution of Lp(a)-c. When lowering Lp(a)-c, measured LDL-c drops as well, but the true LDL-c levels increase. The authors propose a redefinition of the total lipid profile, such that the total cholesterol value includes not only LDL-c, HDL-c, and VLDL-c, but also Lp(a)-c.
References
1. Yeang C, Witztum JL, Tsimikas S. 'LDL-C' = LDL-C + Lp(a)-C: implications of achieved ultra low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering. Curr Opin Lipidol. 2015;26:169-178.
2. Seman LJ, Breckenridge WC. Isolation and partial characterization of apolipoprotein (a) from human lipoprotein (a). Biochem Cell Biol. 1986;64:999-1009.
3. Yeang C, Hung MY, Byun YS, et al. Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein(a). J Clin Lipidol. 2016;10:594.
4. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388:2239-2253.
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