A Novel Triglyceride- and Cholesterol-Enriched Lipoprotein(a) Phenotype in Moderate Hypertriglyceridemia

Figures

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  Figure 1. Methodology of OxPL Immunoassays on ApoB, Apo(a), ApoC-III, and ApoAI Lipoprotein Carriers (A) Overview of chemiluminescent assays in which plasma is added to wells coated with carrier-specific capture antibodies, allowing immobilization of low-density lipoprotein (LDL) or very low density lipoprotein (VLDL), lipoprotein(a) (Lp[a]), or high-density lipoprotein (HDL) particles; oxidized phospholipids (OxPL; red starburst) on captured particles are detected by biotinylated E06 immunoglobulin M, and signal is reported as relative light units (RLU) converted to phosphocholine (PC) equivalents (equiv). (B-E) Individual assays for OxPL–apolipoprotein B (apoB), OxPL–apolipoprotein(a) (apo[a]), OxPL–apolipoprotein C-III (apoC-III), and OxPL–apolipoprotein AI (apoAI), respectively, using capture antibodies to apoB (MB47), apo(a) (LPA4), apoC-III, and apoAI to isolate the corresponding lipoprotein carrier before detection with E06.

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  Figure 2. Temporal Changes in Lp(a)-TG, Lp(a)-C, and Lp(a) in Response to Olezarsen Plasma (A) Lp(a)-associated triglycerides (Lp[a]-TG), (B) Lp(a)-associated cholesterol (Lp[a]-C), and (C) Lp(a) molar concentrations were measured at baseline and at the primary analysis time point (PAT) in placebo- and olezarsen-treated participants. Data are shown for the different olezarsen dosing regimens. Values represent mean percentage change from baseline ± SEM. ∗P = 0.05, ∗∗P = 0.01, and ∗∗∗P < 0.001 at the primary analysis time point compared with placebo. Q2W = every 2 weeks; Q4W = every 4 weeks; QW = every week.

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  Figure 3. Effects of Olezarsen on ApoB-Normalized Lp(a) Lipid Ratios at the Primary Analysis Time Point (A) Adjusted geometric mean percentage change from baseline in the Lp(a)-C/apoB ratio and (B) adjusted geometric mean percentage change from baseline in the Lp(a)-TG/apoB ratio in placebo- and olezarsen-treated participants with moderate hypertriglyceridemia. Data are shown for the primary analysis time point (week 25 for Q4W dosing cohorts and week 27 for Q2W and QW dosing cohorts). Error bars represent asymmetrical 95% CIs. P values are vs pooled placebo. Abbreviations as in Figures 1 and 2.

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  Figure 4. FPLC Distribution of Triglycerides, Cholesterol, Intact Lp(a), Total Apo(a), and Apo(a)-Containing Particles in Placebo-Treated Participants Size distribution of lipids and apo(a)-containing particles in placebo-treated participants. Fast protein liquid chromatography (FPLC) mean profiles from 5 participants showing plasma (A) triglycerides, (B) cholesterol, (C) intact Lp(a), (D) total apo(a), (E) apoC-III-Lp(a) complexes, and (F) apolipoprotein E (apoE)–Lp(a) complexes are shown at baseline and after 6 months of placebo treatment. (A) Triglycerides localized predominantly to VLDL fractions, whereas cholesterol was enriched in LDL- and HDL-sized fractions. Intact Lp(a) and total apo(a) were distributed primarily within LDL-sized fractions. ApoC-III-Lp(a) complexes were enriched in triglyceride-rich fractions, while apoE-Lp(a) complexes were detected mainly in VLDL and LDL fractions. These distributions were largely unchanged after 6 months of placebo treatment, indicating the stability of lipoprotein and apo(a)-containing particle profiles over time. Abbreviations as in Figures 1 and 2.

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  Figure 5. FPLC Distribution of Triglycerides, Cholesterol, Intact Lp(a), Total Apo(a) and Apo(a)-Containing Particles in Olezarsen-Treated (50 mg) Participants Size distribution of lipids and apo(a)-containing particles in olezarsen-treated (50 mg group) participants. FPLC mean profiles from 5 participants showing plasma (A) triglycerides, (B) cholesterol, (C) intact Lp(a), (D) total apo(a), (E) apoC-III-Lp(a) complexes, and (F) apoE-Lp(a) complexes are shown at baseline and after 6 months of olezarsen treatment. Olezarsen markedly reduced triglycerides and cholesterol in VLDL fractions, with preservation of LDL-sized intact Lp(a) and total apo(a) distributions. ApoC-III-Lp(a) complexes were substantially reduced across the lipoprotein distribution, whereas apoE-Lp(a) complexes showed reduction within triglyceride-rich fractions. Abbreviations as in Figures 1, 2, and 4.