Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100-300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose;P< 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III.

Background

Plasma apolipoprotein C-III (apoC-III) levels are associated with coronary artery disease (CAD) risk.

Objective

To assess whether lipoprotein-associated apoC-III levels predict risk of CAD events.

Methods

apoC-III associated with apoB, apoAI, and Lp(a) (apoCIII-apoB, apoCIII-apoAI, and apoCIII-Lp(a), respectively) were measured using high-throughput chemiluminescent enzyme-linked immunoassays in 2711 subjects (1879 controls and 832 cases with CAD) in the European Prospective Investigation into Cancer and Nutrition-Norfolk prospective population study with 7.4 years of follow-up. These measures were correlated with a variety of lipid measurements and the presence of CAD. The indices of "total apoCIII-apoB" and "total apoCIII-apoAI" were derived by multiplying plasma apoB and apoAI, respectively.

Results

apoCIII-apoB (P = .001), apoCIII-Lp(a) (P < .001), apoCIII-apoAI (P = .005) were higher in cases vs controls; tended to correlate positively with body mass index, hsCRP, apoC-III, low-density lipoprotein (LDL) cholesterol, triglycerides, remnant cholesterol, very low density lipoprotein, LDL and high-density lipoprotein particle number and very low density lipoprotein size; but negatively with LDL and high-density lipoprotein particle size (P < .001 for all). apoCIII-apoB, apoCIII-apoAI, apoCIII-Lp(a), total apoCIII-Lp(a), and total apoCIII-apoB were predictors of CAD after adjustment of age, sex, body mass index, smoking, diabetes, hypertensive and lipid-lowering drug use, but they lost their significance after further adjustment of lipid and lipoprotein variables.

Conclusions

This study suggests that enzyme-linked immunoassay-measured lipoprotein-associated apoC-III markers reflect atherogenic lipid particles but do not independently predict risk of CAD events.