Inhibition of hepatic apoC-III synthesis lowers atherogenic VLDL-associated lipoproteins

Very-Low-Density Lipoprotein–Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III

Literature - Pechlaner R, Tsimikas S, Yin X, et al. - J Am Coll Cardiol 2017;69:789-800

Background

CVD risk is mainly associated with specific lipids that belong to certain lipoprotein classes, such as LDL-C and VLDL, although individual molecular lipid species within the same lipid class have different associations with CVD [1]. Lipoprotein functions and metabolism are predominantly dependent on their apolipoprotein content, but no comprehensive analysis of plasma apolipoproteins and lipids has been performed in the same cohort to assess their comparative association with future CVD.

In this study, apolipoproteins were directly measured by mass spectrometry, and their associations with incident CVD were compared. The measurements were based on multiple-reaction monitoring mass spectrometry (MRM-MS), and the associations of apolipoproteins with incident CVD were investigated in 688 individuals included in the prospective population-based Bruneck Study [1]. Moreover, the effect of the inhibition of hepatic apoC-III synthesis with volanesorsen was tested in plasma samples [2-4].

Main results

  • Among 13 apolipoproteins quantified by MRM-MS, the most significant associations with incident CVD were detected for apoC-II, apoC-III, and apoE (P < 0.001 each, after adjustment for age, gender, and statin therapy), followed by apoL-I, apoB-100, and apoH (p ≤ 0.01 each).
  • Additional adjustment for DM, SBP, and current smoking did not significantly change these associations, but further adjustment for HDL-C and non–HDL-C rendered apoB-100 and apo-H non-significant, and weakened the associations obtained for apoC-III, apoC-II, and apoE.
  • The association of TGs with CVD (P < 0.001) lost significance after adjustment for HDL-C and non–HDL-C. Similar results were obtained for the individual endpoints of stroke and MI.
  • Correlations among apolipoproteins: ApoC-II, apoC-III, apoE, and TGs formed one set of highly inter-correlated variables along with non–HDL-C and apoB-100.
  • ApoC-I, which is known to primarily associate with VLDL, correlated most strongly with the apoB-100 cluster, and more weakly with apoA-I and HDL-C.
  • The inhibition of hepatic apoC-III synthesis with volanesorsen reduced significantly the plasma apoC-III levels in all subjects (mean decreases >75%), as well as the plasma levels of apoC-II, apoC-III, triacylglycerols, and diacylglycerols, and increased apoA-I, apoA-II and apo-M (all P<0.05 vs. placebo), whereas the levels of apoB-100 (P=0.73) remained unchanged.

Conclusion

The apolipoproteins apoC-III, apoC-II, and apoE that are found on triglyceride-rich lipoproteins regulate their metabolism. They were found to be stronger predictors of CV events compared with other apolipoproteins, including apoB-100. The inhibition of hepatic apoC-III synthesis with volanesorsen has favourable effects on apolipoprotein and lipid profiles, and might represent a new approach to further reduce of CVD risk.

References

1. Stegemann C, Pechlaner R, Willeit P, et al. Lipidomics profiling and risk of cardiovascular disease in the prospective population-based Bruneck Study. Circulation 2014;129:1821–31.

2. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014;371:2200–6.

3. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373:438–47.

4. Yang X, Lee SR, Choi YS, et al. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. J Lipid Res 2016;57:706–13.

Find this article online at JACC

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