Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment
Davey Smith, George
Wolters Kluwer Health
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Sliz, E., Kettunen, J., Holmes, M., Oliver-Williams, C., Boachie, C., Wang, Q., Mannikko, M., et al. (2018). Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment. Circulation, 138 2499-2512. https://doi.org/10.1161/CIRCULATIONAHA.118.034942
Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial, and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. Methods: 228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Results: Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy ( R 2 =0.88). Alterations in lipoprotein lipid composition and fatty acid balance were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 showed weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P =2x10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no robust effects on amino acids, ketones, and a marker of inflammation (GlycA); in contrast, statin treatment lowered GlycA levels. Conclusions: Genetic inhibition of PCSK9 results in similar metabolic effects as statin therapy across a detailed lipid and metabolite profile. However, for the same lowering of LDL-C, PCSK9 inhibitors are predicted to be less efficacious at lowering VLDL lipids, which could potentially translate into subtle differences in cardiovascular risk reduction.
This study was supported by the Academy of Finland (grant numbers 312476, 312477, 297338 and 307247), University of Oulu Graduate School, Strategic Research Funding from the University of Oulu, Finland, the Novo Nordisk Foundation (grant number NNF17OC0026062 and 15998), the Sigrid Juselius Foundation, and the UK Medical Research Council via the Medical Research Council University of Bristol Integrative Epidemiology Unit (MC_UU_12013/1 and MC_UU_12013/5). MVH is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. QW was supported by a Novo Nordisk Foundation Postdoctoral Fellowship (grant number NNF17OC0027034). NR is supported by Glasgow Molecular Pathology NODE, which is funded by The Medical Research Council and The Engineering and Physical Sciences Research Council (MR/N005813/1). PROSPER metabolic profiling by NMR was supported by the European Federation of Pharmaceutical Industries Associations, Innovative Medicines Initiative Joint Undertaking, European Medical Information Framework grant number 115372, the European Commission under the Health Cooperation Work Programme of the 7th Framework Programme (Grant number 305507) “Heart ‘omics’ in AGEing” (HOMAGE). The INTERVAL study is funded by National Health Service Blood and Transplant (11-01-GEN) and has been supported by the National Institute for Health Research Blood & Transplant Research Units in Donor Health and Genomics (NIHR BTRU-2014-10024) at the University of Cambridge in partnership with National Health Service Blood and Transplant. NMR metablomics of the INTERVAL trial was funded by European Commission Framework Programme 7 (HEALTH-F2-2012-279233).
Medical Research Council (MR/L003120/1)
European Research Council (268834)
British Heart Foundation (None)
External DOI: https://doi.org/10.1161/CIRCULATIONAHA.118.034942
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279954
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/