University of Oulu

Sliz, E., Kettunen, J., Holmes, M., Williams, C., Boachie, C., Wang, Q., Männikkö, M., Sebert, S., Walters, R., Lin, K., Millwood, I., Clarke, R., Li, L., Rankin, N., Welsh, P., Delles, C., Jukema, J., Trompet, S., Ford, I., Perola, M., Salomaa, V., Järvelin, M., Chen, Z., Lawlor, D., Ala-Korpela, M., Danesh, J., Davey Smith, G., Sattar, N., Butterworth, A., Würtz, P. (2018) Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment. Circulation, 138 (22), 2499-2512.

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment

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Author: Sliz, Eeva1,2,3; Kettunen, Johannes1,2,3; Holmes, Michael V.4,5,6,7,8;
Organizations: 1Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland.
2Univ Oulu, Fac Med, Computat Med, Oulu, Finland.
3Bioctr Oulu, Oulu, Finland.
4Univ Oxford, Med Res Council, Populat Hlth Res Unit, Oxford, England.
5Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford, England.
6Univ Oxford, Epidemiol Studies Unit, Nuffield Dept Populat Hlth, Oxford, England.
7Oxford Univ Hosp, Oxford Biomed Res Ctr, Natl Inst Hlth Res, Oxford, England.
8Univ Bristol, Med Res Council, Integrat Epidemiol Unit, Bristol, Avon, England.
9Univ Cambridge, MRC BHF Cardiovasc Epidemiol Unit, Dept Publ Hlth & Primary Care, Cambridge, England.
10Univ Cambridge, Homerton Coll, Cambridge, England.
11Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
12Baker Heart & Diabet Inst, Syst Epidemiol, Melbourne, Vic, Australia.
13Univ Oulu, Fac Med, Northern Finland Birth Cohorts, Oulu, Finland.
14Imperial Coll London, Sch Publ Hlth, Dept Genom Complex Dis, London, England.
15Chinese Acad Med Sci, Beijing, Peoples R China.
16Peking Univ, Sch Publ Hlth, Dept Global Hlth, Beijing, Peoples R China.
17Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
18Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.
19Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands.
20Natl Inst Hlth & Welf, Helsinki, Finland.
21Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.
22Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
23Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London, England.
24Oulu Univ Hosp, Unit Primary Care, Oulu, Finland.
25Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England.
26Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland.
27Monash Univ, Alfred Hosp, Dept Epidemiol & Prevent Med, Sch Publ Hlth & Prevent Med,Fac Med Nursing & Hlt, Melbourne, Vic, Australia.
28Univ Cambridge, Natl Inst Hlth Res, Blood & Transplant Res Unit Donor Hlth & Genom, Cambridge, England.
29Wellcome Trust Sanger Inst, Hinxton, England.
30Nightingale Hlth Ltd, Mannerheimintie 164a, Helsinki 00300, Finland.
31Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
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Language: English
Published: Wolters Kluwer, 2018
Publish Date: 2021-03-25


Background: Both statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these 2 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: Two hundred twenty-eight circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5359 individuals (2659 on treatment) in the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial at 6 months postrandomization. The corresponding metabolic measures were analyzed in 8 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 low-density lipoprotein cholesterol, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R²=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of very-low-density lipoprotein cholesterol compared with statin therapy (54% versus 77% reduction, relative to the lowering effect on low-density lipoprotein cholesterol; P=2×10⁻⁷ for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA), whereas statin treatment weakly lowered GlycA levels.

Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on very-low-density lipoprotein lipids compared with statins for an equivalent lowering of low-density lipoprotein cholesterol, which potentially translate into smaller reductions in cardiovascular disease risk.

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Series: Circulation
ISSN: 0009-7322
ISSN-E: 1524-4539
ISSN-L: 0009-7322
Volume: 138
Issue: 22
Pages: 2499 - 2512
DOI: 10.1161/CIRCULATIONAHA.118.034942
Type of Publication: A1 Journal article – refereed
Field of Science: 3142 Public health care science, environmental and occupational health
3121 General medicine, internal medicine and other clinical medicine
Funding: 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). Dr Holmes 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 Center. Dr Wang was supported by a Novo Nordisk Foundation Postdoctoral Fellowship (grant number NNF17OC0027034). Dr Rankin 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 Program of the 7th Framework Program (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 Program 7 (HEALTH-F2-2012–279233). Data collection and metabolic profiling in the ALSPAC mother’s study were obtained from British Heart Foundation (SP/07/008/24066) and the Wellcome Trust (WT092830M). Genetic data in the ALSPAC mothers was obtained through funding from the Wellcome Trust (WT088806). ALSPAC offspring genetic data were obtained with support from 23andMe. The FINRISK studies have received financial support related to the present study from the National Institute for Health and Welfare, the Academy of Finland (139635), and the Finnish Foundation for Cardiovascular Research. Northern Finland Birth Cohort studies received funding support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant No. 50621, 54231. NFBC1986 received financial support from EU QLG1-CT-2000-01643 (EUROBLCS) Grant no. E51560, Nordic Academy for Advanced Study Grant no. 731, 20056, 30167, USA / NIHH 2000 G DF682 Grant no. 50945. The China Kadoorie Biobank baseline survey and first resurvey was supported by the Kadoorie Charitable Foundation in Hong Kong. Long-term follow-up has been supported by the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), National Key Research and Development Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504), Chinese Ministry of Science and Technology (2011BAI09B01), and National Natural Science Foundation of China (Grants No. 81390540, No. 81390541, No. 81390544). NMR metabolomics of China Kadoorie Biobank was supported by the British Heart Foundation Center of Research Excellence, Oxford (RE/13/1/30181).
Academy of Finland Grant Number: 297338
Detailed Information: 297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
Copyright information: © 2018 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.