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Circulation. 2018 Nov 27;138(22):2499-2512. doi: 10.1161/CIRCULATIONAHA.118.034942. Epub 2018 Aug 15.

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment.

Sliz E1,2, Kettunen J1,2,3, Holmes MV4,5,6,7, Williams CO8,9, Boachie C10, Wang Q1,2,3,11, Männikkö M12, Sebert S1,2,13, Walters R5, Lin K5, Millwood IY5, Clarke R5, Li L14,15, Rankin N16, Welsh P16, Delles C16, Jukema JW17, Trompet S17,18, Ford I10, Perola M19,20,21, Salomaa V19, Järvelin MR1,2,22,23, Chen Z5, Lawlor DA7,24, Ala-Korpela M1,2,3,7,11,24,25,26, Danesh J8,27,28, Davey Smith G7,24, Sattar N16, Butterworth A8,27, Würtz P29,30.

Author information

1
Center for Life Course Health Research, University of Oulu, Oulu, Finland.
2
Biocenter Oulu, Oulu, Finland.
3
Computational Medicine, Faculty of Medicine, University of Oulu, Finland.
4
Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
5
Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
6
National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.
7
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
8
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
9
Homerton College, University of Cambridge, Cambridge, UK.
10
Robertson Centre for Biostatistics, Boyd Orr Building, University of Glasgow, Glasgow, UK.
11
Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
12
Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.
13
Department of Genomics of Complex Diseases, School of Public Health, Imperial College London, UK.
14
Chinese Academy of Medical Sciences, 9 Dongdan San Tiao, Beijing, China.
15
Department of Global Health, School of Public Health, Peking University, Beijing, China.
16
Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
17
Leiden University Medical Centre, Leiden, The Netherlands.
18
Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
19
National Institute for Health and Welfare, Helsinki, Finland.
20
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
21
University of Tartu, Estonian Genome Center, Tartu, Estonia.
22
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
23
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
24
Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
25
NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
26
Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, VIC, Australia.
27
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom.
28
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
29
Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
30
Nightingale Health Ltd, Helsinki, Finland.

Abstract

Background:

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 distribution were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 had 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 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 VLDL lipids compared with statins for an equivalent lowering of LDL-C, which potentially translate into smaller reductions in cardiovascular disease risk.

KEYWORDS:

Mendelian randomization; PCSK9; lipids and lipoprotein metabolism; metabolomics; statin therapy

PMID:
30524137
PMCID:
PMC6254781
[Available on 2019-11-27]
DOI:
10.1161/CIRCULATIONAHA.118.034942

Conflict of interest statement

Conflict of Interest Disclosures PW is employee and shareholder of Nightingale Health Ltd, a company offering NMR based metabolic profiling. JK reports stock options in Nightingale Health. The Clinical Trial Service Unit & Epidemiological Studies Unit (MVH, RW, KL, IM, RC, ZC) has received research grants from Abbott/Solvay/Mylan, AstraZeneca, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, and Schering. MVH has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. VS has received a conference trip and an honorarium from Novo Nordisk. DAL has received support from several government and charity health research funders and from Roche Diagnostics and Medtronic for research unrelated to that published here. NS has consulted or been on the speaker bureau for AstraZeneca, Amgen, Sanofi, Boehringer Ingelheim, Janssen, Novo Nordisk and Eli-Lilly. He has also received funding from Boehringer Ingelheim. ASB has received grants from Merck, Pfizer, Biogen, Bioverativ and AstraZeneca. No other authors reported disclosures.

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