Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment
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Abstract
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 ( R 2 =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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CETP inhibitors exert their relatively modest cardioprotective effects on the basis that in addition to their HDL-C raising effects, more potent CETP inhibitors also lower apolipoprotein B.
“CETP inhibitors exert their relatively modest cardioprotective effects on the basis that in addition to their HDL-C raising effects, more potent CETP inhibitors also lower apolipoprotein B 22,23,75 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [75]
Had CETP not exerted such apolipoprotein B lowering effects, then all trials of CETP inhibitors (including that of anacetrapib) would have likely failed owing to lack of efficacy.
“Had CETP not exerted such apolipoprotein B lowering effects, then all trials of CETP inhibitors (including that of anacetrapib 75 ) would have likely failed owing to lack of efficacy.”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [75]
REVEAL trial of anacetrapib demonstrated evidence of vascular benefit; RCTs of apoA-I infusion have thus far not shown benefit.
“REVEAL trial of anacetrapib 75 demonstrated evidence of vascular benefit; RCTs of apoA-I infusion 111 have thus far not shown benefit”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [75]
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Self-citationAdditional file 1 of A phenome-wide association study of genetically mimicked statins
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Self-citationAdditional file 1 of Low levels of small HDL particles predict but do not influence risk of sepsis
Hamilton, F., Pedersen, K. M., Ghazal, P., Nordestgaard, B. G., & Smith, G. D. (2024) · Figshare · doi:10.6084/m9.figshare.26624815
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Self-citationAdditional file 5 of Low levels of small HDL particles predict but do not influence risk of sepsis
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Self-citationAdditional file 3 of Low levels of small HDL particles predict but do not influence risk of sepsis
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Self-citationAdditional file 4 of Low levels of small HDL particles predict but do not influence risk of sepsis
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Self-citationAdditional file 2 of Low levels of small HDL particles predict but do not influence risk of sepsis
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Self-citation
- Authors
- Sliz, E., Kettunen, J., Holmes, M. V., Williams, C. O., Boachie, C., Wang, Q., Männikkö, M., Sebert, S., Walters, R., Lin, K., Millwood, I. Y., Clarke, R., Li, L., Rankin, N., Welsh, P., Delles, C., Jukema, J. W., Trompet, S., Ford, I., Perola, M., Salomaa, V., Järvelin, M.-R., Chen, Z., Lawlor, D. A., Ala-Korpela, M., Danesh, J., Davey Smith, G., Sattar, N., Butterworth, A., & Würtz, P.
- Affiliations
- University of Oulu (FI)
- National Institute for Health and Care Research (GB)
- MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (C.O.W., J.D., A.B.), University of Cambridge, United Kingdom.
- University of Glasgow (GB)
- Baker Heart and Diabetes Institute (AU)
- Imperial College London (GB)
- University of Oxford (GB)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Leiden University Medical Center (NL)
- University of Helsinki (FI)
- Finnish Institute for Health and Welfare (FI)
- Oulu University Hospital (FI)
- University of Bristol (GB)
- Center for Life Course Health Research (E.S., J.K., Q.W., S.S., M.-R.J., M.A.-K.), University of Oulu, Finland.
- University of Cambridge (GB)
- Medical Research Council Integrative Epidemiology Unit (M.V.H., D.A.L., M.A.-K., G.D.S.), University of Bristol, United Kingdom.
- Corresponding author
- Würtz, Peter
- ORCID
- Sliz, Eeva
- Kettunen, Johannes
- Holmes, Michael V.
- Boachie, Charles
- Wang, Qin
- Männikkö, Minna
- Sebert, Sylvain
- Walters, Robin
- Millwood, Iona Y.
- Clarke, Robert
- Li, Liming
- Rankin, Naomi
- Welsh, Paul
- Delles, Christian
- Jukema, J. Wouter
- Trompet, Stella
- Ford, Ian
- Perola, Markus
- Salomaa, Veikko
- Järvelin, Marjo-Riitta
- Chen, Zhengming
- Lawlor, Debbie A.
- Danesh, John
- Sattar, Naveed
- Butterworth, Adam
- Würtz, Peter
- Venue
- Circulation
- Published
- 2018-11-27
- Volume
- 138
- Issue
- 22
- Pages
- 2499-2512
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC6254781
- OpenAlex
- W2789775146
- Cited by
- 109
- References
- 51
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 16 · 2023: 24 · 2022: 8 · 2021: 21 · 2020: 11 · 2019: 11 · 2018: 1 · 2017: 1
- FWCI
- 11.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Circulation (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Leiden Repository (Leiden University) (submittedVersion)
- UEF eRepo (University of Eastern Finland) (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Explore Bristol Research (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo (cc-by)
- Apollo
- Greater South Information System
- WOS
- Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Biogen
- Foundation for Cardiovascular Research
- Itä-Suomen Yliopisto
- Helsingin Yliopisto
- Wellcome Trust (139635, 2016YFC0900504, 212946/Z/18/Z, 202922, 102215/2/13/2), 104085, 81390544, 2016YFC0900501, 202922/Z/16/Z, 2016YFC 0900500, 733206, 088158/Z/09/Z, 102215, RE/13/1/30181, 104085/Z/14/Z, 088158, WT088806, 81390540, 2011BAI09B01, 81390541)
- Mylan
- Cancer Research UK (102215/2/13/2, 088158/Z/09/Z, 2016YFC0900501, 2016YFC0900500, 2016YFC0900504, 104085/Z/14/Z, 81390540, RE/13/1/30181, 202922/Z/16/Z)
- National Institute for Health and Care Research (NF-SI-0617-10113, NF-SI-0512-10165, WT088806)
- British Heart Foundation (104085/Z/14/Z, G0800270, RE/13/1/30181, SP/09/002, SP/07/008/24066, 088158/Z/09/Z, 2016YFC0900500, 2016YFC0900501, RG/13/13/30194, 81390540, 202922/Z/16/Z, FS/18/23/33512, 2016YFC0900504)
- Imperial College London (H2020)
- University of Oxford (RE/13/1/30181, 104085/Z/14/Z, 202922/Z/16/Z, 088158/Z/09/Z)
- European Commission (WT088806, 633595, 733206, H2020, 279233, 115372, 305507)
- University of Glasgow
- University of Bristol (102215/2/13/2)
- Universiteit Leiden
- Monash University
- National Natural Science Foundation of China (2016YFC0900504, 81390544, 2016YFC0900500, 104085/Z/14/Z, 81390541, 202922/Z/16/Z, 088158/Z/09/Z, 2016YFC0900501, 81390540, 2011BAI09B01)
- Academy of Finland (285547, 633595)
- Ministry of Science and Technology of the People's Republic of China (202922/Z/16/Z, 2011BAI09B01, 088158/Z/09/Z, 81390544, 81390541, 2016YFC0900501, 2016YFC 0900500, 2016YFC0900504, 81390540, 104085/Z/14/Z)
- Novo Nordisk
- State Government of Victoria
- Leids Universitair Medisch Centrum
- Chinese Academy of Medical Sciences
- BHF Centre of Research Excellence, Oxford (RE/13/1/30 181)
- Sydäntutkimussäätiö (633595)
- Oulun Yliopisto
- Tutkijakoulu, Oulun Yliopiston
- Tartu Ülikool
- Peking University
- Novo Nordisk Fonden (NNF17OC0026062, NNF17OC0027034)
- Terveyden ja hyvinvoinnin laitos
- Baker Heart and Diabetes Institute
- MRC-PHE Centre for Environment and Health
- Centers for Disease Control and Prevention
- Horizon 2020 Framework Programme (733,206, 633595)
- Medical Research Council (MC_PC_13049, 102215, MR/N005813/1, WT088806, 2016YFC0900500, 13/1/30181, MC_PC_12026, RE/13/1/30181, 104085/Z/14/Z, SP/09/002, 088158/Z/09/Z, 2016YFC0900501, 202922/Z/16/Z, 633595, 102215/2/13/2, G0800270, 2016YFC0900504, MC_UU_00011/1, MC_PC_14135, 81390540, MR/L003120/1)
- National Key Research and Development Program of China (088158/Z/09/Z, 2016YFC0900500, 202922/Z/16/Z, 104085/Z/14/Z, 81390544, 2016YFC0900501, 81390541, 81390540, 2011BAI09B01, 2016 YFC0900504)
- School of Public Health, Imperial College London
- Biocenter, University of Oulu
- FP7 Ideas: European Research Council (268834)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- PCSK9 inhibitors, statins, LDL cholesterol lowering, VLDL cholesterol, lipoprotein lipid composition, fatty acids, amino acids, glycated proteins, cardiovascular risk, PROSPER trial
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Aged, Aged, 80 and over, Amino Acids, Cardiovascular Diseases, Double-Blind Method, Female, Humans, Cholesterol, LDL, Male, Cholesterol, VLDL, Placebo Effect, Pravastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Metabolomics, Mendelian Randomization Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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