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J Am Coll Cardiol. 2016 Mar 15;67(10):1200-1210. doi: 10.1016/j.jacc.2015.12.060.

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase.

Author information

1
Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland. Electronic address: peter.wurtz@computationalmedicine.fi.
2
Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
3
Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland.
4
Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
5
National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; University of Tartu, Estonian Genome Center, Tartu, Estonia.
6
Institute of Cardiovascular Science, University College London, London, United Kingdom.
7
Primary Health Care, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
8
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
9
Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, Tampere, Finland.
10
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
11
Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
12
National Institute for Health and Welfare, Helsinki, Finland.
13
Department of Epidemiology and Public Health, University College London, London, United Kingdom; Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
14
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Helsinki, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, Imperial College London, London, United Kingdom; Oulu University Hospital, Oulu, Finland.
15
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
16
Primary Health Care, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; Primary Health Care, Central Finland Central Hospital, Jyväskylä, Finland.
17
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
18
Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Oulu University Hospital, Oulu, Finland; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; Computational Medicine, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom. Electronic address: mika.ala-korpela@computationalmedicine.fi.

Abstract

BACKGROUND:

Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized.

OBJECTIVES:

This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways.

METHODS:

Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts.

RESULTS:

Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R(2) = 0.94, slope 1.00 ± 0.03).

CONCLUSIONS:

Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.

KEYWORDS:

Mendelian randomization; cholesterol lowering; drug development; lipoproteins; metabolomics

PMID:
26965542
PMCID:
PMC4783625
DOI:
10.1016/j.jacc.2015.12.060
[Indexed for MEDLINE]
Free PMC Article

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