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

Peter Würtz, Qin Wang, Pasi Soininen, Antti J. Kangas, Ghazaleh Fatemifar, Tuulia Tynkkynen, Mika Tiainen, Markus Perola, Therese Tillin, Alun D. Hughes, Pekka Mäntyselkä, Mika Kähönen, Terho Lehtimäki, Naveed Sattar, Aroon D. Hingorani, Juan-Pablo Casas, Veikko Salomaa, Mika Kivimäki, Marjo-Riitta Järvelin, George Davey SmithMauno Vanhala, Debbie A. Lawlor, Olli T. Raitakari, Nish Chaturvedi, Johannes Kettunen, Mika J Ala-Korpela

Research output: Contribution to journalArticle (Academic Journal)peer-review

77 Citations (Scopus)
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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 (R2 = 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.
Original languageEnglish
Pages (from-to)1200-1210
Number of pages11
JournalJournal of the American College of Cardiology
Volume67
Issue number10
Early online date7 Mar 2016
DOIs
Publication statusPublished - 15 Mar 2016

Keywords

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

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