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Pharmacometabolomic signature links simvastatin therapy and insulin resistance

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Abstract

Introduction

Statins, widely prescribed drugs for treatment of cardiovascular disease, inhibit the biosynthesis of low density lipoprotein cholesterol (LDL-C). Despite providing major benefits, sub populations of patients experience adverse effects, including muscle myopathy and development of type II diabetes mellitus (T2DM) that may result in premature discontinuation of treatment. There are no reliable biomarkers for predicting clinical side effects in vulnerable individuals. Pharmacometabolomics provides powerful tools for identifying global biochemical changes induced by statin treatment, providing insights about drug mechanism of action, development of side effects and basis of variation of response.

Objective

To determine whether statin-induced changes in intermediary metabolism correlated with statin-induced hyperglycemia and insulin resistance; to identify pre-drug treatment metabolites predictive of post-drug treatment increased diabetic risk.

Methods

Drug-naïve patients were treated with 40 mg/day simvastatin for 6 weeks in the Cholesterol and Pharmacogenetics (CAP) study; metabolomics by gas chromatography-time-of-flight mass-spectrometry (GC–TOF–MS) was performed on plasma pre and post treatment on 148 of the 944 participants.

Results

Six weeks of simvastatin treatment resulted in 6.9% of patients developing hyperglycemia and 25% developing changes consistent with development of pre-diabetes. Altered beta cell function was observed in 53% of patients following simvastatin therapy and insulin resistance was observed in 54% of patients. We identified initial signature of simvastatin-induced insulin resistance, including ethanolamine, hydroxylamine, hydroxycarbamate and isoleucine which, upon further replication and expansion, could be predictive biomarkers of individual susceptibility to simvastatin-induced new onset pre-type II diabetes mellitus. No patients were clinically diagnosed with T2DM.

Conclusion

Within this short 6 weeks study, some patients became hyperglycemic and/or insulin resistant. Diabetic markers were associated with decarboxylated small aminated metabolites as well as a branched chain amino acid directly linked to glucose metabolism and fatty acid biosynthesis. Pharmacometabolomics provides powerful tools for precision medicine by predicting development of drug adverse effects in sub populations of patients. Metabolic profiling prior to start of drug therapy may empower physicians with critical information when prescribing medication and determining prognosis.

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Funding

This work is supported by National Institute of General Medical Sciences Grants R24 GM078233 and RC2GM092729 for RKD ; and U01 HL069757, “Pharmacogenomics and Risk of Cardiovascular Disease” (RMK) and by NIH Grant DK097154 (ME-S and OF) is acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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    Authors and Affiliations

    1. West Coast Metabolomics Center, Genome Center, University of California - Davis, Davis, CA, USA

      Mona Elbadawi-Sidhu & Oliver Fiehn

    2. Rosa & Co LLC, 751 Laurel St., Ste. 127, San Carlos, CA, 94070, USA

      Rebecca A. Baillie

    3. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

      Hongjie Zhu

    4. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research, Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA

      Yii-Der Ida Chen & Jerome I. Rotter

    5. Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

      Mark O. Goodarzi

    6. Children’s Hospital Oakland Research Institute, Oakland, CA, USA

      Ronald M. Krauss

    7. Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia

      Oliver Fiehn

    8. Department of Internal Medicine; Department of Psychiatry and Behavioral Sciences, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC, USA

      Rima Kaddurah-Daouk

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    1. Mona Elbadawi-Sidhu
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    Correspondence to Ronald M. Krauss, Oliver Fiehn or Rima Kaddurah-Daouk.

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    The authors declare that they do not have any conflicts of interest.

    Ethical approval

    Approval for the analysis of simvastatin response in the CAP study was granted by the Children’s Hospital and Research Center Institutional Review Board, University of California San Francisco Committee on Human Research, and University of California Los Angeles Office of the Human Research Protection Program.

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    We obtained written, informed consent from all participants for inclusion in the original study and future studies. The research was conducted in accordance with the Declaration of Helsinki.

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    Mona Elbadawi-Sidhu, Rebecca A. Baillie and Hongjie Zhu have equally contributed to this work.

    Trial Registration: ClinicalTrials.gov NCT00451828.

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    Elbadawi-Sidhu, M., Baillie, R.A., Zhu, H. et al. Pharmacometabolomic signature links simvastatin therapy and insulin resistance. Metabolomics 13, 11 (2017). https://doi.org/10.1007/s11306-016-1141-3

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