Pharmacometabolomic signature links simvastatin therapy and insulin resistance

Mona Elbadawi-Sidhu, Rebecca A. Baillie, Hongjie Zhu, Yii Der Ida Chen, Mark O. Goodarzi, Jerome I. Rotter, Ronald M. Krauss, Oliver Fiehn, Rima Kaddurah-Daouk

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number11
JournalMetabolomics
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2017

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Simvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Insulin Resistance
Drug therapy
Insulin
Medical problems
Biosynthesis
Biomarkers
Metabolites
Metabolism
Pharmaceutical Preparations
Therapeutics
Branched Chain Amino Acids
Hydroxylamine
Ethanolamine
Hyperglycemia
Type 2 Diabetes Mellitus
Isoleucine
Gas chromatography
LDL Cholesterol

Keywords

  • Diabetes and hyperglycemia
  • Insulin resistance
  • Metabolic profiling
  • Metabolomics
  • Personalized medicine
  • Pharmacometabolomics
  • Pharmacometabonomics
  • Precision medicine
  • Simvastatin
  • Statin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry

Cite this

Elbadawi-Sidhu, M., Baillie, R. A., Zhu, H., Chen, Y. D. I., Goodarzi, M. O., Rotter, J. I., ... Kaddurah-Daouk, R. (2017). Pharmacometabolomic signature links simvastatin therapy and insulin resistance. Metabolomics, 13(1), [11]. https://doi.org/10.1007/s11306-016-1141-3

Pharmacometabolomic signature links simvastatin therapy and insulin resistance. / Elbadawi-Sidhu, Mona; Baillie, Rebecca A.; Zhu, Hongjie; Chen, Yii Der Ida; Goodarzi, Mark O.; Rotter, Jerome I.; Krauss, Ronald M.; Fiehn, Oliver; Kaddurah-Daouk, Rima.

In: Metabolomics, Vol. 13, No. 1, 11, 01.01.2017.

Research output: Contribution to journalArticle

Elbadawi-Sidhu, M, Baillie, RA, Zhu, H, Chen, YDI, Goodarzi, MO, Rotter, JI, Krauss, RM, Fiehn, O & Kaddurah-Daouk, R 2017, 'Pharmacometabolomic signature links simvastatin therapy and insulin resistance', Metabolomics, vol. 13, no. 1, 11. https://doi.org/10.1007/s11306-016-1141-3
Elbadawi-Sidhu M, Baillie RA, Zhu H, Chen YDI, Goodarzi MO, Rotter JI et al. Pharmacometabolomic signature links simvastatin therapy and insulin resistance. Metabolomics. 2017 Jan 1;13(1). 11. https://doi.org/10.1007/s11306-016-1141-3
Elbadawi-Sidhu, Mona ; Baillie, Rebecca A. ; Zhu, Hongjie ; Chen, Yii Der Ida ; Goodarzi, Mark O. ; Rotter, Jerome I. ; Krauss, Ronald M. ; Fiehn, Oliver ; Kaddurah-Daouk, Rima. / Pharmacometabolomic signature links simvastatin therapy and insulin resistance. In: Metabolomics. 2017 ; Vol. 13, No. 1.
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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-na{\"i}ve 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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AU - Baillie, Rebecca A.

AU - Zhu, Hongjie

AU - Chen, Yii Der Ida

AU - Goodarzi, Mark O.

AU - Rotter, Jerome I.

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AU - Kaddurah-Daouk, Rima

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N2 - 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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KW - Metabolomics

KW - Personalized medicine

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KW - Pharmacometabonomics

KW - Precision medicine

KW - Simvastatin

KW - Statin

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