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2017 ; 13
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Pharmacometabolomic signature links simvastatin therapy and insulin resistance
#MMPMID29732238
Elbadawi-Sidhu M
; Baillie RA
; Zhu H
; Chen YI
; Goodarzi MO
; Rotter JI
; Krauss RM
; Fiehn O
; Kaddurah-Daouk R
Metabolomics
2017[Jan]; 13
(ä): ä PMID29732238
show ga
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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