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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus

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BACKGROUND: Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response to ARBs in patients with diabetes mellitus and micro- or macroalbuminuria.

METHODS: Liquid chromatography-tandem mass spectrometry metabolomics was performed on serum samples. Data from patients with type 2 diabetes and microalbuminuria (n = 49) treated with irbesartan 300 mg/day were used for discovery. LASSO and ridge regression were performed to develop the classifier. Improvement in albuminuria response prediction was assessed by calculating differences in R(2) between a reference model of clinical parameters and a model with clinical parameters and the classifier. The classifier was externally validated in patients with type 1 diabetes and macroalbuminuria (n = 50) treated with losartan 100 mg/day. Molecular process analysis was performed to link metabolites to molecular mechanisms contributing to ARB response.

RESULTS: In discovery, median change in urinary albumin excretion (UAE) was -42 % [Q1-Q3: -69 to -8]. The classifier, consisting of 21 metabolites, was significantly associated with UAE response to irbesartan (p < 0.001) and improved prediction of UAE response on top of the clinical reference model (R(2) increase from 0.10 to 0.70; p < 0.001). In external validation, median change in UAE was -43 % [Q1-Q35: -63 to -23]. The classifier improved prediction of UAE response to losartan (R(2) increase from 0.20 to 0.59; p < 0.001). Specifically ADMA impacting eNOS activity appears to be a relevant factor in ARB response.

CONCLUSIONS: A serum metabolite classifier was discovered and externally validated to significantly improve prediction of albuminuria response to ARBs in diabetes mellitus.

Original languageEnglish
JournalJournal of Translational Medicine
Volume14
Issue number1
Pages (from-to)203
ISSN1479-5876
DOIs
Publication statusPublished - 5 Jul 2016

    Research areas

  • Journal Article

ID: 49713672