title: Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  A serum metabolite classifier was discovered and externally validated to significantly improve prediction of albuminuria response to ARBs in diabetes mellitus.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, P. O. Box 30.001, 9700RB, Groningen, The Netherlands.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Pena
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinzel
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.|Faculty of Health Science, University of Aarhus, Aarhus, Denmark.|University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Department of Medical Endocrinology, Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.affiliation: Biocrates Life Sciences AG, Innsbruck, Austria.
authors.forename: Guido
authors.initials: G
authors.lastname: Dallmann
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Rossing
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Andersen
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, P. O. Box 30.001, 9700RB, Groningen, The Netherlands. h.j.lambers.heerspink@umcg.nl.
authors.forename: Hiddo J L
authors.initials: HJ
authors.lastname: Heerspink
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000097:blood / Q000150:complications; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D000077405:Irbesartan; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D055442:Metabolome / Q000187:drug effects; D008875:Middle Aged; D008958:Models, Molecular; D013777:Tetrazoles / Q000627:therapeutic use
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan; D019808:Losartan
keywords: ARB response; Albuminuria; Metabolomics