title: Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study.
abstract: ESSENTIALS: It is not known if initiation of glucose-lowering drugs alters the efficacy of vitamin K antagonists (VKA). We examined if glucose-lowering drugs affected international normalized ratio (INR) in VKA-treated patients. Upon initiating glucose-lowering drugs, 51% of patients had INR values below the therapeutic window. Monitoring of INR levels should be intensified upon initiation of glucose-lowering drugs.
  
  
  BACKGROUND
  It is not known whether initiation of antidiabetic treatment affects the effect of vitamin K antagonists (VKAs). It was previously shown that metformin affects the effect of one VKA, phenprocoumon.
  
  
  OBJECTIVE
  The aim of this study was to determine if initiation of glucose-lowering treatment affects the international normalized ratio (INR) and dose requirements of the anticoagulant VKAs warfarin and phenprocoumon.
  
  
  METHODS
  We performed a self-controlled retrospective register-based study. A total of 118 patients commencing glucose-lowering treatment while being treated with warfarin or phenprocoumon were included in the study. We compared INR, dose/INR and proportion of patients with at least one sub-therapeutic INR measurement before and after initiation of glucose-lowering treatment.
  
  
  RESULTS
  Initiation of glucose-lowering treatment caused mean INR to decrease from 2.5 to 2.2 (decrease of -0.3 [95% CI: -0.1; -0.5]) and led to more than half of the patients having at least one sub-therapeutic INR measurement. Six to 12 weeks later, the VKA dose/INR was increased by 11%, indicating a weakened effect of the VKA.
  
  
  CONCLUSIONS
  Initiation of glucose-lowering treatment reduces the anticoagulant effect of VKAs to an extent that is likely to be clinically relevant. This finding needs confirmation and mechanistic explanation.
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.|Pharmacometrics Group, Department of Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: T B
authors.initials: TB
authors.lastname: Stage
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: A
authors.identifier: http://orcid.org/0000-0001-9314-5679
authors.initials: A
authors.lastname: Pottegård
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: D P
authors.identifier: http://orcid.org/0000-0003-1303-6195
authors.initials: DP
authors.lastname: Henriksen
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.|Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: M M H
authors.initials: MM
authors.lastname: Christensen
authors.affiliation: Department of Endocrinology, Odense University Hospital, Odense, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Højlund
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Brøsen
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.|Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Damkier
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001786:Blood Glucose / Q000032:analysis* / Q000737:chemistry / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D019934:International Normalized Ratio; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D008875:Middle Aged; D010644:Phenprocoumon / Q000008:administration & dosage; D012042:Registries; D012189:Retrospective Studies; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D014859:Warfarin / Q000008:administration & dosage
chemical_list: D000925:Anticoagulants; D001786:Blood Glucose; D005343:Fibrinolytic Agents; D007004:Hypoglycemic Agents; D014812:Vitamin K; D014859:Warfarin; D008687:Metformin; D010644:Phenprocoumon
keywords: antidiabetic drugs; drug interactions; pharmacoepidemiology; phenprocoumon; warfarin