Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study

J Thromb Haemost. 2016 Jan;14(1):129-33. doi: 10.1111/jth.13187. Epub 2015 Dec 29.


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.

Objectives: 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.

Patients/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.

Conclusion: 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.

Keywords: antidiabetic drugs; drug interactions; pharmacoepidemiology; phenprocoumon; warfarin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anticoagulants / administration & dosage*
  • Blood Glucose / analysis*
  • Blood Glucose / chemistry
  • Blood Glucose / drug effects
  • Drug Interactions
  • Female
  • Fibrinolytic Agents / administration & dosage
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • International Normalized Ratio
  • Male
  • Metformin / administration & dosage
  • Middle Aged
  • Phenprocoumon / administration & dosage
  • Registries
  • Retrospective Studies
  • Vitamin K / antagonists & inhibitors*
  • Warfarin / administration & dosage


  • Anticoagulants
  • Blood Glucose
  • Fibrinolytic Agents
  • Hypoglycemic Agents
  • Vitamin K
  • Warfarin
  • Metformin
  • Phenprocoumon