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

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

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Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Pharmacometrics Group, Department of Biosciences, Uppsala University, Uppsala, Sweden.
Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
Department of Endocrinology, Odense University Hospital, Odense, Denmark.


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.


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.


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.


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.


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.


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.


antidiabetic drugs; drug interactions; pharmacoepidemiology; phenprocoumon; warfarin

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