PT-027 - DO GLUCOSE-LOWERING DRUGS AFFECT DRUG METABOLISM AND WARFARIN EFFICACY?

A. Dunvald¹, F. Nielsen¹, J. Madsen², J. Søndergaard¹, E. Pearson³, A. Pottegård¹, T. Stage^1,4; ¹University of Southern Denmark, Odense, Denmark, ²Lillebaelt Hospital, Vejle, Denmark, ³University of Dundee, Dundee, Scotland, ⁴Odense University Hospital, Odense, Denmark.

Background: We have previously shown that initiation of glucose-lowering drugs reduces the anticoagulant efficacy of warfarin. We aimed to confirm this effect and understand the underlying mechanism of this putative drug-drug interaction (DDI) using a translational approach.

Methods: We conducted a self-controlled register-based cohort study in Danish and Scottish cohorts of warfarin users (n=1026). We identified new users of a glucose-lowering drug and assessed the International Normalized Ratio (INR) before and after initiation, overall and stratified by the glycemic response (change in HbA1c). To gain mechanistic insight, we conducted a self-controlled clinical pharmacokinetic study comprising ten patients with treatment-naïve type 2 diabetes. Before and after three and 12 weeks of metformin treatment, patients ingested the Basel Cocktail (caffeine (CYP1A2), efavirenz (CYP2B6), losartan (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)).

Results: INR decreased 5-7 weeks after initiation of glucose-lowering treatment by -0.26 (95% CI: -0.35;-0.17) and -0.21 (95% CI: -0.52;0.11) in the Danish and Scottish cohorts, respectively. Patients with a strong effect of glucose-lowering treatment had a more pronounced reduction in INR. The pharmacokinetic trial found clinically and statistically insignificant changes in CYP enzyme activity after three weeks and 12 weeks of metformin treatment (geometric mean ratio of CYP3A4 metabolic ratio: 1.12 (95% CI: 0.95;1.32) and 1.16 (95% CI: 0.93;1.44), respectively).

Conclusion: Initiation of glucose-lowering drugs among chronic warfarin users is associated with decreased INR values of potential clinical importance. The observed DDI appears to be unrelated to warfarin drug metabolism. Further mechanistic studies should aim to understand this DDI.