Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin—But not through altered drug metabolism in patients with type 2 diabetes

TY - JOUR

T1 - Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin—But not through altered drug metabolism in patients with type 2 diabetes

AU - Dunvald, Ann-Cathrine Dalgård

AU - Nielsen, Flemming

AU - Olsen, Dorte Aalund

AU - Ernst, Martin Thomsen

AU - Donnelly, Louise

AU - Soto-Pedre, Enrique

AU - Kristiansen, Maja Refshauge

AU - Nielsen, Jens Steen

AU - Persson, Frederik

AU - Højlund, Kurt

AU - Madsen, Jonna Skov

AU - Søndergaard, Jens

AU - Pearson, Ewan

AU - Pottegård, Anton

AU - Stage, Tore Bjerregaard

N1 - Funding Information: This research was funded by Lundbeck Foundation Fellowship (R307-2018-2980). Copyright: © 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

PY - 2023/8

Y1 - 2023/8

N2 - Aims: Drug metabolism might be altered in patients with type 2 diabetes. We aimed to evaluate if initiation of glucose-lowering drugs impacts warfarin efficacy and drug metabolism. Methods: First, we conducted a register-based self-controlled cohort study on Danish and Scottish warfarin users. Warfarin efficacy (international normalized ratio [INR]) was compared before and after initiation of glucose-lowering drugs. Second, we conducted a clinical pharmacokinetic trial comprising treatment-naïve type 2 diabetes patients. Patients ingested probe drugs for drug-metabolizing enzymes (the Basel Cocktail) before initiating glucose-lowering treatment, and after 3 and 12 weeks of treatment. Drug metabolism, glycaemic control, and inflammation were assessed on each visit. Results: In the Danish and Scottish cohorts (n = 982 and n = 44, respectively), initiating glucose-lowering drugs reduced warfarin efficacy. INR decreased from 2.47 to 2.21 in the Danish cohort (mean difference −0.26; 95% CI −0.35; −0.17) and from 2.33 to 2.13 in the Scottish cohort (−0.21; 95% CI −0.52; 0.11) after initiation of glucose-lowering treatment. This impact on INR was more pronounced among individuals with stronger effects of glucose-lowering treatment. In the clinical pharmacokinetic trial (n = 10), initiating metformin did not affect drug metabolism after 3 weeks (geometric mean ratio of CYP3A metabolic ratio: 1.12 [95% CI: 0.95; 1.32]) or 12 weeks of metformin treatment. Glycaemic control improved during treatment, while inflammation remained low and unchanged during treatment. Conclusions: In conclusion, initiation of glucose-lowering drugs among chronic warfarin users seems associated with a reduction in INR, particularly among individuals with a large decrease in HbA 1c. This effect seems unrelated to CYP enzyme activity and warfarin drug metabolism.

AB - Aims: Drug metabolism might be altered in patients with type 2 diabetes. We aimed to evaluate if initiation of glucose-lowering drugs impacts warfarin efficacy and drug metabolism. Methods: First, we conducted a register-based self-controlled cohort study on Danish and Scottish warfarin users. Warfarin efficacy (international normalized ratio [INR]) was compared before and after initiation of glucose-lowering drugs. Second, we conducted a clinical pharmacokinetic trial comprising treatment-naïve type 2 diabetes patients. Patients ingested probe drugs for drug-metabolizing enzymes (the Basel Cocktail) before initiating glucose-lowering treatment, and after 3 and 12 weeks of treatment. Drug metabolism, glycaemic control, and inflammation were assessed on each visit. Results: In the Danish and Scottish cohorts (n = 982 and n = 44, respectively), initiating glucose-lowering drugs reduced warfarin efficacy. INR decreased from 2.47 to 2.21 in the Danish cohort (mean difference −0.26; 95% CI −0.35; −0.17) and from 2.33 to 2.13 in the Scottish cohort (−0.21; 95% CI −0.52; 0.11) after initiation of glucose-lowering treatment. This impact on INR was more pronounced among individuals with stronger effects of glucose-lowering treatment. In the clinical pharmacokinetic trial (n = 10), initiating metformin did not affect drug metabolism after 3 weeks (geometric mean ratio of CYP3A metabolic ratio: 1.12 [95% CI: 0.95; 1.32]) or 12 weeks of metformin treatment. Glycaemic control improved during treatment, while inflammation remained low and unchanged during treatment. Conclusions: In conclusion, initiation of glucose-lowering drugs among chronic warfarin users seems associated with a reduction in INR, particularly among individuals with a large decrease in HbA 1c. This effect seems unrelated to CYP enzyme activity and warfarin drug metabolism.

KW - clinical pharmacokinetic trial

KW - drug-drug interaction

KW - inflammation

KW - glucose-lowering drugs

KW - metformin

KW - observational study

KW - pharmacokinetic

KW - translational research

KW - type 2 diabetes

KW - drug–drug interaction

KW - pharmacokinetics

KW - warfarin

UR - https://www.scopus.com/pages/publications/85153249836

U2 - 10.1111/bcp.15725

DO - 10.1111/bcp.15725

M3 - Article

C2 - 36967527

SN - 0306-5251

VL - 89

SP - 2529

EP - 2541

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

IS - 8

ER -