Assistant Professor London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT London, United Kingdom
Background: A number of observational studies and small trials have suggested that higher levels of circulating vitamin K1 might improve insulin sensitivity, and therefore protect against the development of Type II Diabetes (T2DM). We hypothesised that treatment with vitamin K-inhibitors, such as warfarin, may lead to an increased risk of developing T2DM compared to alternative oral anticoagulants (OACs).
Objectives: To compare the risk of T2DM onset among atrial fibrillation (AF) patients initiating warfarin vs direct-acting oral anticoagulants (DOACs).
Methods: We included AF patients with no history of diabetes newly prescribed OACs in Clinical Practice Research Datalink (CPRD) Aurum between 01.01.2013 and 31.01.2019. Patients were followed from 30 days after the first OAC prescription to 21.01.2020, death, de-registration or the first occurrence of a diagnostic code for T2DM. Potential confounders were identified using a directed acyclic graph, and adjusted hazard ratios (aHR) were obtained from a cox regression comparing the risk of T2DM between warfarin and DOAC initiators. We investigated a-priori interactions with gender and age and conducted subgroup analyses according to type of DOAC.
Results: A total of 94,394 OAC initiators (63,789 DOAC initiators and 30,605 warfarin initiators) were included, 46.3% were female and the average age was 74.7 (SD 11.6) years. After a mean follow-up of 2.8 years (IQR 1.5-4.2) 7,041 patients developed T2DM, with the crude Kaplan-Meier risk slightly lower among DOAC initiators (11.6%, 95%CI=11.1 – 12.1) compared to warfarin initiators (13.2%, 95%CI = 12.7 – 13.6). After adjusting for potential confounders, a modest protective association between DOACs and incident T2DM was found (aHR=0.94, 95%CI 0.89-0.99; p=0.02). No interaction by age group or gender was observed (p=0.10 and 0.47, respectively). Subgroup analyses were consistent, with potentially somewhat more marked protective effects for initiators of dabigatran and rivaroxaban compared to warfarin, although confidence intervals were wide [HR=0.87 (95%CI 0.77-0.98) and HR=0.93 (95%CI 0.88-0.99), respectively]. Sensitivity analyses applying a lagged index date (initiation + 180 days) led to consistent results.
Conclusions: Use of DOACs compared to warfarin was associated with a relatively modest reduction in the risk of developing T2DM in this cohort, in contrast to previous studies reporting strong protective effects. We did not find any evidence that the association differed according to patient gender or age.
