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). The use of vitamin K-inhibitors, such as warfarin, may lead to an increased risk of developing T2DM compared to alternative oral anticoagulants (OACs). Objective: To compare the risk of developing T2DM among atrial fibrillation 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 to 31.01.2019. Patients were followed from 30 days after the first OAC prescription to 21.01.2020, death, deregistration or the first occurrence of a diagnostic code for T2DM. Potential confounders were identified using a directed acyclic graph, and Cox regression was used to calculate adjusted hazard ratios (aHR), comparing the hazard of T2DM between warfarin and DOAC initiators. We investigated a-priori interactions with sex and age and conducted subgroup analyses according to the type of DOAC. An on-treatment analysis was added post-hoc to take into account treatment switches and discontinuation. Results: A total of 94,394 OAC initiators were included, 46.34% were female, and the average age was 74.78 (SD 11.6) years. After a mean follow-up of 2.77 years (IQR 1.45-4.19), 7,041 patients developed T2DM, with the crude Kaplan-Meier risk slightly lower among DOAC initiators (13.58%, 95%CI=12.89 – 14.31) compared to warfarin initiators (15.53%, 95%CI = 14.99 – 16.09). After adjusting for a-priori identified confounders, a modest protective association between DOACs and incident T2DM was found (aHR=0.90, 95%CI 0.84-0.95; p<0.001). No interaction by age group or sex was observed (p=0.11 and 0.61, respectively). Subgroup analyses were consistent, with potentially somewhat more marked protective effects for initiators of edoxaban and dabigatran compared to warfarin, although confidence intervals were wide [HR=0.82 (95%CI 0.63-1.08) and HR=0.86 (95%CI 0.76-0.96), respectively]. Sensitivity analyses applying a lagged index date (initiation + 180 days) led to consistent results. On-treatment analysis showed a more marked protective effect, with an adjusted HR of 0.69 (0.65, 0.73). Conclusions: Treatment initiation with DOACs compared to warfarin was associated with a relatively modest reduction in the risk of developing T2DM in this cohort. We did not find any evidence that the association differed according to patient sex or age.

Purpose: There is increasing recognition of the importance of transparency and reproducibility in scientific research. This study aimed to quantify the extent to which programming code is publicly shared in pharmacoepidemiology, and to develop a set of recommendations on this topic. Methods: We conducted a literature review identifying all studies published in “Pharmacoepidemiology and Drug Safety” (PDS) between 2017 and 2022, Data was extracted on the frequency and types of programming code shared, and other key open science practices (clinical codelist sharing, data sharing, study pre-registration, and use of reporting guidelines). We developed six recommendations for investigators who choose to share to programming code and gathered feedback from members of the International Society of Pharmacoepidemiology (ISPE). Results: Programming code sharing by articles published in PDS ranged from 2.4% in 2017 to 13.4% in 2022. It was more prevalent among articles with a methodological focus, simulation studies, and papers which also shared record-level data. We recommend that reporting of open science practices, including code sharing, is standardised to enable continued monitoring. When sharing programming code, we recommend the use of permanent digital identifiers, appropriate licenses, and, where possible, adherence to good software practices around the provision of metadata and documentation, computational reproducibility, and data privacy. Conclusion: Programming code sharing is rare but increasing in pharmacoepidemiology studies published in Pharmacoepidemiology and Drug Safety. We recommend improved and consistent reporting of code sharing, and adherence to good programming practices in order to maximize the utility of code when this is shared.