Abstract Body (Do not enter title and authors here): Background
Direct oral anticoagulants (DOACs) are commonly prescribed for patients with atrial fibrillation or venous thromboembolism. Unlike Warfarin, the fixed-dose DOACs do not require close monitoring, and have minimal increase on bleeding. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce weight and delay gastric emptying, witch may lead to DOAC overdosing with more adverse events. The safety of GLP-1RA initiation in patients concurrently using DOAC remains unclear. Dipeptidyl peptidase-4 (DPP4) inhibitors have minimal effect on weight and are not associated with increased bleeding risk, making them a suitable active comparator.

Research Question
Is GLP-1RA initiation, compared to DPP4 inhibitors, associated with risks of stroke and bleeding in T2D patients with stable DOAC use?

Methods
We emulated a prevalent new-user design trial using 15% of U.S. Medicare beneficiaries from 01/01/2011 to 12/31/2020. Patients entered the base cohort once diagnosed with T2D. Then they were randomly assigned to initiate GLP-1RA or receive DPP4 inhibitors using propensity score matching with 1:1 ratio. We included patients aged >65, with stable DOAC use (defined by MPR≥80%), and continuous Medicare enrollment during one year before the index date. Outcomes include stroke and all-cause bleeding events. Patients were followed until the first occurrence of an outcome, bariatric surgery, death, Medicare disenrollment, or 12/31/2020. Cox proportional hazards models were applied.

Results
After matching, 2,002 patients were included with mean follow-up of 2 years. Mean age was 74.2 vs. 76.2 years, and 51.3% vs. 45.7% were female (GLP-1RA vs. DPP4). The risks of stroke and all-cause bleeding were both comparable between GLP-1RA and DPP4 groups (stroke: 0.68 vs. 0.64/100 person-year; HR: 1.25, 95% CI: 0.57–2.75; bleeding: 4.56 vs. 6.15/100 person-year; HR: 0.79, 95% CI: 0.59–1.05).

Conclusions
In T2D patients with stable DOAC use, initiation of GLP-1RA does not significantly impact the risk of stroke or bleeding. However, due to the timeframe, liraglutide was the most prescribed GLP-1RA. Studies with latest data and larger sample size are needed to further investigate the association, especially among patients received semaglutide.