Purpose To compare the incidence of diabetic ketoacidosis (DKA) among patients with type 2 diabetes mellitus (T2DM) who were new users of sodium glucose co‐transporter 2 inhibitors (SGLT2i) versus other classes of antihyperglycemic agents (AHAs). Methods Patients were identified from four large US claims databases using broad (all T2DM patients) and narrow (intended to exclude patients with type 1 diabetes or secondary diabetes misclassified as T2DM) definitions of T2DM. New users of SGLT2i and seven groups of comparator AHAs were matched (1:1) on exposure propensity scores to adjust for imbalances in baseline covariates. Cox proportional hazards regression models, conditioned on propensity score‐matched pairs, were used to estimate hazard ratios (HRs) of DKA for new users of SGLT2i versus other AHAs. When I2 <40%, a combined HR across the four databases was estimated. Results Using the broad definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (HR [95% CI]: 1.53 [1.31‐1.79]), DPP‐4i (1.28 [1.11‐1.47]), GLP‐1 receptor agonists (1.34 [1.12‐1.60]), metformin (1.31 [1.11‐1.54]), and insulinotropic AHAs (1.38 [1.15‐1.66]). Using the narrow definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (1.43 [1.01‐2.01]). New users of SGLT2i had a lower risk of DKA versus insulin and a similar risk as thiazolidinediones, regardless of T2DM definition. Conclusions Increased risk of DKA was observed for new users of SGLT2i versus several non‐SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misclassified patients, an increased risk of DKA with SGLT2i was observed compared with sulfonylureas.

Background Antithrombotic therapies are associated with an increased bleeding risk. Abnormal uterine bleeding data have been reported in clinical trials of patients with venous thromboembolism (VTE), but data are limited for patients with atrial fibrillation (AF). Objective Using real-world data from four US healthcare databases (October 2010 to December 2018), we compared the occurrence of severe uterine bleeding among women newly exposed to rivaroxaban, apixaban, dabigatran, and warfarin stratified by indication. Methods To reduce potential confounding, patients in comparative cohorts were matched on propensity scores. Treatment effect estimates were generated using Cox proportional hazard models for each indication, in each database, and only for pairwise comparisons that met a priori study diagnostics. If estimates were homogeneous ( I 2 < 40%), a meta-analysis across databases was performed and pooled hazard ratios reported. Results Data from 363,919 women newly exposed to a direct oral anticoagulant or warfarin with a prior diagnosis of AF (60.8%) or VTE (39.2%) were analyzed. Overall incidence of severe uterine bleeding was low in the populations exposed to direct oral anticoagulants, although relatively higher in the younger VTE population vs the AF population (unadjusted incidence rates: 2.8–33.7 vs 1.9–10.0 events/1000 person-years). In the propensity score-matched AF population, a suggestive, moderately increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [hazard ratios and 95% confidence intervals from 0.83 (0.27–2.48) to 2.84 (1.32–6.23) across databases with significant heterogeneity], apixaban [pooled hazard ratio 1.45 (0.91–2.28)], and dabigatran [2.12 (1.01–4.43)], which were sensitive to the time-at-risk period. In the propensity score-matched VTE population, a consistent increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [2.03 (1.19–3.27)] and apixaban [2.25 (1.45–3.41)], which were insensitive to the time-at-risk period. Conclusions For women who need antithrombotic therapy, personalized management strategies with careful evaluation of benefits and risks are required. ClinicalTrials.gov Registration NCT04394234; registered in May 2020. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01060-4.