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.

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e14656 Background: In the VELOUR trial, in metastatic colorectal cancer (mCRC) patients, ziv-aflibercept (Afl) combined with FOLFIRI demonstrated significant improvements in median overall survival (OS) by 1.44 mos and median progression-free survival (PFS) by 2.23 mos when compared with FOLFIRI + placebo. We utilized a systematic approach to evaluate the benefit/risk profile of the regimen in the target disease population. Objectives: To evaluate favorable and unfavorable effects of Afl in combination with FOLFIRI in patients with mCRC previously treated with an oxaliplatin-based regimen using the MCDA method. Methods: Data from VELOUR were used to compare the 2 treatment arms (Afl + FOLFIRI vs placebo + FOLFIRI). An 8-step process based on the MCDA was used to construct a value tree that displayed evaluation criteria for favorable and unfavorable effects, determined score, assigned weight for each criteria, and then combined weights and scores for each treatment arm to derive an overall value. Sensitivity analysis was also conducted. Results: The final value tree comparing the 2 treatment arms had 2 branches representing favorable and unfavorable effects. Favorable effects criteria included survival probability at 12, 18, and 24 mos, median OS, median PFS, and overall response rate. Unfavorable effects criteria included 11 anti-VEGF- and FOLFIRI-associated adverse events (AEs), as well as deaths and treatment discontinuation due to AEs. The survival rate at 24 mos had the highest weight (100), followed by median OS (95). For unfavorable effects, diarrhea had the highest weight (15), followed by arterial thromboembolism (ATE) (12). AEs seen with Afl + FOLFIRI were generally manageable; their clinical impact did not outweigh the benefits. The overall value combining favorable and unfavorable effects for Afl + FOLFIRI was 53 vs 40 for placebo + FOLFIRI. Conclusions: Results from this quantitative benefit-risk analysis indicate that the benefit-risk balance for ziv-aflibercept in combination with FOLFIRI is favorable compared with FOLFIRI alone in adults with mCRC previously treated with an oxaliplatin-based regimen. Clinical trial information: NCT00561470.

Introduction: Diabetic ketoacidosis (DKA) is a serious acute metabolic complication of diabetes. Rare DKA events have occurred in patients taking sodium glucose co-transporter 2 inhibitors (SGLT2i). This study evaluated the risk of DKA in patients with type 2 diabetes mellitus (T2DM) taking SGLT2i versus other antihyperglycemic agents (AHAs) in clinical practice. Methods: This study, per protocol reviewed and approved by the European Medicines Agency, identified patients from 4 large US claims databases using broad and narrow definitions of T2DM; the broad definition captured all patients with a T2DM diagnosis and the narrow definition was intended to exclude T1DM misclassified as T2DM. DKA was identified from diagnosis codes in inpatient or emergency room claims. Eligible new users of SGLT2i and 7 groups of AHA comparators were matched (1:1) on exposure propensity scores (PS) to adjust for imbalances in baseline covariates. Cox proportional hazard models conditioned on PS-matched pairs were used to estimate hazard ratios (HR) of DKA risk for new users of SGLT2i versus other AHAs. P values were calibrated using negative control outcomes to address potential residual bias. Pooled HRs were calculated when I 2 was <40% across 4 databases. Results: The number of new users of SGLT2i in each database ranged from 11,141 to 152,728 using the broad T2DM definition and from 7,779 to 130,708 using the narrow definition. Across databases, the unadjusted incidence rates of DKA (events per 1000 patient-years) ranged from 2.75 to 8.84 with SGLT2i and 1.38 to 15.82 with other AHAs using the broad T2DM definition and from 1.15 to 3.91 with SGLT2i and 0.75 to 7.94 with other AHAs using the narrow definition. Using the broad T2DM definition, a significantly increased risk of DKA was observed among new users of SGLT2i versus 5 groups of other AHAs; when using the narrow definition, an increased risk of DKA with SGLT2i was observed only compared with sulfonylureas ( Figure ). Conclusion: In this claims database study, an increased risk of DKA was observed for new users of SGLT2i versus new users of several non-SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misdiagnosed T1DM patients, an increased risk of DKA with SGLT2i was observed compared to sulfonylureas.