Background: The EMPA-REG OUTCOME trial showed that empagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2i), reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes (T2D) and established CV disease (CVD). The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study aims to assess empagliflozin's effectiveness, safety, and healthcare utilization in routine care from 08/2014 through 09/2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin vs. sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i). Methods: Within two commercial and one federal (Medicare) claims data sources in the U.S., we identified a 1:1 propensity-score (PS) matched cohort of T2D patients ≥18 years initiating empagliflozin or sitagliptin from 08/2014 through 09/2016. The HHF outcome was defined as a HF discharge diagnosis in the primary position (HHF-specific); a broader definition was based on a HF discharge diagnosis in any position (HHF-broad). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis. Results: After PS-matching, we identified 16,443 patient pairs who initiated empagliflozin or sitagliptin. Average age was approximately 59 years, almost 54% of the participants were males, and approximately 25% had records of existing cardiovascular disease. Compared to sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% (HR = 0.50; 95% CI = 0.28-0.91), and the risk of HHF-broad by 49% (HR: 0.51;95% CI: 0.39-0.68), over a mean follow-up of 5.3 months. Results were consistent in patients with and without baseline cardiovascular disease, and for both empagliflozin 10 mg or 25mg daily dose; analyses comparing

Background: Regulators are evaluating the use of non-interventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT-DUPLICATE initiative uses a structured process to design RWE studies emulating randomized controlled trials (RCTs) and compare results. Here, we report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications. Methods: We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion/exclusion criteria, selected primary endpoints, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 pre-exposure confounders. All study parameters were prospectively defined and protocols registered before hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. Success criteria for the primary analysis were pre-specified for each replication. Results: Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a HR estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation. Conclusions: Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922

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