CVD-REAL Investigator and Study Group.(518K, docx) Acknowledgements The authors acknowledge Kevin Kennedy (Saint Luke’s Mid America Heart Institute) for his independent validation of the meta analyses. Fabian Hoti, Solomon Christopher and Minna Vehkala (StatFinn & EPID Research, Espoo, Finland) and Bendix Carstensen (Diabetes Center, Gentofte, Denmark) are all acknowledged for database management and statistical work. Data from your Norwegian Patient Register have been used in this publication. ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects. Results Following matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396?days for SGLT-2i initiation and 406?days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58C0.75; p?0.001), ACD (HR: 0.52, 95%CI 0.45C0.60; p?0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53C0.68; p?0.001), MI (HR: 0.85, 95%CI 0.78C0.92; p?0.001), and stroke (HR: 0.78, 95%CI 0.72C0.85; p?0.001); regardless of patient characteristics, including established cardiovascular disease, or geographic region. Conclusions This CVD-REAL study extends the findings from your SGLT-2i clinical trials to the Xanthotoxol broader setting of an ethnically and geographically diverse populace, and across multiple subgroups. "type":"clinical-trial","attrs":"text":"NCT02993614","term_id":"NCT02993614"NCT02993614 Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01345-z. angiotensin transforming enzyme, angiotensin receptor blockers, chronic kidney disease, cardiovascular, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, other glucose-lowering drug, peripheral artery disease, sodiumCglucose cotransporter-2, standardized difference, sulfonylureas, thiazolidinediones The incidence rate (IR) for each outcome was assessed by treatment group as the number of events divided by the total quantity of person-years at risk. The time to first event was compared between groups using Cox proportional hazards models, presented as hazard ratios (HR; 95%CI) for each outcome separately by country. The primary analysis used an intent-to-treat (ITT) approach where patients were followed from the start of index treatment until either occurrence of the first end result event or the censoring date (whichever came first), regardless of whether index treatment was discontinued. The HRs for each endpoint from each individual country were then pooled for an overall weighted summary , using random-effects models with inverse variance weighting for each ActRIB country . Analyses for each outcome were also stratified according to the presence of prior CVD [defined as history of myocardial infarction, unstable angina, heart failure, atrial fibrillation, stroke, percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)]; patient age and sex; history of heart failure, chronic kidney disease (CKD), or malignancy; baseline use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), -blockers, high ceiling diuretics, aldosterone antagonists, insulin, sulphonylureas, and statins. Sensitivity analyses were performed in order to Xanthotoxol evaluate the stability of the findings: data for the primary analysis were additionally adjusted for multiple covariates [age, gender, frailty (defined as at least one hospitalization of at least three consecutive days during the 12 months prior to index), history of heart failure, history of myocardial infarction, atrial fibrillation history, hypertension (if available), obesity/BMI (if available), duration of diabetes (if available), and use of ACEi or ARBs, -blockers, Ca2+-channel blockers, statins, loop diuretics Xanthotoxol and thiazide diuretics]; analyses were repeated using an on-treatment approach (follow-up censored at index treatment discontinuation). Informed consent was not required, as the data were collected for clinical and administrative purposes and were analysed after de-identification. Analyses of data were conducted in accordance with local laws and regulations, and received approvals from Scientific/Ethics/Data Protection Committees in each country. Country-specific analyses were conducted by impartial academic/statistical groups in each country. Meta-analyses were conducted by Statisticon AB, Uppsala (Sweden) and validated by impartial academic statisticians at Saint Lukes Mid America Heart Institute, Kansas City, Missouri (USA). Role of funding source This analysis was overseen by the CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SodiumCGlucose Cotransporter-2 Inhibitors) Academic Scientific Committee, Study Group and Investigators, including members from your sponsor. The sponsor was involved in the design of the analysis, and the collection/interpretation of data. No payment was received by any author for writing this manuscript. The corresponding author and senior author had full access to all data, and vouch for the accuracy and completeness of data reported. All authors made the final decision to submit the manuscript. Results Study population A total of 9,631,497 patients who newly initiated either SGLT-2i or oGLD treatment during the study period was recognized (Additional file 1: Physique S1); 477,894 (5.0%) were new users of SGLT-2i and 9,153,603 (95.0%) were new users of oGLD. To propensity rating coordinating Prior, the individuals who initiated SGLT-2i had been younger, got much Xanthotoxol less common center failing somewhat, cKD and stroke in baseline and.