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Background: Studies that have reported lower risk for cardiovascular outcomes in users of Sodium–Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). Methods and results: Adults initiating empagliflozin and DPP-4i in 2014–2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64–0.86), CVM (HR 0.55; 95% CI 0.38–0.80), HHF or CVM (HR 0.57; 95% CI 0.48–0.67) and stroke (HR 0.79; 95% CI 0.67–0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. Conclusion: These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status. [ABSTRACT FROM AUTHOR]

Background: Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies., Methods: The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014-2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined., Findings: Among 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions., Interpretation: Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors., Competing Interests: Declaration of Competing Interest Avraham Karasik has received research grants and consulting fees from Boehringer Ingelheim; research grants from Astra Zeneca; research grants, consulting fees, and speaker fees from Novo Nordisk. Daisuke Yabe has received consulting/lecture fees from Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Company Limited, and grants from Arkray Inc., Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim, Ono Pharmaceutical Co. Ltd., Taisho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, and Terumo Corporation. Dae Jung Kim has received grants support from Boehringer Ingelheim, AstraZeneca, Sanofi-Aventis Korea, Jeil Pharmaceutical, and Chong Kun Dang, speaker fees from Boehringer-Ingelheim, Novo Nordisk, Boryung, Hanmi, Novartis, Donga ST, Celltrion, AstraZeneca, and Dong Wha Pharmaceuticals. Wayne HH Sheu has been an advisor and/or speaker for AstraZeneca, Bayer HealthCare, Boehringer Ingelheim Pharmaceuticals, Daiichi-Sankyo, Eli Lilly and Company, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda Pharmaceutical Company. Kamlesh Khunti has acted as a consultant, speaker or received consultation/lecture grants for investigator-initiated studies for Astra Zeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, and Merck Sharp & Dohme, Boehringer Ingelheim, Bayer. Francesco Zaccardi has received speaker fees from Boehringer Ingelheim and Napp Pharmaceuticals. Thomas Nyström has received unrestricted grants from AstraZeneca and NovoNordisk and has been a national advisor of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD, and Boehringer Ingelheim. Leo Niskanen has received speaker and consulting fees from Boehringer Ingelheim, MSD, AstraZeneca, and Sanofi, research grant to the institution, consulting fees, and speaker fees from Novo Nordisk. Majken Linnemann Jensen, Fabian Hoti, Riho Klement are employees of IQVIA and contracted by Boehringer Ingelheim to conduct the analyses. Soulmaz Fazeli Farsani, Anouk Déruaz-Luyet are employees of Boehringer Ingelheim International GmbH. Moe H Kyaw was employee of Boehringer Ingelheim. Lisette Koeneman is employee of Eli Lilly & Company and owns stock of Eli Lilly & Company. Dorte Vistisen has received research grants from Bayer A/S, Sanofi, Novo Nordisk A/S, and Boehringer Ingelheim. She holds shares in Novo Nordisk A/S. Sigrun Halvorsen has received speaker fees from Sanofi, Novartis, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb. Gisle Langslet has received consulting/lecture fees from Amgen, Sanofi, and Boehringer Ingelheim. Elisabetta Patorno has received a research grant from Boehringer Ingelheim. Julio Núñez reports personal fees from AstraZeneca, Novartis, Boehringer-Ingelheim, Eli Lilly, Rovi, Novo Nordisk, and Vifor Pharma (outside the submitted work). Stefanie Lanzinger, Reinhard W Holl, Elise Chia-Hui Tan, Cheli Melzer-Cohen, Kyong Hwa, Bendix Carstensen: None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

International differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N = 1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF ≥40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF ≥40%. β-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9 years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF ≥40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF ≥40%. These data may inform the design of future international trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)