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Zusammenfassung  Humanes aktiviertes Protein C (APC) ist eine Serinprotease und wichtiger physiologischer Inhibitor des Gerinnungssystems, dem neben seiner antikoagulativen Wirkung zusätzlich profibrinolytische und antiinflammatorische Eigenschaften zugeschrieben werden. Die Anwendung von APC in rekombinanter Form (Xigris®, Drotrecogin alfa (aktiviert); rekombinantes humanes aktiviertes Protein C, rhAPC) führte bei Patienten mit schwerer Sepsis und Multiorganversagen zu einer signifikanten Senkung der Gesamtletalität. Aus In-vitro-Untersuchungen und Tierversuchen wurden neben den bekannten Wirkmechanismen zusätzlich antiapoptotische Effekte sowie positive Wirkungen von rhAPC auf das Immunsystem, die Permeabilität von Endothelzellen und auf die Mikrozirkulation postuliert. Resultierend aus den vielfältigen Wirkprinzipien wird aktuell der Einsatz von rhAPC in weiteren Indikationsbereichen experimentell untersucht, wie z. B. beim akuten Lungen- und Nierenversagen, beim Schlaganfall, bei Ischämie-Reperfusions-Störungen und der Pankreatitis. Die bessere Kenntnis der Wirkungsmechanismen von rhAPC könnte zukünftig sowohl für die Dosierung und Applikationsweise als auch für eine Erweiterung des Indikationsbereiches von Bedeutung sein. [ABSTRACT FROM AUTHOR]

Background and Aims: Hypertension has a high prevalence in heart failure with preserved ejection fraction (HFpEF), which can be controlled, uncontrolled, or even resistant. The effects of empagliflozin on systolic blood pressure (SBP), time in target range, incidence of hypertensive urgencies, and studied cardiovascular and renal outcomes in different hypertension categories and after treatment with empagliflozin in the EMPEROR-Preserved trial were explored., Methods: A total of 5533 patients were studied and the population was separated into resistant (resHTN), uncontrolled (uctrHTN), and controlled (ctrHTN) hypertension. The effect of SBP on outcomes and treatment effects of empagliflozin were explored. Analyses were done with Cox regression analyses adjusted for demographic and clinical confounders and with a mixed model for repeated measures., Results: Empagliflozin reduced SBP in resHTN slightly more than in the other categories in the first weeks, while thereafter there were no significant differences. The modest reduction in SBP resulted in a moderate increase in time at target and reduced hypertensive urgencies. The primary endpoint was more prevalent in resHTN (P = .0358), but the treatment effect of empagliflozin on the primary endpoint was similar in resHTN, uctrHTN, and ctrHTN (P for interaction = .92) as was the improvement of the estimated glomerular filtration rate slope (P for interaction = .95) and change in quality of life by empagliflozin., Conclusions: In HFpEF, the prevalence of resHTN is high and is associated with frequently higher outcome rates compared with ctrHTN and uctrHTN. The treatment effect was not modified by hypertension categories. This indicates that in HFpEF, moderate modifications of blood pressure do not affect overall outcomes and treatment effects of empagliflozin., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: In the EMPA-KIDNEY trial, empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, had positive cardiorenal effects in patients with chronic kidney disease who were at risk for disease progression. Post-trial follow-up was designed to assess how the effects of empagliflozin would evolve after the discontinuation of the trial drug., Methods: In the active trial, patients with chronic kidney disease were randomly assigned to receive either empagliflozin (10 mg once daily) or matching placebo and were followed for a median of 2 years. All the patients had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m 2 of body-surface area or an eGFR of at least 45 but less than 90 ml per minute per 1.73 m 2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Subsequently, surviving patients who consented were observed for 2 additional years. No trial empagliflozin or placebo was administered during the post-trial period, but local practitioners could prescribe open-label SGLT2 inhibitors, including open-label empagliflozin. The primary composite outcome was kidney disease progression or cardiovascular death as assessed from the start of the active-trial period to the end of the post-trial period., Results: Of the 6609 patients who had undergone randomization in the active trial, 4891 (74%) were enrolled in the post-trial period. During this period, the use of open-label SGLT2 inhibitors was similar in the two groups (43% in the empagliflozin group and 40% in the placebo group). During the combined active- and post-trial periods, a primary-outcome event occurred in 865 of 3304 patients (26.2%) in the empagliflozin group and in 1001 of 3305 patients (30.3%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.72 to 0.87). During the post-trial period only, the hazard ratio for a primary-outcome event was 0.87 (95% CI, 0.76 to 0.99). During the combined periods, the risk of kidney disease progression was 23.5% in the empagliflozin group and 27.1% in the placebo group; the risk of the composite of death or end-stage kidney disease was 16.9% and 19.6%, respectively; and the risk of cardiovascular death was 3.8% and 4.9%, respectively. There was no effect of empagliflozin on death from noncardiovascular causes (5.3% in both groups)., Conclusions: In a broad range of patients with chronic kidney disease at risk for progression, empagliflozin continued to have additional cardiorenal benefits for up to 12 months after it was discontinued. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EuDRACT number, 2017-002971-24.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: There is limited published information on outcome adjudication in heart failure (HF) trials, particularly in heart failure with preserved ejection fraction (HFpEF)., Objectives: The study sought to compare investigator reports with clinical events committee (CEC) adjudication and assess the impact of the SCTI (Standardized Data Collection for Cardiovascular Trials) criteria., Methods: In the EMPEROR-Preserved (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction) trial, we compared investigator reports with CEC for concordance, treatment effect on primary composite outcome events and components (first event primary heart failure hospitalization [HHF] or cardiovascular [CV] mortality), prognosis after first HHF, total HHF, and trial duration with and without SCTI criteria., Results: The CEC confirmed 67.4% investigator-reported events for the primary outcome (CV mortality 82.7%, HHF 66.3%). The HR for treatment effect did not differ between adjudication methods for the primary outcome: investigator reports (HR: 0.77; 95% CI: 0.69-0.87), CEC (HR: 0.79; 95% CI: 0.69-0.90), its components, or total HHFs. The prognosis after the first HHF for all-cause mortality and CV mortality also did not differ between investigator reports and the CEC, nor did investigator reports and HHFs with a different CEC cause. SCTI criteria were present in 92% of CEC HHFs with a similar treatment effect to non-SCTI criteria. The investigator-reported primary events reached the protocol target number 6 months earlier than the CEC (7 months with full SCTI criteria)., Conclusions: Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation in HFpEF. The use of granular (SCTI) criteria did not improve trial performance. Our data suggest that a broader definition of an HHF event could be particularly beneficial in HFpEF clinical trials. (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction; NCT03057951)., Competing Interests: Funding Support and Author Disclosures The EMPEROR-Preserved trial was funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Dr Carson has received consulting fees from Boehringer Ingelheim and IQVIA related to work on a clinical events committee during the conduct of the study. Dr Teerlink has received research support from and/or served as a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. Dr Komajda has received consulting fees from Boehringer Ingelheim related to work on a clinical events committee during the conduct of the study; and personal fees from Novartis, Servier, Amgen, Sanofi, Bayer, AstraZeneca, Lilly, and Torrent. Dr Anand has received consulting fees from Boehringer Ingelheim related to work on a clinical events committee during the conduct of the study; and personal fees from Novartis, Servier, Amgen, Sanofi, Bayer, AstraZeneca, Lilly, and Torrent. Dr Packer has received consulting fees from AbbVie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson and Johnson, Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, VWave, and Vifor; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Doehner has received consulting fees from Boehringer Ingelheim related to work on the clinical events committee during the conduct of the study; personal fees from Aimediq, Bayer, Boehringer Ingelheim, Medtronic, Pfizer, Sanofi, Sphingotec, and Vifor Pharma; and research support from the European Union (Horizon2020), the German Ministry of Education and Research, the German Center for Cardiovascular Research, Vifor Pharma, and ZS Pharma. Dr Ferreira has received consulting fees from Boehringer Ingelheim; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Filippatos has received lecture fees from and/or committee member contributions from clinical trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, and Amgen; research support from the European Union; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Haass has received consulting fees from Boehringer Ingelheim related to work on the clinical events committee during the conduct of the study. Dr Miller has received consulting fees from Abbott, Boehringer Ingelheim, Respicardia, CVRx, Pfizer, and AbbVie. Dr Pehrson has received consulting fees and/or lecture fees from Boehringer Ingelheim, GlaxoSmithKline, Celgene, Bristol Myers Squibb, Bayer, and Johnson and Johnson. Dr Pocock has received consulting fees and payment or honoraria for lectures, presentations, Speakers Bureau service, manuscript writing, or educational events from Boehringer Ingelheim; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Drs Iwata, Brueckmann, and Gasior are employees of Boehringer Ingelheim. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Anker has received grants and personal fees from Vifor International and Abbott Vascular; personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor)., (Copyright © 2025 American College of Cardiology Foundation. All rights reserved.)

Objective: The objective of this study was to describe the rationale and design of two multinational phase 3 clinical trials of survodutide, an investigational glucagon and glucagon-like peptide-1 receptor dual agonist for the treatment of obesity with or without type 2 diabetes (T2D; SYNCHRONIZE-1 and -2)., Methods: In these ongoing double-blind trials, participants were randomized to once-weekly subcutaneous injections of survodutide or placebo added to lifestyle modification. Survodutide doses are uptitrated to 3.6 or 6.0 mg, and dose flexibility is permitted. Participants (n = 726) in SYNCHRONIZE-1 (NCT06066515) have a baseline BMI ≥ 30 kg/m 2 or ≥27 kg/m 2 with at least one obesity-related complication but without T2D; participants (n = 755) in SYNCHRONIZE-2 (NCT06066528) have a baseline BMI ≥ 27 kg/m 2 and T2D. The primary endpoints are percentage change in body weight and proportion of participants achieving ≥5% body weight reduction from baseline to week 76. Secondary endpoints include change in systolic blood pressure and measures of glycemia. A SYNCHRONIZE-1 substudy is evaluating changes in body composition and liver fat content using magnetic resonance imaging., Conclusions: These trials are designed to provide robust evaluation of the efficacy, safety, and tolerability of survodutide for the treatment of obesity in the presence or absence of T2D., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Aims: In the EMPACT-MI trial, empagliflozin reduced heart failure (HF) hospitalizations but not mortality in acute myocardial infarction (MI). Contemporary reports of clinical event rates with and without type 2 diabetes mellitus (T2DM) in acute MI trials are sparse. The treatment effect of empagliflozin in those with and without T2DM in acute MI is unknown., Methods and Results: A total of 6522 patients with acute MI with newly reduced left ventricular ejection fraction (LVEF) to <45%, congestion, or both, were randomized to empagliflozin 10 mg or placebo. The primary endpoint was time to first HF hospitalization or all-cause death. Rates of endpoints with and without T2DM and the efficacy and safety of empagliflozin according to T2DM status were assessed. Overall, 32% had T2DM; 14% had pre-diabetes; 16% were normoglycaemic; 38% had unknown glycaemic status. Patients with T2DM, compared to those without T2DM, were at higher risk of time to first HF hospitalization or all-cause death (hazard ratio [HR] 1.44; 95% confidence interval [CI] 1.06-1.95) and all-cause death (HR 1.70; 95% CI 1.13-2.56). T2DM did not confer a higher risk of first HF hospitalization (HR 1.22, 95% CI 0.82-1.83). Empagliflozin reduced first and total HF hospitalizations, but not all-cause mortality, regardless of presence or absence of T2DM. The safety profile of empagliflozin was the same with and without T2DM., Conclusion: Patients with acute MI, LVEF <45% and/or congestion who had T2DM were at a higher risk of mortality than those without T2DM. Empagliflozin reduced first and total HF hospitalizations regardless of the presence or absence of T2DM., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcome in patients with heart failure (HF) and reduce serum uric acid (SUA). The relevance of this metabolic effect in patients with heart failure with preserved ejection fraction (HFpEF) is unclear., Objectives: The authors investigated the effect of empagliflozin on SUA levels in relation to the therapeutic efficacy in patients with HFpEF., Methods: This post hoc analysis of the EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction; NCT03057951) trial assessed the clinical effect of SUA reduction in relation to the outcome endpoints of the trial (composite primary outcome of cardiovascular mortality or hospitalization for HF, its individual components, and all-cause mortality in patients with HFpEF)., Results: Hyperuricemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) was prevalent in 49% of patients. Elevated SUA (highest tertile SUA 8.8 ± 1.4 g/dL) was associated with advanced HF severity and with higher risk of adverse outcome (primary endpoint HR: 1.23 [95% CI: 0.98-1.53]; P = 0.07; HF hospitalization HR: 1.42 [95% CI: 1.08-1.86]; P = 0.01). SUA was reduced early (after 4 weeks vs placebo -0.99 ± 0.03 mg/dL; P < 0.0001) and throughout follow-up, with reduction in all prespecified subgroups. Empagliflozin reduced clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of antigout therapy) by 38% (HR: 0.62 [95% CI: 0.51-0.76]; P < 0.0001). The treatment benefit on the primary endpoint was not influenced by baseline SUA (HR: 0.79 [95% CI: 0.69-0.90]; P = 0.0004). The change in SUA was an independent correlate of the treatment benefit on the primary endpoint (P = 0.07)., Conclusions: Hyperuricemia is a common complication in HFpEF and is related to advanced disease severity and adverse outcome. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricemia., Competing Interests: Funding Support and Author Disclosures This study was funded by Boehringer Ingelheim and Eli Lilly and Company Alliance. Graphical assistance was provided by 7.4 Ltd, HCG, and was funded by Boehringer Ingelheim. Dr Doehner has received consulting fees from Boehringer Ingelheim related to work on clinical events committee during the conduct of the study and personal fees from Aimediq, Bayer, Boehringer Ingelheim, Medtronic, Vifor Pharma and research support from EU (Horizon 2020), German ministry of Education and Research, German Center for Cardiovascular Research, Vifor Pharma, and ZS Pharma. Dr Anker has received grants and personal fees from Vifor Int and Abbott Vascular; and personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Medtronic, Novartis, Occlutech, Servier, V-Wave, and Vifor Int. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, LivaNova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Dr Filippatos has received lecture fees and/or committee member contributions in clinical trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Amgen, and Boehringer Ingelheim; and research support from the European Union. Dr Coats has received fees from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards, Eli Lilly, Menarini, Novartis, Servier, Vifor, Abbott, Actimed, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Impulse Dynamics, Respicardia, and Viatris. Dr Ferreira has received research support from Boehringer Ingelheim, Novartis, and AstraZeneca through the University of Porto. Drs Henrichmoeller and Brueckmann are employees of Boehringer Ingelheim International. Ms Schueler is an employee of mainanalytics GmbH contracted by Boehringer Ingelheim. Dr Pocock has received consultancy fees from Boehringer Ingelheim. Dr Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott, Applied Therapeutics, HeartFlow Inc, Innolife, and Roche Diagnostics; has received consulting fees from Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Jana Care, Janssen, Novartis, Merck, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Intercept, Pfizer, and Takeda. Dr Packer has received personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra, outside of the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors may be more effective than GLP-1 receptor agonism alone in reducing body weight, but the cardiovascular (CV) effects are unknown. The authors describe the rationale and design of SYNCHRONIZE-CVOT, a phase 3, randomized, double-blind, parallel-group, event-driven, CV safety study of survodutide, a dual glucagon and GLP-1 receptor agonist, administered subcutaneously once weekly compared with placebo in adults with a body mass index ≥27 kg/m 2 and established CV disease or chronic kidney disease, and/or at least 2 weight-related complications or risk factors for CV disease. The primary endpoint of SYNCHRONIZE-CVOT is time to first occurrence of the composite adjudicated endpoint of 5-point major adverse CV events. This global CV outcomes trial is currently enrolling, with a target recruitment of 4,935 participants. SYNCHRONIZE-CVOT is the first trial that will determine the CV safety and efficacy of survodutide in people with obesity and increased CV risk. (A Study to Test the Effect of Survodutide [BI 456906] on Cardiovascular Safety in People With Overweight or Obesity [SYNCHRONIZE-CVOT]; NCT06077864)., Competing Interests: Funding Support and Author Disclosures The SYNCHRONIZE-CVOT was funded by Boehringer Ingelheim. Dr Kosiborod has received research grants (payments to institution) from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant on advisory boards (payments to institution) for 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Regeneron, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support (Data Analytic Center Fees – payments to institution) from AstraZeneca and Vifor Pharma; has received honoraria (payments to institution) from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received stock options (personal) from Artera Health and Saghmos Therapeutics. Dr Platz’s employer has received support from Novartis for consulting work; and she has consulted for scPharmaceuticals; has received research support from the National Institutes of Health, American Heart Association, and AstraZeneca; and has served on the clinical trial steering committee of the SYNCHRONIZE 1 and 2 trials and SYNCHRONIZE-CVOT funded by Boehringer Ingelheim. Dr Wharton has received research funding from Novo Nordisk and Bausch Health Canada; and has received honoraria for academic talks and advisory board from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Regeneron, Bausch Health Canada, Merck, iNova, and Currax. Dr le Roux has received grants from the EU Innovative Medicine Initiative, Irish Research Council, Science Foundation Ireland, Anabio, and the Health Research Board; serves on advisory boards and speaker panels of Novo Nordisk, Roche, Herbalife, GI Dynamics, Eli Lilly, Johnson & Johnson, Glia, Irish Life Health, Boehringer Ingelheim, Currax, Zealand Pharma, Keyron, AstraZeneca, Arrow Pharma, and Rhythm Pharma; is the Chair of the Irish Society for Nutrition and Metabolism; and he provides obesity clinical care in the My Best Weight clinic and Beyond BMI clinic and is a shareholder in these clinics. Drs Brueckmann, Startseva, and Ajaz Hussain are full-time employees of Boehringer Ingelheim International GmbH. Ms Unseld is a full-time employee of Boehringer Ingelheim Pharma GmbH and Co KG. Dr Kaplan has served as a consultant to Altimmune, Amgen, Bain Capital, Boehringer Ingelheim, Cytoki, Gelesis, Gilead Sciences, Glyscend, Intellihealth, Johnson and Johnson, Kallyope, Eli Lilly and Co, Novo Nordisk, Optum Health, Perspectum, Pfizer, Sidekick Health, Skye Bioscience, twenty30.health, and Xeno Biosciences. The authors meet criteria for authorship as recommended by the ICMJE (International Committee of Medical Journal Editors), were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors did not receive payment related to the development of this manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared to placebo with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11,000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Aims: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization., Methods and Results: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004)., Conclusions: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The aim of this work is to compare empagliflozin systemic exposure between patients with heart failure (HF) and patients with type 2 diabetes (T2D)., Methods: Analysis of covariance (ANCOVA) compared steady state trough concentrations of empagliflozin 10 mg in EMPEROR-reduced (patients with HF with reduced ejection fraction [HFrEF]) and EMPA-REG OUTCOME (patients with T2D at high cardiovascular risk) after adjusting for eGFR and body weight., Results: The difference in geometric Mean (gMean) empagliflozin steady state trough concentration of 10 mg empagliflozin between EMPEROR-reduced and EMPA-REG OUTCOME was 1.47-fold (95% confidence interval [CI]: 1.33, 1.63). Additionally, ANCOVA for the sub-group of patients with both T2D and HF conditions revealed a difference in gMean steady state trough concentration of 1.53-fold (95% CI: 1.26, 1.85). In both patients with HFrEF and HF with preserved EF (HFpEF), there was no major difference in empagliflozin steady state trough exposure by New York Heart Association (NYHA) classification or by use of angiotensin receptor-neprilysin inhibitor as comedication. A weak positive correlation was observed for NT-proBNP at Week 12 and empagliflozin steady state trough concentration in both patients with HFrEF and HFpEF (Pearson correlation r = 0.19)., Conclusions: Plasma concentrations of empagliflozin in patients with HF were higher compared to patients with T2D, but the exposure resulting from the 10 mg dose was still below the exposure resulting from the dose of 25 mg approved in patients with T2D. The difference in exposure was attributable to demographic characteristics and HF-induced pathophysiological changes. Overall, the results confirm 10 mg as the appropriate empagliflozin dose in patients with HF., (© 2024 Boehringer Ingelheim Pharma GmbH & Co. KG. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: To assess the effect of empagliflozin on patients with comorbid heart failure (HF) and diabetes with or without baseline insulin, and to study the impact of empagliflozin on insulin requirements over time., Materials and Methods: We performed a post-hoc analysis of pooled patient-level data from two cardiovascular outcomes trials of empagliflozin in HF (EMPEROR-Reduced and EMPEROR-Preserved trials). We undertook a subgroup analysis stratified by baseline insulin use, including all patients with diabetes. The studied endpoints included the primary composite endpoint of first hospitalization for HF or cardiovascular death, rate of decline of estimated glomerular filtration rate, composite renal outcome and rates of sustained insulin initiation., Results: Among 4794 patients with diabetes, 1333 (658 in empagliflozin, 675 in placebo) were using insulin at baseline. The treatment effect of empagliflozin on the primary endpoint was consistent irrespective of insulin use [no insulin, hazard ratio 0.74, 95% confidence interval (CI) 0.63-0.86; using insulin, hazard ratio 0.81, 95% CI 0.66-1.00, p interaction  = .49], as was the effect on the rate of decline of the estimated glomerular filtration rate (p interaction  = .75). There was no effect of empagliflozin on the composite renal outcome in patients using or not using insulin (p interaction  = .30). Among patients not using insulin at baseline, those randomized to empagliflozin initiated insulin less frequently throughout the follow-up period compared with those receiving placebo (2.6% vs. 3.8%, odds ratio 0.66, 95% CI 0.50-0.88)., Conclusions: Empagliflozin exerts a consistent benefit on cardiovascular outcomes and renal function decline, irrespective of baseline insulin use, and reduces the need for sustained insulin initiation in patients with HF and diabetes., (© 2024 John Wiley & Sons Ltd.)

Background: Empagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI)., Objectives: This study sought to evaluate the association of left ventricular ejection fraction (LVEF), congestion, or both, with outcomes and the impact of empagliflozin in reducing HF risk post-AMI., Methods: In the EMPACT-MI (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF<45%, congestion, or both, to empagliflozin (10 mg daily) or placebo and were followed up for a median of 17.9 months., Results: Among 6,522 patients, the mean baseline LVEF was 41 ± 9%; 2,648 patients (40.6%) presented with LVEF <45% alone, 1,483 (22.7%) presented with congestion alone, and 2,181 (33.4%) presented with both. Among patients in the placebo arm of the trial, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (HR: 1.49; 95% CI: 1.31-1.69; P < 0.0001), first HF hospitalization (HR: 1.64; 95% CI: 1.37-1.96; P < 0.0001), and total HF hospitalizations (rate ratio [RR]: 1.89; 95% CI: 1.51-2.36; P < 0.0001). The presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR: 1.52, 1.94, and RR: 2.03, respectively). Empagliflozin reduced the risk for first (HR: 0.77; 95% CI: 0.60-0.98) and total (RR: 0.67; 95% CI: 0.50-0.89) HF hospitalizations, irrespective of LVEF or congestion, or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status., Conclusions: In patients with AMI, the severity of left ventricular dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion. (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction [EMPACT-MI]; NCT04509674)., Competing Interests: Funding Support and Author Disclosures Funding support was provided by Boehringer Ingelheim and Eli Lilly and Company. Dr Udell has served on the advisory boards of Boehringer Ingelheim, Novavax, Novo Nordisk, and Sanofi; has received speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly; and has received research funding to his institution from Amgen, Bayer, Boehringer Ingelheim, and Novartis. Dr Petrie has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and has served as a consultant and on trial committees for Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, AbbVie, Bayer, Horizon Therapeutics, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences. Dr Jones has received research grants from Bayer, Boehringer Ingelheim, Merck, Novartis, PCORI, and the National Institutes of Health (NIH). Dr Mattheus is an employee of Boehringer Ingelheim. Dr Seide is an employee of Boehringer Ingelheim. Dr Amir has served as a national principal investigator and as a steering committee member for the study; has participated in paid lectures and advisory board meetings and has clinical trials with Boehringer Ingelheim. Dr Bahit has received modest honoraria from MSD, Pfizer, Bristol Myers Squibb, CSL Behring, Janssen, Boehringer Ingelheim, and Anthos Therapeutics. Dr Bauersachs has received honoraria for lectures or consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, Norgine, Edwards Lifesciences, and Roche, unrelated to this work; and has received research support for the department from Zoll, CVRx, Abiomed, Norgine, and Roche, unrelated to this work. Dr Bayes-Genis has lectured and/or participated in advisory boards for Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche, and Vifor. Dr Goodman has received research grant support (steering committee or data and safety monitoring committee) and/or speaker or consulting honoraria (advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE Ltd, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and has received salary support or honoraria from the Canadian Heart Failure Society, Canadian Heart Research Centre, and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Center for Clinical Research, Duke Clinical Research Institute, Jewish General Hospital, New York University Clinical Coordinating Centre, PERFUSE Research Institute, Peter Munk Cardiac Centre Clinical Trials and Translation Unit, and the TIMI Study Group (Brigham Health). Dr Goto has served on the advisory boards of Antos Therapeutic and Janssen; and has received honoraria from the American Heart Association (Associate Editor); and has served on the grant evaluation committee for the Nakatani Foundation and the Kaketsuken Foundation. Dr Gasior is an employee of Boehringer Ingelheim. Dr Jamal is an employee of Boehringer Ingelheim. Dr Januzzi has served as a trustee of the American College of Cardiology; has served as a board member of Imbria Pharmaceuticals; has served as director at Jana Care; has received research support from Abbott, Applied Therapeutics, Bayer, Bristol Myers Squibb, HeartFlow, Innolife, Medtronic, and Roche; has received consulting income from Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Cytokinetics, Janssen, Merck, Novartis, Prevencio, Quidel/Ortho, and Roche; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Axon, Bayer, CVRx, Medtronic, Pfizer, Roche, and Takeda. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Daiichi-Sankyo, and Novo Nordisk; and has received funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. Dr Martinez-Traba is an employee of Boehringer Ingelheim. Dr Parikh has served as a consultant for Medtronic; and has received institutional research grants from Abbott and Edwards Lifesciences. Dr Parkhomenko has received research grants and personal fees from Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squib/Pfizer, and Daiichi-Sankyo. Dr Schou has received lecture fees from Novartis, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr van der Meer has received grant support from the European Research Council (ERC CoG 101045236, DISSECT-HF) and the University Medical Centre Groningen; and Dr van der Meer’s employer, has received consultancy fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, AstraZeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi-Sankyo, Boehringer Ingelheim, and Ionis. Dr Vinereanu has received research grants and consultancy fees from Boehringer Ingelheim; and has received research grants from Bayer Healthcare, Novartis, and Servier. Dr Zieroth has received research grant support, served on advisory boards for, or participated in speaker engagements with AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Salubrisbio, Servier, and Vifor Pharma; has served on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, and Pfizer; and has nonindustry relationships with the Canadian Medical and Surgical KT Group, CCS, CHFS, Charite, EOCI, Liv, Medscape, Ology, PACE-CME, Radcliffe, Reach MD, and the Translational Medicine Academy. Dr Brueckmann is an employee of Boehringer Ingelheim. Dr Sumin is an employee of Boehringer Ingelheim. Dr Bhatt has served on the advisory boards of Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; has served on the Board of Directors of the American Heart Association New York City, Angiowave (with stock options), Bristol Myers Squibb (with stock), DRS.LINQ (with stock options), and High Enroll (with stock); has served as a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; has served on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); has served as Deputy Editor for Clinical Cardiology; has been named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, which assigned it to Lexicon; neither Dr Bhatt nor Brigham and Women’s Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has served as a trustee of the American College of Cardiology; and has conducted unfunded research for FlowCo. Dr Hernandez has served as a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Intellia, Intercept, Myokardia, Novartis, Novo Nordisk, Prolaio, and TikkunLev; and has received research funding from American Regent, Amgen, Bayer, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk, and Verily. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Eli Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown., Methods: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes., Results: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P =0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P =0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P <0.05)., Conclusions: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674., Competing Interests: Disclosures Dr Hernandez has served as a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Intellia, Intercept, MyoKardia, Novartis, Novo Nordisk, Prolaio, and TikkunLev; and has received research funding from American Regent, Amgen, Bayer, Boehringer Ingelheim, Lilly, Merck, Novartis, Novo Nordisk, and Verily. Dr Bhatt has served on advisory boards for ANGIOWave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; on the board of directors for American Heart Association New York City, ANGIOWave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); has served as a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; has served on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, ACC accreditation oversight committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor-in-chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); is named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, which was assigned to Lexicon (neither Dr Bhatt nor Brigham and Women’s Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (editor, Braunwald’s Heart Disease); has served as site coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has served as trustee for American College of Cardiology; and performed unfunded research for FlowCo. Dr Butler has served as a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Goto reports serving as Associate Editor for Circulation and receipt of a steering committee fee from the Duke Clinical Research Institute for EMPACT-MI. Dr Lopes reports research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis; funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. Dr Amir reports serving as National PI-Steering committee member for the study and participated in paid lectures and advisory board meetings and clinical trials in Dr Amir’s department at Boehringer Ingelheim. Dr Beyes-Genis has lectured or participated in advisory boards for Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche Diagnostics, and Vifor. Dr Bahit reports modest honorarium from MSD, Pfizer, Bristol Myers Squibb, CSL Behring, Janssen, Boehringer Ingelheim, and Anthos Therapeutics. Dr Bauersachs received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, Norgine, Edwards, and Roche not related to this article; and research support for Dr Bauersachs’ department from Zoll, CVRx, Abiomed, Norgine, and Roche, not related to this article. Dr Schou reports lecture fees from Novartis, Astra Zeneca, Bohringer, and Novo Nordisk. Dr Steg reports research grants from Amarin and Sanofi; clinical trial participation for Amarin, Amgen, AstraZeneca, Idorsia, Janssen, Novartis, Novo-Nordisk, and Sanofi; consulting or speaking for Amarin, Amgen, and Novo-Nordisk; and serving as senior associate editor at Circulation. Dr Parikh reports serving as a consultant for Medtronic, Inc and receipt of an institutional research grant from Abbott and Edwards Lifesciences. Dr Januzzi reports participation as a trustee of the American College of Cardiology, board member of Imbria Pharmaceuticals, and director at Jana Care; has received research support from Abbott, Applied Therapeutics, Bayer, BBMS, HeartFlow Inc, Innolife, and Roche Diagnostics, and consulting income from Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Janssen, Medtronic, Novartis, Prevencio, Quidel/Ortho, Roche Diagnostics, and Vascular Dynamics; and participates in clinical end point committees or data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Medtronic, Pfizer, Roche Diagnostics, and Takeda. Dr Goodman reports research grant support (eg, steering committee or data and safety monitoring committee) or speaker or consulting honoraria (eg, advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE Ltd, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and salary support or honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and TIMI Study Group (Brigham Health). Dr van der Meer reports support from the European Research Council (ERC CoG 101045236, DISSECT-HF); the UMCG, which employs Dr van der Meer, received consultancy fees or grants from Novartis, Pharmacosmos, Vifor Pharma, Astra Zeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi Sankyo, Boehringer Ingelheim, and Ionis. Dr Petrie reports research funding from Boehringer Ingelheim, Roche, SQ Innovations, Astra Zeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and consultancy or trial committee participation from Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, Astra Zeneca, Novo Nordisk, AbbVie, Bayer, Horizon Therapeutics, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences. Dr Parkhomenko reports research grants and personal fees from Bayer, Amgen, Astra Zeneca, Boehringer Ingelheim, BMS/Pfizer, and Daiichi-Sankyo. Dr Vinereanu reports research grants and consultancy fees from Boehringer Ingelheim and research grants from Bayer Healthcare, Novartis, and Servier Pharmaceuticals LLC. Dr Zieroth reports research grant support, served on advisory boards for, or had speaker engagements with AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Salubrisbio, Servier, and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis and Pfizer; nonindustry participation includes Canadian Medical and Surgical KT Group, CCS, CHFS, Charite, EOCI, Liv, Medscape, Ology, PACE-CME, Radcliffe, Reach MD, and Translational Medicine Academy. Dr Jones reports research grants from Bayer, Boehringer Ingelheim, Merck, Novartis, PCORI, and the National Institutes of Health. Drs Seide, Mattheus, Zwiener, Sumin, Gasior, Jamal, and Brueckmann are employees of Boehringer Ingelheim.

Background: Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown., Methods: In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis., Results: A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups., Conclusions: Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.)., (Copyright © 2024 Massachusetts Medical Society.)

Aims: Renal function (estimated glomerular filtration rate [eGFR]) changes early after the introduction of empagliflozin have not been described in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to describe early eGFR changes, assess its determinants and its clinical impact on cardiovascular and renal outcomes in patients with HFpEF enrolled in EMPEROR-Preserved., Methods and Results: Estimated glomerular filtration rate changes (absolute and relative) from randomization to week 4 were calculated and landmark analyses performed. Initial eGFR change was available in 5836 patients (97.5% of the population). Empagliflozin induced a mean eGFR change of -3.2 ml/min/1.73 m 2 versus placebo from baseline to week 4. After week 4, in the empagliflozin group, the risk of the primary outcome (composite of heart failure hospitalization or cardiovascular death), cardiovascular, all-cause mortality and sustained ≥50% eGFR decrease or end-stage renal disease (ESRD) did not differ by eGFR change levels. In contrast, in the placebo group, patients included in the tertile with most profound eGFR decrease (i.e. ≥5.1% from baseline) had a higher risk of the primary outcome (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.17-1.82), cardiovascular mortality (HR 1.38, 95% CI 1.01-1.89) and sustained ≥50% eGFR decrease or ESRD (HR 2.20, 95% CI 1.20-4.04) versus tertile with eGFR increase., Conclusion: An initial relatively small eGFR decrease may be expected after empagliflozin initiation. Such small eGFR decrease was not associated with adverse cardiovascular outcomes with empagliflozin. In contrast, eGFR decrease was associated with poor cardiovascular outcomes with placebo., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium-glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF)., Methods and Results: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41-49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all-cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41-49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], p interaction  = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint., Conclusion: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in-hospital initiation of empagliflozin regardless of LVEF., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Both low and high body mass index (BMI) are associated with poor heart failure outcomes. Whether BMI modifies benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) requires further investigation., Methods and Results: Using EMPEROR-Preserved data, the effects of empagliflozin versus placebo on the risks for the primary outcome (hospitalization for heart failure [HHF] or cardiovascular [CV] death), change in estimated glomerular filtration rate (eGFR) slopes, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and secondary outcomes across baseline BMI categories (<25 kg/m 2 , 25 to <30 kg/m 2 , 30 to <35 kg/m 2 , 35 to <40 kg/m 2 and ≥40 kg/m 2 ) were examined, and a meta-analysis conducted with DELIVER. Forty-five percent had a BMI of ≥30 kg/m 2 . For the primary outcome, there was a consistent treatment effect of empagliflozin versus placebo across the BMI categories with no formal interaction (p trend = 0.19) by BMI categories. There was also no difference in the effects on secondary outcomes including total HHF (p trend = 0.19), CV death (p trend = 0.20), or eGFR slope with slower declines with empagliflozin regardless of BMI (range 1.12-1.71 ml/min/1.73 m 2 relative to placebo, p trend = 0.85 for interaction), though there was no overall impact on the composite renal endpoint. The difference in weight change between empagliflozin and placebo was -0.59, -1.48, -1.54, -0.87, and - 2.67 kg in the lowest to highest BMI categories (p trend = 0.016 for interaction). A meta-analysis of data from EMPEROR-Preserved and DELIVER showed a consistent effect of SGLT2i versus placebo across BMI categories for the outcome of HHF or CV death. There was a trend toward greater absolute KCCQ-CSS benefit at 32 weeks with empagliflozin at higher BMIs (p = 0.08)., Conclusions: Empagliflozin treatment resulted in broadly consistent cardiac effects across the range of BMI in patients with HFpEF. SGLT2i treatment yields benefit in patients with HFpEF regardless of baseline BMI., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Congenital heart disease (CHD) is common in children and associated with greater risk of thrombotic complications. Management of these complications with standard-of-care treatment is suboptimal for these children., Methods and Results: The effectiveness and safety of dabigatran were demonstrated in pivotal pediatric studies for the treatment of acute venous thromboembolism (VTE; NCT01895777) and secondary VTE prevention (NCT02197416). We report safety and efficacy outcomes from subgroup analyses of these studies for children with CHD (diagnosed according to local practice) and those without. In NCT01895777, 17/21 (81.0%) and 16/27 (59.3%) patients with CHD (including cyanotic) treated with dabigatran and standard of care, respectively, met the primary end point (complete thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; odds ratio [OR], 0.34 [95% CI, 0.08-1.23]). In patients without CHD, 41.0% (n=64) versus 34.9% (n=22) achieved this end point with the respective treatments (OR, 0.77 [95% CI, 0.42-1.41]). Although numerical differences were observed, no heterogeneity in treatment effect of dabigatran on the composite primary end point was detected in patients with and without CHD (interaction P =0.2674). In NCT02197416, recurrent VTE at 12 months occurred in 0/17 patients with CHD versus 3/194 (1.5%) without. No patient with CHD experienced major or clinically relevant nonmajor bleeding events., Conclusions: Data on favorable anticoagulant alternatives for the unmet needs of children with CHD are emerging, and our exploratory results suggest that dabigatran could be an appropriate treatment choice, although challenging sample size limitations in pediatric studies require cautious interpretation of findings., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01895777, NCT02197416.

Background: The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF)., Objectives: The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy., Methods: The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline., Results: A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; P trend test  = 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents., Conclusions: Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, PhaseBio, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial; has served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Butler has received research support from the National Institutes of Health, Patient Centered Outcomes Research, and the European Union; has served on the Speakers Bureau for Novartis, Janssen, and Novo Nordisk; and has served as a consultant and has served on steering committee, clinical events committee, or data safety monitoring boards for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin-Cures, Boehringer Ingelheim, Bristol Myers Squib, Cardiocell, CVRx, G3 Pharmaceutical, Innolife, Janssen, Lantheus, LinaNova, Luitpold, Medscape, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Stealth-Peptide, SC Pharma, V-Wave Limited, Vifor, and ZS Pharma. Dr Anker has received grants and personal fees from Vifor International and Abbott Vascular; and has received personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International. Dr Ferreira is a consultant for Boehringer Ingelheim. Dr Filippatos has received lecture fees and/or committee member contributions in trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Amgen, and Boehringer Ingelheim; and has received research support from the European Union. Dr Januzzi is a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, Applied Therapeutics, Innolife, Novartis Pharmaceuticals and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has received fees as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research and Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and holds a position as co-founder and nonexecutive director of Us2.ai. Dr Sattar has received personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp and Dohme, Novo Nordisk, Pfizer, and Sanofi; and has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside of the submitted work. Dr Zaremba-Pechmann is a contractor to Boehringer Ingelheim via Elderbrook Solutions Gmbh. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Drs Nordaby and Brueckmann are employees of Boehringer Ingelheim International GmbH. Dr Pocock is a consultant for Boehringer Ingelheim. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Dr Packer has received personal fees from Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Data Sharing Statement: To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript and secondary analyses in a peer-reviewed journals and regulatory and reimbursement activities are completed, normally within 1 year after the marketing application has been granted by major Regulatory Authorities. Researchers should use https://vivli.org/ to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Numerous studies have demonstrated that low, unstable, or contingent self-esteem negatively affects youth development and is linked to adolescent psychopathology. However, most previous studies have applied variable-oriented approaches, and less is known about the natural combination of self-esteem facets in school-aged adolescents, how parental conditional regard affects self-esteem profiles, and how these profiles relate to self-kindness, self-judgement, and life satisfaction., Methods: By employing a longitudinal person-oriented approach (i.e., latent profile analysis and latent transition analysis) on two-wave longitudinal data from 587 German secondary school students (52.3% female, M age =13.52 years), this study aims to (1) identify adolescents' self-esteem profiles based on the level, stability, and contingency of self-esteem; (2) examine the impact of parental conditional regard on the self-esteem profiles explained using self-determination theory; and (3) examine these profiles' relationship with self-kindness, self-judgement, and life satisfaction., Results: Four self-esteem profiles were derived: optimal-secure (~ 8%), good (~ 18%), average (~ 36%), and low-insecure (~ 38%). The results reveal a concerningly high proportion as well as a high stability of low-insecure self-esteem (~ 98%) and indicate the strong negative influence of parental conditional regard on the development of optimal-secure self-esteem. Furthermore, the results demonstrate strong correlations between optimal-secure self-esteem, highly developed self-kindness, and high life satisfaction., Conclusions: Using a longitudinal person-oriented approach, it was possible to identify a group with highly vulnerable self-esteem, characterised by particularly low self-kindness, strong self-judgment, and lower life satisfaction. The findings of this study support the need for prevention and intervention targeting adolescents with low-insecure self-esteem., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aims: In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. This study aimed to evaluate the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751)., Methods and Results: In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, heart failure events, and a ≥5 point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at 90 days, assessed using the win ratio (WR). First heart failure hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRAs at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR 1.46, 95% confidence interval [CI] 1.08-1.97 and WR 1.27, 95% CI 0.93-1.73 in MRA users and non-users, respectively; interaction p = 0.52). The effect of empagliflozin on first heart failure hospitalization or cardiovascular death was not modified by MRA use (hazard ratio [HR] 0.58, 95% CI 0.30-1.11 and HR 0.85, 95% CI 0.47-1.52 in MRA users and non-users, respectively; interaction p = 0.39). Investigator-reported and severe hyperkalaemia events were infrequent (<6%) irrespective of MRA use., Conclusions: In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF., (© 2023 European Society of Cardiology.)

Background: The presence of ischemic heart disease impacts prognosis in patients affected by heart failure and reduced ejection fraction (HFrEF). It is not well known how the extent of vascular disease impacts prognoses and responses to therapy in this setting., Methods: In this post hoc analysis of the EMPEROR-Reduced trial, outcomes and the effects of empagliflozin, were assessed in study participants according to the extent (none vs mono 1 vs poly [≥ 2] vascular bed) of vascular disease. Vascular disease was defined as investigator-reported coronary artery disease (CAD), peripheral artery disease (PAD) and cerebrovascular disease at baseline. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Incidence rates are presented per 100 person-years (py) of follow-up., Results: Of the 3730 study participants enrolled, 1324 (35.5%) had no vascular disease, 1879 (50.4%) had monovascular disease, and 527 (14.1%) had polyvascular disease. Participants with polyvascular disease tended to be older and male and to have had histories of hypertension, diabetes and smoking. In the placebo arm, a significantly higher risk for cardiovascular death existed in those with polyvascular disease (HR 1.57, 95% CI1.02, 2.44, compared to those with no vascular disease). In adjusted analysis, the benefit of empagliflozin in cardiovascular death or hospitalization due to HF, HF hospitalization, cardiovascular death, renal composite endpoint, estimated glomerular filtration slope changes, and health status scores were seen across the 3 groups (interaction P > 0.05 for all) but were attenuated in those with polyvascular disease. Adverse events were higher in those with polyvascular disease, but no major differences were noted between empagliflozin or placebo assignment in the 3 groups., Conclusion: In patients with HFrEF, the extent of vascular disease is associated with the risk for adverse cardiovascular outcomes. Empagliflozin offers cardiovascular and renal benefits in HFrEF across the extent of vascular disease, but this benefit is attenuated in those with polyvascular disease., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy., Methods: In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment., Results: From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P =0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P =0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo ( P <0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P <0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients., Conclusions: These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: NCT03057977 and NCT03057951., Competing Interests: Disclosures Dr Butler reports consulting fees from Abbott Fund, American Regent, Amgen, Applied Therapeutics, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiac Dimensions, Cardior, CVRx, Inc, Cytokinetics, Edwards Lifesciences, Element Sciences, Eli Lilly & Company, Impulse Dynamics, Imbria, Inventiva, Innolife, Janssen Global, Lexicon Pharmaceuticals, Liva Nova USA, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, Novo Nordisk, Pharmacosmos, Roche Diagnostics, Occlutech, Relypsa, SQ Innovation, Sequana, Stelthpeptide, Vifor Pharma. Dr Zannad reports consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cellprothera, Merck, Novartis, Novo Nordisk, Owkin, Pfizer, Servier Affaires Medicale, Vifor Fresenius. Dr Ferreira reports consulting fees from Boehringer Ingelheim. Dr Packer reports consulting fees from 89bio, Abbvie, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Reata, Relypsa, Salamandra. Dr Anker reports consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cardior, Cordio, CVRx, Inc., Edwards Lifesciences, GlaxoSmithKline, Impulse Dynamics (USA) Inc., Novartis, Pfizer, Servier, V-Wave, Vectorious, Vifor International. Dr Pocock reports consulting fees from Boehringer Ingelheim. Drs Brueckmann and Zeller are employees of Boehringer Ingelheim. Dr Usman reports no conflicts.

Aims: There are limited data on health status and changes in it over time across major subgroups of patients with heart failure and preserved ejection fraction (HFpEF), including ejection fraction spectrum, age, sex, region, body mass index (BMI), and comorbidities including diabetes, chronic kidney disease (CKD), anaemia, and atrial fibrillation/flutter., Methods and Results: In the EMPEROR-Preserved trial, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was assessed at baseline, 12, 32 and 52 weeks. Determinants of baseline KCCQ score and change over time, and the impact of empagliflozin on KCCQ scores were studied in specified subgroups. A Cox model was used to assess the association between 5- and 10-point increase and 5-point decrease in KCCQ score from baseline to week 12 and later outcomes. Among 2979 participants in the placebo arm, mean KCCQ clinical summary score (CSS) was 70.7 (20.8). Older age, female sex, BMI, anaemia, and a history of diabetes, and CKD were associated with worse scores. KCCQ-CSS score improved during follow-up; patients with atrial fibrillation/flutter at enrollment (p trend = 0.014) and CKD (p trend < 0.001) had less improvement. A 5-point increase in KCCQ-CSS at week 12 was associated with lower risk of cardiovascular death or heart failure hospitalization (5%), cardiovascular death (8%), and first heart failure hospitalization (4%) subsequently. A similar trend was seen with KCCQ total symptom score (TSS) and overall summary score (OSS). Empagliflozin improved KCCQ-CSS, -TSS and -OSS scores similarly across subgroups studied except for greater improvement in patients with the highest BMI (p trend = 0.153, 0.08 and 0.078, respectively)., Conclusion: Health status in patients with HFpEF is impaired, especially in elderly, women, and those with obesity and comorbidities. Empagliflozin improved health status among all key subgroups studied with a greater effect in obese patients., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: The prognostic implication of elevated liver tests in heart failure with preserved ejection fraction (HFpEF) is uncertain. This analysis investigates the association of liver markers with hospitalization for heart failure (HHF) and cardiovascular death (CVD), and the treatment effect of empagliflozin across the range of liver marker levels., Methods and Results: The double-blind, placebo-controlled EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure with Preserved Ejection Fraction) enrolled 5988 patients with HFpEF (ejection fraction >40%). Patients in New York Heart Association class II-IV and elevated N-terminal pro-B-type natriuretic peptide were randomized to receive empagliflozin 10 mg daily or placebo in addition to usual therapy. Patients with significant liver disease were excluded. The primary endpoint was time to first adjudicated HHF or CVD. We explored the association of liver function abnormalities with heart failure outcomes in patients on placebo, the effects of empagliflozin on liver tests and the treatment effects of empagliflozin on heart failure outcomes across categories of liver laboratory values. High alkaline phosphatase (p trend < 0.0001), low albumin (p trend < 0.0001) and high bilirubin (p = 0.02) were associated with poorer outcomes for HHF or CVD, while high aspartate aminotransferase was not, and high alanine aminotransferase was associated with better outcomes. Empagliflozin had no significant effects on liver tests compared to placebo except for albumin which was significantly increased. The treatment effect of empagliflozin on outcomes was not modified by liver tests., Conclusion: Abnormalities of liver function tests are associated differently with heart failure outcomes. Salutary effects of empagliflozin on liver tests were not observed although albumin increased. The treatment benefits of empagliflozin were not affected by baseline values of liver parameters., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Importance: The diuretic effect of sodium-glucose cotransporter 2 inhibitors may result in interaction with background diuretic therapy in patients with heart failure and preserved ejection fraction (HFpEF)., Objective: To assess the safety and efficacy of empagliflozin in combination with background diuretic therapy and the association of empagliflozin with the need for conventional diuretics., Design, Setting, and Participants: This was a post hoc analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved). EMPEROR-Preserved was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from March 2017 to April 2021. Patients with class II to IV heart failure and left ventricular ejection fraction greater than 40% were included. Of 5988 patients enrolled, 5815 (97.1%) had baseline data on diuretic use and were included in this analysis, which was conducted from November 2021 to August 2022., Interventions: Participants in EMPEROR-Preserved were randomized to empagliflozin or placebo. In this analysis, participants were divided into 4 subgroups: no diuretics and furosemide-equivalent diuretic dose of less than 40 mg, 40 mg, and greater than 40 mg at baseline., Main Outcomes and Measures: The main outcomes of interest were first hospitalization for heart failure (HHF) or cardiovascular death (CV death) and its components. Association of empagliflozin vs placebo with outcomes by baseline diuretic status (no diuretic vs any dose) and dose (no diuretic, <40 mg, 40 mg, and > 40mg) was assessed. Association of empagliflozin use with changes in diuretic therapy was also studied., Results: Among 5815 patients (mean [SD] age, 71.9 [9.4] years; 2594 [44.6%] female) with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking less than 40 mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking greater than 40 mg. In the placebo arm, patients with higher diuretic doses had worse outcomes. Empagliflozin decreased the risk of HHF or CV death, regardless of background diuretic status (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93] for the diuretic group vs HR, 0.72; 95% CI, 0.48-1.06 for the nondiuretic group; P for interaction = .58). Similarly, diuretic status was not associated with changes in improvements in first HHF, total HHF, rate of decline in estimated glomerular filtration rate, and Kansas City Cardiomyopathy Questionnaire 23 clinical summary score with empagliflozin. Findings were consistent when patients were categorized by diuretic dose. Empagliflozin was associated with a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65-0.84) and an increased likelihood of de-escalation (HR, 1.15; 95% CI, 1.02-1.30). Empagliflozin was associated with an increased risk of volume depletion in patients taking diuretics (HR, 1.34; 95% CI, 1.13-1.59)., Conclusion: In this study, treatment with empagliflozin was similar regardless of diuretic use or dose. Empagliflozin use was associated with decreased conventional diuretic dosing., Trial Registration: ClinicalTrials.gov Identifier: NCT03057951.

Aims: Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF., Methods and Results: In this pre-defined secondary analysis of EMPEROR-Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66-0.93] vs. 0.78 [0.64-0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57-0.94] vs. 0.72 [0.54-0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m 2 /year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF., Conclusions: In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Empagliflozin reduces the risk of major heart failure outcomes in heart failure with reduced or preserved ejection fraction., Objectives: The goal of this study was to evaluate the effect of empagliflozin across the spectrum of chronic kidney disease in a pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced or Preserved Ejection Fraction, respectively)., Methods: A total of 9,718 patients were grouped into Kidney Disease Improving Global Outcomes (KDIGO) categories based on estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio into low-, moderate-, high-, and very-high-risk categories, comprising 32.0%, 29.1%, 21.9%, and 17.0% of the participants, respectively., Results: In the placebo arm, when compared with lower risk categories, patients at higher risk experienced a slower rate of decline in eGFR, but a higher risk of a composite kidney event. Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalizations similarly in all KDIGO categories (HR: 0.81; 95% CI: 0.66-1.01 for low-; HR: 0.63; 95% CI: 0.52-0.76 for moderate-; HR: 0.82; 95% CI: 0.68-0.98 for high-; and HR: 0.84; 95% CI: 0.71-1.01 for very-high-risk groups; P trend = 0.30). Empagliflozin reduced the rate of decline in eGFR whether it was estimated by chronic slope, total slope, or unconfounded slope. When compared with the unconfounded slope, the magnitude of the effect on chronic slope was larger, and the effect on total slope was smaller. In EMPEROR-Reduced, patients at lowest risk experienced the largest effect of empagliflozin on eGFR slope; this pattern was not observed in EMPEROR-Preserved., Conclusions: The benefit of empagliflozin on major heart failure events was not influenced by KDIGO categories. The magnitude of the renal effects of the drug depended on the approach used to calculate eGFR slopes., Competing Interests: Funding Support and Author Disclosures Boehringer Ingelheim and Eli Lilly and Company funded EMPEROR-Reduced and EMPEROR-Preserved. The manuscript was sponsored by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Dr Butler has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, Occlutech, and Vifor; and is a Trial Executive Committee member of Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Packer has received consulting fees from AbbVie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Dr Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Verma has received research and/or speaking honoraria from Amgen, Amarin, AstraZeneca, Bayer, CMS, Janssen, HLS, Sanofi, Novo Nordisk, Novartis, Merck, and PhaseBio; has received personal fees from Boehringer Ingelheim; is president of the Canadian Medical and Surgical Knowledge Translation Research Group; and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. Dr Wanner has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly and Company, GSK, Gilead, MSD, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius. Dr Ferreira has received consulting fees from Boehringer Ingelheim; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Pocock has received consulting fees and payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Filippatos has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim, Medtronic, Vifor, Servier, and Novartis; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Anker has received grants from Abbott Vascular and Vifor (International) Ltd; has received consulting fees from Abbott Vascular, Bayer, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor (International) Ltd; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Zannad has recieved payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, and Bayer; other financial or nonfinancial interests in CVCT and Cardiorenal; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Drs Brueckmann and Gergei, and Tomoko Iwata are employees of Boehringer Ingelheim, the manufacturer of empagliflozin. Dr Siddiqi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and preserved ejection fraction. This study aims to evaluate if systolic blood pressure (SBP) moderates these effects., Methods and Results: The association of SBP and the treatment effects of empagliflozin in EMPEROR-Preserved (empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction) was evaluated. Randomized patients (n 5988) were grouped according to SBP at baseline (110 mmHg, n 455; 110130 mmHg, n 2415; 130 mmHg, n 3118). The effect of empagliflozin on blood pressure, cardiovascular death or HF hospitalization (primary outcome), total HF hospitalizations, and rate of decline in estimated glomerular filtration rate was studied. Over a median of 26.2 months, the placebo-corrected decline was small and not significantly different across baseline SBP. On placebo, the risk of cardiovascular death or hospitalization for HF was 8.58 at 130 mmHg, 8.26 at 110130 mmHg, and 11.59 events per 100 patient-years at 110 mmHg (P 0.12 vs. 130 mmHg, P 0.08 vs. 110130 mmHg). There was no evidence for baseline SBP moderating the effect of empagliflozin on risk of HF events (primary endpoint interaction P 0.69, recurrent HF hospitalizations interaction P 0.55). When comparing empagliflozin with placebo, SBP did not meaningfully associate with adverse events such as hypotension, volume depletion, and acute renal failure., Conclusion: In EMPEROR-Preserved, empagliflozin was effective and safe without SBP meaningfully moderating empagliflozins treatment effects. This analysis of EMPEROR-Preserved shows that empagliflozin can be used safely and effectively without blood pressure being a meaningful moderator of the drug benefit., Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT03057951., Competing Interests: Conflict of interest: M.B. is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322 900 939) and reports personal fees from Abbott, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Edwards, Medtronic, Novartis, Recor, Servier, and Vifor during the conduct of the study. S.D.A reports grants and personal fees from Vifor Int. and Abbott Vascular, and personal fees from Astra-Zeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor Int. Personal fees from Boehringer Ingelheim during the conduct of the study. J.B. reports consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd., and Vifor. Personal fees from Boehringer Ingelheim during the conduct of the study. J.P.F. reports consulting fees from Boehringer Ingelheim during the conduct of the study. G.F. reports Committee Member contributions in trials. Personal fees from Boehringer Ingelheim during the conduct of the study. F.M. reports grants and personal fees from Medtronic, personal fees from Recor, Boehringer Ingelheim and Berlin Chemie, outside the submitted work; L.L. reports speaker honoraria from Medtronic and ReCor Medical. S.P. reports personal fees from Boehringer Ingelheim during the conduct of the study. I.S. and M.B. are employees of Boehringer Ingelheim. E.S. is employee of mainanalytics, contracted by Boehringer Ingelheim. C.W. reports personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly, GSK, GILEAD, MSD, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius outside the submitted work; F.Z. has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Personal fees from Boehringer Ingelheim during the conduct of the study. M.P. reports consulting fees from Boehringer Ingelheim, during the conduct of the study; consulting fees from Abbvie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, NovoNordisk, outside the submitted work., (The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients., Methods: We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m 2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m 2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m 2 , a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes., Results: A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups., Conclusions: Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.)., (Copyright © 2022 Massachusetts Medical Society.)

Background Outcomes and treatment effects of therapy may vary according to the cause of heart failure (HF). Methods and Results In this post hoc analysis of the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial, the effect of empagliflozin on cardiovascular and renal outcomes was assessed according to the cause of HF. The cause of HF was investigator reported and stratified as ischemic or nonischemic. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs. Of the 3730 patients enrolled, 1929 (51.7%) had ischemic cause. In the placebo arm, patients with ischemic cause of HF did not have a significantly higher risk of cardiovascular mortality (HR, 1.21 [95% CI, 0.90-1.63]) and hospitalization for HF (HR, 0.90 [95% CI, 0.72-1.12]) compared with nonischemic cause. Empagliflozin compared with placebo significantly reduced the risk of cardiovascular death or hospitalization for HF in patients with ischemic and nonischemic cause (HR, 0.82 [95% CI, 0.68-0.99] for ischemic and HR, 0.67 [95% CI, 0.55-0.82] for nonischemic cause; P interaction=0.15). The benefit of empagliflozin on HF hospitalization, the renal composite end point, estimated glomerular filtration slope changes, and health status scores were also consistent in both groups without treatment by cause modification. Conclusions Empagliflozin offers cardiovascular and renal benefits in patients with heart failure with reduced ejection fraction regardless of the cause of HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Aims: Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated., Methods and Results: A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL -1.97 (-2.86, -1.08), -1.74 (-2.73, -0.74); -1.53 (-2.75, -0.31) kg; for WL-adjusted: -2.31 (-3.77, -0.85), -2.79 (-5.03, -0.54), -3.18 (-6.08, -0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001)., Conclusion: Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90., Competing Interests: Conflict of interest: A.A.V. has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. S.P.C. is a consultant for Aiphia, Siemens, Bristol Myers Squibb, Boehringer Ingelheim, and Vixiar and receives research support from the NIH, PCORI, AstraZeneca, and Beckman Coulter. M.N.K. has received research grants from AstraZeneca and Boehringer Ingelheim, and has served as a consultant for Alnylam, AstraZeneca, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Sanofi, and Vifor. J.R.T. has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. C.E.A. has received research support from and/or has been a consultant for Abbott, Boehringer Ingelheim, Medtronic, Novartis, ResMed, Thermo Fisher, Vifor, and German Federal Ministry of Education and Research. J.T. is supported by the National University of Singapore Start-up grant, the tier 1 grant from the ministry of education and the CS-IRG New Investigator Grant from the National Medical Research Council; has received consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche diagnostics, and Us2.ai, owns patent US-10702247-B2 unrelated to the present work. J.P.F. is a consultant for Boehringer Ingelheim and receives research support from AstraZeneca. M.E.N. has received speaking honoraria from Abbott, and is a consultant for Vifor, Roche, and Amgen. P.P. reports personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, Berlin Chemie, and grants and personal fees from Vifor Pharma. J.P.B. is an employee of Elderbrook Solutions. M.B. and A.S. are employees of Boehringer Ingelheim. J.B. and M.A.P. have no competing interests., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: Empagliflozin improves cardiovascular and renal outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but its efficacy and safety across patient's age is not well established., Methods and Results: We assessed the effects of empagliflozin (10 mg daily) versus placebo, on top of standard HF therapy, in symptomatic HFrEF patients with a left ventricular ejection fraction ≤40% and increased natriuretic peptides stratified by age (<65, 65-74, ≥75 years). The primary endpoint was a composite of cardiovascular death or HF hospitalization. Key secondary endpoints included first and recurrent HF hospitalizations and slope of change in estimated glomerular filtration rate (eGFR); the latter was supported by an analysis of a renal composite endpoint (chronic dialysis or renal transplantation or profound and sustained reduction in eGFR). Of 3730 patients, 38% were <65 years, 35% were 65-74 years and 27% were ≥75 years. Compared with placebo, empagliflozin reduced the primary endpoint consistently across the three age groups (hazard ratio 0.71 [95% confidence interval 0.57-0.89] for <65 years, 0.72 [0.57-0.93] for 65-74 years, 0.86 [0.67-1.10] for ≥75 years, interaction p-trend test = 0.24). The effects of empagliflozin were also consistent across age groups for key secondary endpoints of first and recurrent HF hospitalization (p-trend = 0.30), the rate of decline in eGFR (p-trend = 0.78) and the renal composite (p-trend = 0.94). Adverse events (AEs), serious AEs and AEs leading to drug discontinuation increased with age in both treatment arms, but empagliflozin did not increase their incidence over placebo within each age group., Conclusion: The efficacy and safety of empagliflozin in improving cardiovascular and renal outcomes in HFrEF was consistent across the spectrum of age, including older patients (aged ≥75)., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The EMPEROR-Preserved trial showed that the sodium-glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF)  > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41-49%). In patients with LVEF  ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71-0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66-1.04, P = 0.11). For patients with an LVEF of 41-49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57-0.88, P = 0.002) for the primary outcome (P interaction  = 0.27), and 0.57 (95%CI: 0.42-0.79, P < 0.001) for total HHF (P interaction  = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure., (© 2022. The Author(s).)

Importance: Albuminuria, routinely assessed as spot urine albumin-to-creatinine ratio (UACR), indicates structural damage of the glomerular filtration barrier and is associated with poor kidney and cardiovascular outcomes. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been found to reduce UACR in patients with type 2 diabetes, but its use in patients with heart failure (HF) is less well studied., Objective: To analyze the association of empagliflozin with study outcomes across baseline levels of albuminuria and change in albuminuria in patients with HF across a wide range of ejection fraction levels., Design, Setting, and Participants: This post hoc analysis included all patients with HF from the EMPEROR-Pooled analysis using combined individual patient data from the international multicenter randomized double-blind parallel-group, placebo-controlled EMPEROR-Reduced and EMPEROR-Preserved trials. Participants in the original trials were excluded from this analysis if they were missing baseline UACR data. EMPEROR-Preserved was conducted from March 27, 2017, to April 26, 2021, and EMPEROR-Reduced was conducted from April 6, 2017, to May 28, 2020. Data were analyzed from January to June 2022., Interventions: Randomization to empagliflozin or placebo., Main Outcomes and Measures: New-onset macroalbuminuria and regression to normoalbuminuria and microalbuminuria., Results: A total of 9673 patients were included (mean [SD] age, 69.9 [10.4] years; 3551 [36.7%] female and 6122 [63.3%] male). Of these, 5552 patients had normoalbuminuria (UACR <30 mg/g) and 1025 had macroalbuminuria (UACR >300 mg/g). Compared with normoalbuminuria, macroalbuminuria was associated with younger age, races other than White, obesity, male sex, site region other than Europe, higher levels of N-terminal pro-hormone brain natriuretic peptide and high-sensitivity troponin T, higher blood pressure, higher New York Heart Association class, greater HF duration, more frequent previous HF hospitalizations, diabetes, hypertension, lower eGFR, and less frequent use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and mineralocorticoid receptor antagonists. An increase in events was observed in individuals with higher UACR levels. The association of empagliflozin with cardiovascular mortality or HF hospitalization was consistent across UACR categories (hazard ratio [HR], 0.80; 95% CI, 0.69-0.92 for normoalbuminuria; HR, 0.74; 95% CI, 0.63-0.86 for microalbuminuria; HR, 0.78; 95% CI, 0.63-0.98 for macroalbuminuria; interaction P trend = .71). Treatment with empagliflozin was associated with lower incidence of new macroalbuminuria (HR, 0.81; 95% CI, 0.70-0.94; P = .005) and an increase in rate of remission to sustained normoalbuminuria or microalbuminuria (HR, 1.31; 95% CI, 1.07-1.59; P = .009) but not with a reduction in UACR in the overall population; however, UACR was reduced in patients with diabetes, who had higher UACR levels than patients without diabetes (geometric mean for diabetes at baseline, 0.91; 95% CI, 0.85-0.98 and for no diabetes at baseline, 1.08; 95% CI, 1.01-1.16; interaction P = .008)., Conclusions and Relevance: In this post hoc analysis of a randomized clinical trial, compared with placebo, empagliflozin was associated with reduced HF hospitalizations or cardiovascular death irrespective of albuminuria levels at baseline, reduced progression to macroalbuminuria, and reversion of macroalbuminuria., Trial Registration: ClinicalTrials.gov Identifiers: NCT03057977 and NCT03057951.

Background: Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction)., Methods: The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed., Results: Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; P interaction =0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; P interaction =0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score., Conclusions: Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03057951.

Aims: Empagliflozin reduces cardiovascular death (CVD) or heart failure hospitalization (HHF) in patients with heart failure and preserved ejection fraction (HFpEF). Treatment effects and safety in relation to resting heart rate (RHR) have not been studied., Methods and Results: The interplay of RHR and empagliflozin effects in EMPEROR-Preserved was evaluated. We grouped patients (n = 5988) according to their baseline RHR (<70 bpm [n = 2650], 70-75 bpm [n = 967], >75 bpm [n = 1736]) and explored the influence of RHR on CVD or HHF (primary outcome) and its components in sinus rhythm or atrial fibrillation/flutter (AF) and adverse events. We studied the efficacy of empagliflozin across the RHR spectrum. Compared to placebo, empagliflozin did not change heart rate over time. The primary outcome (p for trend = 0.0004) and its components CVD (p trend = 0.0002), first HHF (p for trend = 0.0099) and all-cause death (p <  0.0001) increased with RHR only in sinus rhythm but not AF. The risk increase with RHR was similar in patients with heart failure and mildly reduced ejection fraction (left ventricular ejection fraction [LVEF] 40-49%) and HFpEF (LVEF ≥50%). Baseline RHR had no influence on the effect of empagliflozin on the primary outcomes (p for trend = 0.20), first HHF (p for trend = 0.49). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the RHR groups., Conclusion: Resting heart rate associates with outcomes only in sinus rhythm but not in AF. Empagliflozin reduced outcomes over the entire RHR spectrum without increase of adverse events., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved clinical outcomes in patients hospitalized for acute heart failure. In patients with chronic heart failure, SGLT2 inhibitors cause an early decline in estimated glomerular filtration rate (eGFR) followed by a slower eGFR decline over time than placebo. However, the effects of SGLT2 inhibitors on renal function during a hospital admission for acute heart failure remain largely unknown., Methods and Results: Between 1 and 5 days after a hospitalization for acute heart failure, 530 patients with an eGFR >20 ml/min/1.73 m 2 were randomized to 10 mg of empagliflozin or placebo and treated for 90 days. Renal function and electrolytes were measured at baseline, and after 15, 30 and 90 days. We evaluated the effect of empagliflozin on eGFR over time and the impact of baseline eGFR on the primary hierarchical outcome of death, worsening heart failure events and quality of life. Mean baseline eGFR was 52.4 ml/min/1.73 m 2 in the empagliflozin group and 55.7 ml/min/1.73 m 2 in the placebo group. Empagliflozin caused an initial decline in eGFR (-2 ml/min/1.73 m 2 at day 15 compared to placebo). At day 90, eGFR was similar between empagliflozin and placebo. Investigator-reported acute renal failure occurred in 7.7% of empagliflozin versus 12.1% of placebo patients. The overall clinical benefit (hierarchical composite of all-cause death, heart failure events and quality of life) of empagliflozin was unaffected by baseline eGFR., Conclusion: In patients hospitalized for acute heart failure, empagliflozin caused an early modest decline in renal function which was no longer evident after 90 days. Acute renal events were similar in both groups. The clinical benefit of empagliflozin was consistent regardless of baseline renal function., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The sodium-glucose cotransporter-2 inhibitor empagliflozin decreases the risk of cardiovascular death or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction. Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in patients with HF is unclear. This study aimed to investigate the effect of empagliflozin on SUA levels and the therapeutic efficacy of empagliflozin in relation to SUA., Methods: The association between SUA and the composite primary outcome of cardiovascular death or hospitalization for worsening HF, its components, and all-cause mortality was investigated in 3676 patients of the EMPEROR-Reduced trial (98.6% of the study cohort). The treatment effect of empagliflozin was studied in relation to SUA as continuous variable, to clinical hyperuricaemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) and in subgroups of patients of tertiles of SUA., Results: Hyperuricaemia was prevalent in 53% of patients with no sex differences. Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) was associated with advanced severity of HF and with worst outcome [composite outcome, hazard ratio (HR) 1.64 (95% confidence interval, CI 1.28-2.10); cardiovascular mortality, HR 1.98 (95% CI 1.35-2.91); all-cause mortality, HR 1.8 (95% CI 1.29-2.49), all P < 0.001] in multivariate adjusted analyses, as compared with the lowest tertile. SUA was reduced following treatment with empagliflozin at 4 weeks (vs. placebo: -1.12 ± 0.04 mg/dL, P < 0.0001) and remained lower throughout follow-up, with a similar reduction in all prespecified subgroups. Empagliflozin reduced events of clinically relevant hyperuricaemia (acute gout, gouty arthritis or initiation of anti-gout therapy) by 32% [HR 0.68 (95% CI 0.52-0.89), P = 0.004]. The beneficial effect of empagliflozin on the primary endpoint was independent of baseline SUA [HR 0.76 (95% CI 0.65-0.88), P < 0.001) and of the change in SUA at 4 weeks [HR 0.81 (95% CI 0.69-0.95), P = 0.012]. As a hypothesis-generating finding, an interaction between SUA and treatment effect suggested a benefit of empagliflozin on mortality (cardiovascular and all-cause mortality) in patients in elevated SUA (P for interaction = 0.005 and = 0.011, respectively)., Conclusion: Hyperuricaemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricaemia. The benefit of empagliflozin on the primary outcome was observed independently of SUA., Competing Interests: Conflict of interest: W.D. reports consulting fees from Boehringer Ingelheim (BI) related to work on clinical events committee during the conduct of the study and personal fees from Aimediq, Bayer, BI, Medtronic, Pfizer, Sanofi-Aventis, Sphingotec, Vifor Pharma and research support from EU (Horizon2020), German ministry of Education and Research, German Center for Cardiovascular Research, Vifor Pharma, and ZS Pharma. S.D.A. reports grants from Abbott Vascular and Vifor (International) Ltd; consulting fees from Abbott Vascular; consulting fees from Bayer, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor (International) Ltd and is a Trial Executive Committee member of BI and Eli Lilly and Company (ELC) Diabetes Alliance (trial sponsor). J.B. reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca (AZ), Bayer, BerlinCures, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, Occlutech, and Vifor and is a Trial Executive Committee member of BI and ELC Diabetes Alliance (trial sponsor). F.Z. reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from BI, Amgen, CVRx, AZ, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, and Bayer; other financial or nonfinancial interests in CVCT and Cardiorenal; and is a Trial Executive Committee member of BI and ELC Diabetes Alliance (trial sponsor). G.F. reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from BI, Medtronic, Vifor, Servier, and Novartis; research grants from the European Commission, and is a Trial Executive Committee member of BI and ELC Diabetes Alliance (trial sponsor). J.P.F. reports consulting fees from BI; grants from AZ, Bayer and Novartis; honoraria payments from BI and AZ. and is a Trial Executive Committee member of BI and ELC Diabetes Alliance (trial sponsor). A.S. and M.B. are employees of BI. C.C. is an employee of mainanalytics GmbH, Sulzbach, contracted by Boehringer Ingelheim. S.P. reports consulting fees and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from BI and is a Trial Executive Committee member of BI and ELC Diabetes Alliance (trial sponsor). J.L.J. is a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals and Abbott Diagnostics, consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics, and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. M.P. reports consulting fees from Abbvie, Actavis, Amgen, Amarin, AZ, BI, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, ELC, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance and is a Trial Executive Committee member of BI and ELC Diabetes Alliance (trial sponsor)., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background:  Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children., Objectives:  This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT])., Methods:  Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [ N  = 358]; dTT 2,348 [ N  = 324]; ECT 2,929 [ N  = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements; N  = 1,978). Population models were fitted using nonlinear mixed-effects modeling. Covariates (e.g., sex, age) were assessed on baseline and drug-effect parameters, using a stepwise covariate model-building procedure., Results:  Overall, relationships between dabigatran, aPTT, dTT, and ECT were similar in children and adults. For children aged <6 months, a higher proportion of baseline samples were outside or close to the upper aPTT and ECT adult ranges. No age-related differences were detected for dTT. With increasing dabigatran concentration, aPTT rose nonlinearly (half the maximum effect at 368 ng/mL dabigatran) while dTT and ECT increased linearly (0.37 and 0.73% change per ng/mL dabigatran, respectively). Mean baseline aPTT (45 vs. 36 seconds) and ECT (40 vs. 36 seconds) were slightly increased for those aged <6 months versus older children., Conclusion:  The similar relationships of laboratory parameters observed across pediatric age groups suggests that developmental changes in the hemostatic system may have little effect on response to dabigatran., Competing Interests: L.G.M. is a member of a pediatric expert working group for Boehringer Ingelheim and has received a research grant from Bristol Myers Squibb. D.R. is an employee of Pharmetheus, contracted as an external consultant by Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals. F.H., D.J., I.T., S.G., and M.B. are all employees of Boehringer Ingelheim. M.A. is a member of a pediatric expert working group for Boehringer Ingelheim and has received advisory board fees from Daiichi Sankyo. L.R.B. is a member of a pediatric expert working group for Boehringer Ingelheim and has received advisory board fees from Boehringer Ingelheim. L.B. is a member of a pediatric expert working group for Boehringer Ingelheim, and reports fees to her institution from Janssen Pharmaceuticals. E.C. is a member of a pediatric expert working group for Boehringer Ingelheim, and reports personal fees from Roche, Sobi, Bristol Myers Squibb, CSL Behring, and Shire/Takeda. J.H. is a member of a pediatric expert working group for Boehringer Ingelheim and has received honoraria from Boehringer Ingelheim for congress presentation. M.L. is a member of a pediatric expert working group for Boehringer Ingelheim., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated., Methods: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes., Results: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; P interaction =0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m 2 in patients without diabetes; P interaction =0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome ( P interaction =0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo., Conclusions: In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03057951.

Aims: To report data from EMPEROR-Preserved according to prespecified endpoints of DELIVER., Methods and Results: In order to assess the impact of DELIVER-like definition on EMPEROR-Preserved outcomes, the following differences were reconciled: (1) the primary outcome in DELIVER added urgent heart failure (HF) visits to cardiovascular death or HF hospitalizations; (2) the EMPEROR-Preserved trial did not require documentation of physical findings or laboratory tests for confirming a HF hospitalization and it included events of 12-24 h if intensification of treatment was not only oral diuretics; (3) DELIVER excluded undetermined causes of deaths from the primary endpoint; (4) the composite renal endpoint in DELIVER included a sustained ≥50% decline in estimated glomerular filtration rate and incorporated renal death; and (5) DELIVER will assess outcomes in the overall population and in patients with ejection fraction (EF) <60% separately. Using the endpoint definitions from DELIVER, the primary outcome overall occurred in 13.1% in the empagliflozin and 16.8% in the placebo group (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.67-0.87; p < 0.0001). The relative risk reduction (RRR) changed from 21% to 24% when urgent HF visits were added, and undetermined death was eliminated. Compared to overall population RRR of 24%, it was 28% in patients with EF <60%. Death from cardiovascular causes excluding undetermined causes occurred in 6.2% in the empagliflozin and in 7.1% in the placebo group (HR 0.88, 95% CI 0.73-1.07). The RRR for the composite renal endpoint changed from 22% in the overall population (HR 0.78, 95% CI 0.54-1.13) to 40% when patients with EF <60% were assessed (p = 0.037)., Conclusion: Findings from EMPEROR-Preserved were modestly altered when analysed using cardiovascular trial endpoint definitions of the DELIVER trial. For the composite renal endpoint, the effect of empagliflozin became statistically significant in patients with EF <60% using the DELIVER definition., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized)., Methods: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model., Results: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01-2.20], 1.37 [0.94-1.99], and 1.48 [1.00-2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32-8.59], P =0.03; 4.80 [95% CI, 0.00-9.61], P =0.05; 4.66 [95% CI, 0.32-9.01], P =0.04; 4.85 [95% CI, 0.77-8.92], P =0.02; and 4.40 points [95% CI, 0.33-8.48], P =0.03, respectively)., Conclusions: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT0415775.

Background: Empagliflozin reduces cardiovascular death (CVD) or heart failure (HF) hospitalization (HFH) in patients with HF and preserved ejection fraction. Treatment effects and safety in relation to age have not been studied., Objectives: The purpose of this study was to evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction)., Methods: We grouped patients (n = 5,988) according to their baseline age (<65 years [n = 1,199], 65-74 years [n = 2,214], 75-79 years [n = 1,276], ≥80 years [n = 1,299]). We explored the influence of age on empagliflozin effects on CVD or HFH (primary outcome), total HFH, rate of decline in estimated glomerular filtration rate, health-related quality of life with the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and frequency of adverse events., Results: Considering only patients on placebo, the incidence of primary outcomes (P trend = 0.02) and CVD (P trend = 0.003) increased with age. Empagliflozin reduced primary outcomes (P trend = 0.33), first HFH (P trend = 0.22), and first and recurrent HFH (P trend = 0.11) across all age groups with an effect being similar at ≥75 years (P interaction = 0.22) or >80 years (P interaction = 0.51). Empagliflozin improved Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at week 52 and attenuated the decline of estimated glomerular filtration rate without age interaction (P = 0.48 and P = 0.32, respectively). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the age groups., Conclusions: Empagliflozin reduced primary outcomes and first and recurrent HFH and improved symptoms across a broad age spectrum. High age was not associated with reduced efficacy or meaningful intolerability. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT0305951)., Competing Interests: Funding Support and Author Disclosures All authors were involved in the EMPEROR-Preserved trial, which was funded by Boehringer Ingelheim and Eli Lilly. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Filippatos has received Committee Member contributions in trials and personal fees from Boehringer Ingelheim during the conduct of the study. Dr Ferreira has received consulting fees from Boehringer Ingelheim during the conduct of the study. Dr Pocock has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Mahfoud has received grants and personal fees from Medtronic; and has received personal fees from Recor, Boehringer Ingelheim, and Berlin Chemie. Dr Brueckmann is an employee of Boehringer Ingelheim. Dr Gollop is an employee of Boehringer Ingelheim. Ms Iwata is an employee of Boehringer Ingelheim. Dr Ponikowski has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. Dr Wanner has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline, Gilead, Merck Sharp & Dohme, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius outside the submitted work. Dr Zannad has received Steering Committee or Advisory Board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Packer has received consulting fees from Boehringer Ingelheim during the conduct of the study; and has received consulting fees from AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and Novo Nordisk, outside the submitted work. Dr Anker has received grants and personal fees from Vifor International, and Abbott Vascular; has received personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Abdin has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)