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Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have previously demonstrated cardioprotective properties in patients with type 2 diabetes, suggesting a preventive effect on heart failure (HF). The Empire Prevent trial program investigates the therapeutic potential for HF prevention by evaluating the cardiac, metabolic, and renal effects of the SGLT2 inhibitor empagliflozin in patients with increased risk of developing HF, but without diabetes or established HF., Methods: The Empire Prevent trial program is an investigator-initiated, double-blind, randomized clinical trial program including elderly and obese patients (60-84 years, body mass index >28 kg/m 2 ) with at least one manifestation of hypertension, cardiovascular or chronic kidney disease, but no history of diabetes or HF. The aims are to investigate the effects of empagliflozin on 1) physical capacity and left ventricular and atrial structural changes with peak oxygen consumption and left ventricular mass as primary endpoints (Empire Prevent Cardiac), and 2) cardiac-adipose tissue interaction and volume homeostasis with primary endpoints of changes in epicardial adipose tissue and estimated extracellular volume (Empire Prevent Metabolic). At present, 138 of 204 patients have been randomized in the Empire Prevent trial program. Patients are randomized 1:1 to 180 days treatment with empagliflozin 10 mg daily or placebo, while undergoing a comprehensive examination program at baseline and follow-up., Discussion: The Empire Prevent trial program will mark the first step towards elucidating the potential of SGLT2 inhibition for HF prevention in an outpatient setting in elderly and obese patients with increased risk of developing HF, but with no history of diabetes or established HF. Furthermore, the Empire Prevent trial program will supplement the larger event-driven trials by providing mechanistic insights to the beneficial effects of SGLT2 inhibition., Trial Registration: Both parts of the trial program have been registered on September 13th 2021 (Clinical Trial Registration numbers: NCT05084235 and NCT05042973) before enrollment of the first patient. All patients will provide oral and written informed consent. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Medicines Agency. Data will be disseminated through scientific meetings and peer-reviewed journals irrespective of outcome., Competing Interests: Conflict of interest C.F.A. reports grants from the Danish Heart Foundation, Toyota-Fonden, Arvid Nilsson's Foundation, Aase & Ejnar Danielsen's Foundation, Fru Asta Florida Bolding's Memorial Grant, KV Foundation and The Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Herlev, Denmark, during the conduct of the submitted work; personal fees from AstraZeneca and has acted as an unpaid sub-investigator in two trials from Novo Nordisk, outside the submitted work. J.H.L. reports grants from Danish Heart Foundation, Odense University Hospital Ph.D. Foundation, Steno Diabetes Center Odense Ph.D. Foundation, Eva and Henry Frænkel's Memorial Grant, Kurt and Grethe Bønnelykke's Foundation, Guldsmed A.L. Rasmussen's Memorial Grant. Funding organizations had no role in the trial program design, data collection, writing of the article or decision to submit the paper. J.J. reports grants from the Danish Heart Foundation, The CARDIOHGH at the Department of Cardiology, Herlev and Gentofte University Hospital, and The Capital Region of Denmark; personal fees from AstraZeneca (advisory board) and Boehringer Ingelheim (advisory board and contribution to the KARDINAL study), all outside the submitted work. M.A.O reports grants from the Danish Heart Foundation; Steno Diabetes Center Odense, Denmark; and the A.P. Møller Foundation, outside the submitted work. N.N. reports speaker fees from AstraZeneca and Bayer, all outside the submitted work. C.K. has received speaker fees or served on advisory boards for AstraZeneca, Boehringer Ingelheim, Novartis Genzyme, Amicus and Chiesi. C.T. reports speaker fees from Orion Pharma, personal fees for advisory board participation from Boehringer Ingelheim and Bayer A/S, all outside the submitted work. F.G. reports speaker fees from Orion Pharma, Vifor Pharma and Novartis, and personal fees for advisory board participation from Abbott, Pfizer, AstraZeneca, Ionis, Alnylam and Bayer, all outside the submitted work. F.K.K. has served on scientific advisory panels and/or been part of speaker's bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, Lupin, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Pharmacosmos, Sanofi, ShouTi, Zealand Pharma and Zucara; and is a minority shareholder in Antag Therapeutics and co-owner of the weight loss clinic Medicinsk Vægttabsbehandling ApS. F.S.D. reports grants from The CARDIOHGH at the Department of Cardiology, Herlev and Gentofte University Hospital, the Novo Nordisk Foundation and speaker fees from Bayer, all outside the submitted work. K.H. reports grants from the Novo Nordisk Foundation, the Independent Research Fund Denmark, the Region of Southern Denmark, Odense University Hospital, Lilly and Herbert Hansen's Foundation, Jascha Fonden, the Ministry of Higher Education and Science, and the Danish Diabetes Academy all outside submitted work. L.K. reports speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis and Bayer. L.A. reports speaker fees from Novartis. M.S. reports grants from the Danish Heart Foundation, during the conduct of the study; personal fees and non-financial support from AstraZeneca, personal fees from Novo Nordisk and Boehringer Ingelheim, outside the submitted work. J.E.M. reports speaker fees from Novartis, Boehringer Ingelheim, Abiomed, Orion and Abbott, advisory board from Orion and Boehringer Ingelheim, and research grant Abiomed and Roche, all outside submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)