Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy.

BACKGROUND

Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity.

OBJECTIVES

The study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo

METHODS

A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo

RESULTS

The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo

CONCLUSIONS

Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).

Informations de copyright

Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Funding Support and Author Disclosures This study was funded by Applied Therapeutics, Inc. Dr Januzzi is supported in part by the Adolph Hutter Professorship at Harvard Medical School; is a trustee of the American College of Cardiology; is a Board member of Imbria Pharmaceuticals; is a director at Jana Care; has received research support from Abbott, Applied Therapeutics, Bayer, Bristol Myers Squibb, HeartFlow Inc, Innolife, Medtronic and Roche Diagnostics; has received consulting income from Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Cytokinetics, Janssen, Merck, Novartis, Prevencio, Quidel/Ortho, and Roche Diagnostics; and participates in Clinical Endpoint Committees/Data Safety Monitoring Boards for Abbott, AbbVie, Axon, Bayer, CVRx, Medtronic, Pfizer, Roche Diagnostics, and Takeda. Dr Butler is 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, 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. Dr Del Prato has served as president of the European Society for the Study of Diabetes/European Foundation for the Study of Diabetes (2020-2022); has received research grants to the institution from AstraZeneca and Boehringer Ingelheim; has served as an advisor for Abbott, Amarin Corporation, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, EvaPharma, Jiangsu Hengrui Pharmaceuticals Co, Menarini International, Merck Sharpe & Dohme, Novartis Pharmaceutical Co, Novo Nordisk, Sanofi, and Sun Pharmaceuticals; and has received fees for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, Laboratori Guidotti, Menarini International, Merck Sharpe & Dohme, and Novo Nordisk. Dr Ezekowitz has received research support for trial leadership, honoraria, or grants from American Regent, Applied Therapeutics, AstraZeneca, Bayer, Cytokinetics, Merck & Co, Novo Nordisk, and Otsuka. Dr Ibrahim has served as a consultant for Cytokinetics; and has served on the Steering Committee for Applied Therapeutics. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr Lewis has received research funding from the National Institutes of Health (U01 HL160278, R01-HL 151841, R01-HL131029, R01-HL159514), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, Imbria, Pfizer, Rivus, and SoniVie; has received honoraria for consulting and Advisory Boards outside of the current study from American Regent, Amgen, Cytokinetics, Edwards, Pfizer, Merck, Boehringer Ingelheim, NXT, and Amgen; and receives royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Perfetti is an employee of Applied Therapeutics. Dr Rosenstock has served on Scientific Advisory Boards and received honoraria or consulting fees from Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Eli Lilly, Endogenex, Hanmi, Novo Nordisk, Oramed, Regor, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharma, and Zealand; and has received grants/research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Merck, Oramed, Novartis, Novo Nordisk, Pfizer, and Sanofi. Dr Solomon has received a research grant to his institution from Applied Therapeutics for the conduct of the trial; has received research grants to his institution from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI outside the submitted work; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo outside the submitted work. Dr Tang has served as consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Boston Scientific, WhiteSwell, Kiniksa Pharmaceuticals, Intellia Therapeutics, CardiaTec Biosciences, Bristol Myers Squibb, and Alleviant Medical; and has received honoraria from Springer Nature, Belvoir Media Group, and the American Board of Internal Medicine. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; holds stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and is the founder of Cardiovascular Clinical Trialists. Dr Marwick has reported that he has no relationships relevant to the contents of this paper to disclose.