Uric Acid and SGLT2 Inhibition With Empagliflozin in Heart Failure With Preserved Ejection Fraction: The EMPEROR-Preserved Trial.

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.

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

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.