Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial.

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.

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Déclaration de conflit d'intérêts

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).