Dapagliflozin reduces uric acid concentration, an independent predictor of adverse outcomes in DAPA-HF

Kirsty McDowell, Paul Welsh, Kieran F. Docherty, David A. Morrow, Pardeep S. Jhund, Rudolf A. de Boer, Eileen O'Meara, Silvio E. Inzucchi, Lars Køber, Mikhail N. Kosiborod, Felipe A. Martinez, Piotr Ponikowski, Ann Hammarstedt, Anna Maria Langkilde, Mikaela Sjöstrand, Daniel Lindholm, Scott D. Solomon, Naveed Sattar, Marc S. Sabatine, John J.V. McMurray*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Scopus)

Abstract

Aims: Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium–glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial. Methods and results: The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dl) versus tertile 1 (<5.4 mg/dl) were younger (66.3 ± 10.8 vs. 68 ± 10.2 years), more often male (83.1% vs. 71.5%), had lower estimated glomerular filtration rate (58.2 ± 17.4 vs. 70.6 ± 18.7 ml/min/1.73 m2), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06–1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut-off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI −0.93 to −0.74) over 12 months (p < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration. Conclusion: Uric acid remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.

Original languageEnglish
Pages (from-to)1066-1076
Number of pages11
JournalEuropean Journal of Heart Failure
Volume24
Issue number6
DOIs
Publication statusPublished - Jun 2022
Externally publishedYes

Bibliographical note

Funding Information:
DAPA‐HF was funded by AstraZeneca. JJVM is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217.

Funding Information:
: P.W. reports grant income from Roche Diagnostics, AstraZeneca, Boehringer Ingelheim, and Novartis outside the submitted work. K.F.D.'s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA‐HF trial; K.F.D reports personal fees from AstraZeneca and Eli Lilly outside the submitted work. D.A.M. reports grants to the TIMI Study Group from Abbott Laboratories, Amgen, Anthos Therapeutics, AstraZeneca, BRAHMS, Eisai, GlaxoSmithKline, Medicines Co., Merck, Novartis, Pfizer, Roche Diagnostics, Quark, Siemens, and Takeda, and consultant fees from InCardia, Merck & Co, Novartis, and Roche Diagnostics. P.S.J.'s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA‐HF trial and the DELIVER trial; P.S.J. reports speakers and advisory board fees from AstraZeneca, speakers and advisory board fees from Novartis, and advisory board fees and grants from Boehringer Ingelheim. R.A.d.B. has received research grants and/or fees to his institution (UMCG) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche outside the submitted work, and speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche, outside the submitted work. E.O'M. reports serving as a consultant and speaker for AstraZeneca, Bayer, Boehringer Ingelheim and Novartis; steering committee and national lead investigator contracts between her institution (Montreal Heart Institute Research Center) and American Regent, AstraZeneca, Cytokinetics, Merck and Novartis; clinical trial participation with Amgen, Abbott, American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eidos, Novartis, Merck, Pfizer, and Sanofi. S.E.I. reports membership on scientific/research advisory boards for Boehringer Ingelheim, AstraZeneca, Intarcia, Lexicon, Janssen, Sanofi, Merck & Co. and Novo Nordisk, has received research supplies to Yale University from Takeda, and has participated in medical educational projects, for which unrestricted funding from Boehringer Ingelheim, Eli Lilly, and Merck & Co. was received by Yale University. L.K. has received speakers honoraria from Novartis, AstraZeneca, Novo, and Boehringer Ingelheim. M.N.K. has received grant and research support from AstraZeneca, grant and honoraria from Boehringer Ingelheim, and honoraria from Sanofi, Amgen, Novo Nordisk, Merck (Diabetes), Janssen, Bayer, Novartis, Eli Lilly, and Vifor Pharma. N.S. has consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Novo Nordisk, Novartis, Sanofi, and Pfizer; and has received grant support from Boehringer Ingelheim. M.S.S. reports research grant support through Brigham and Women's Hospital from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda, and consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol‐Myers Squibb, CVS Caremark, DalCor, Dr. Reddy's Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis. M.S.S. and D.A.M. are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer, Daiichi‐Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. Conflict of interest

Funding Information:
J.J.V.McM. is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; his employer, Glasgow University, has received payment for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, Theracos; and he has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medscape. A.H., A.M.L., D.L., and M. Sjöstrand are employees of AstraZeneca. K.McD. has nothing to disclose.

Publisher Copyright:
© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

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