Relationship of Dapagliflozin With Serum Sodium: Findings From the DAPA-HF Trial

Abstract

Objectives: This study aimed to assess the prognostic importance of hyponatremia and the effects of dapagliflozin on serum sodium in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.

Background: Hyponatremia is common and prognostically important in hospitalized patients with heart failure with reduced ejection fraction, but its prevalence and importance in ambulatory patients are uncertain.

Methods: We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) and secondary outcomes according to sodium category (≤135 and >135 mmol/L). Additionally, we assessed: 1) whether baseline serum sodium modified the treatment effect of dapagliflozin; and 2) the effect of dapagliflozin on serum sodium.

Results: Of 4,740 participants with a baseline measurement, 398 (8.4%) had sodium ≤135 mmol/L. Participants with hyponatremia were more likely to have diabetes, be treated with diuretics, and have lower systolic blood pressure, left ventricular ejection fraction, and estimated glomerular filtration rate. Hyponatremia was associated with worse outcomes even after adjustment for predictive variables (adjusted HRs for the primary outcome 1.50 [95% CI: 1.23-1.84] and all-cause death 1.59 [95% CI: 1.26-2.01]). The benefits of dapagliflozin were similar in patients with and without hyponatremia (HR for primary endpoint: 0.83 [95% CI: 0.57-1.19] and 0.73 [95% CI: 0.63-0.84], respectively, P for interaction = 0.54; HR for all-cause death: 0.85 [95% CI: 0.56-1.29] and 0.83 [95% CI: 0.70-0.98], respectively, P for interaction = 0.96). Between baseline and day 14, more patients on dapagliflozin developed hyponatremia (11.3% vs 9.4%; P = 0.04); thereafter, this pattern reversed and at 12 months fewer patients on dapagliflozin had hyponatremia (4.6% vs 6.7%; P = 0.003).

Conclusions: Baseline serum sodium concentration was prognostically important, but did not modify the benefits of dapagliflozin on morbidity and mortality in heart failure with reduced ejection fraction. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]: NCT03036124).

Keywords: dapagliflozin; heart failure; hyponatremia; sodium; sodium glucose cotransporter 2 inhibitor.

Conflict of interest statement

Funding Support and Author Disclosures The DAPA-HF trial was funded by AstraZeneca. Dr McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217. Dr Docherty has received fees from AstraZeneca (sponsor of DAPA-HF) for his involvement in the DAPA-HF trial to his employer, The University of Glasgow; and has received personal fees from Eli Lilly outside the submitted work. Dr Jhund has been an employee of AstraZeneca and Novartis; has received grants and personal fees from Boehringer Ingelheim; has received personal fees from Cytokinetics and Vifor Pharma outside the submitted work; and is the director of Global Clinical Trials Partners Ltd. Dr Petrie has received fees from AstraZeneca and Eli Lilly during the conduct of the study; and has received personal fees from Novo Nordisk, AstraZeneca, NAPP Pharmaceuticals, Takeda Pharmaceutical, Alnylam, Bayer, Resverlogix, and Cardiorentis; and has received grants and personal fees from Boehringer Ingelheim and Novartis outside the submitted work. Dr Inzucchi has received personal fees from AstraZeneca during the conduct of the study; and has received personal fees from AstraZeneca, Boehringer Ingelheim, Merck, VTV Therapeutics, Sanofi/Lexicon, and Novo Nordisk outside the submitted work. Dr Kober has received grants from AstraZeneca to the institution for participation in the DAPA-HF trial steering committee during the conduct of the study; and has received personal fees from AstraZeneca and Novartis outside the submitted work. Dr Kosiborod has received grants and personal fees from AstraZeneca and Boehringer Ingelheim; and has received personal fees from Sanofi, Amgen, Novo Nordisk, Merck, Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia, Novartis, Applied Therapeutics, Amarin, and Eli Lilly outside the submitted work. Dr Martinez has received personal fees from AstraZeneca during the conduct of the study. Dr Ponikowski has received personal fees and fees to his institution from participation as an investigator in clinical trials from AstraZeneca during the conduct of the study; and has received personal fees from Boehringer Ingelheim, Servier, Novartis, Berlin-Chemie, Bayer, Renal Guard Solutions, Pfizer, Respicardia, Cardiorentis, and Cibiem; and has received grants, personal fees, and fees to his institution from Impulse Dynamics; and has received fees to his institution from Vifor, Corvia, and Revamp Medical outside the submitted work. Dr Sabatine has received grants and personal fees from AstraZeneca during the conduct of the study; and has received grants and personal fees from Amgen, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis; and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, Ionis; and has received grants from Daiichi-Sankyo, Bayer, Pfizer, Poxel, Eisai, GlaxoSmithKline, Quark Pharmaceuticals, and Takeda outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Roche, and Zora Biosciences. Dr Bengtsson has received personal fees from AstraZeneca outside the submitted work. Drs Boulton, Greasley, Langkilde, and Sjöstrand are employees and/or shareholders of AstraZeneca. Dr Boulton is a stockholder of Bristol-Myers Squibb Company. Dr Solomon has received grants from AstraZeneca during the conduct of the study; and has received grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has received personal fees from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya outside the submitted work. Dr McMurray has received grants from and his employer has been paid by AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study; and he has received grants and his employer has been paid by Novartis, Amgen, Bristol-Myers Squibb, Bayer, Abbvie, Dal-Cor, Kidney Research UK, and Cardurion; and he has received grants from the British Heart Foundation outside the submitted work.

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