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Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial.

Publication ,  Journal Article
Selvaraj, S; Patel, S; Sauer, AJ; McGarrah, RW; Jones, P; Kwee, LC; Windsor, SL; Ilkayeva, O; Muehlbauer, MJ; Newgard, CB; Borlaug, BA ...
Published in: JACC Heart Fail
April 3, 2024

BACKGROUND: Although sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF. OBJECTIVES: The goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF. METHODS: Targeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed. RESULTS: The mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro-B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro-B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction. CONCLUSIONS: Leveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235).

Duke Scholars

Published In

JACC Heart Fail

DOI

EISSN

2213-1787

Publication Date

April 3, 2024

Location

United States

Related Subject Headings

  • 3201 Cardiovascular medicine and haematology
  • 1102 Cardiorespiratory Medicine and Haematology
 

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Selvaraj, S., Patel, S., Sauer, A. J., McGarrah, R. W., Jones, P., Kwee, L. C., … PRESERVED-HF Investigators, . (2024). Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial. JACC Heart Fail. https://doi.org/10.1016/j.jchf.2024.02.018
Selvaraj, Senthil, Shachi Patel, Andrew J. Sauer, Robert W. McGarrah, Philip Jones, Lydia Coulter Kwee, Sheryl L. Windsor, et al. “Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial.JACC Heart Fail, April 3, 2024. https://doi.org/10.1016/j.jchf.2024.02.018.
Selvaraj S, Patel S, Sauer AJ, McGarrah RW, Jones P, Kwee LC, et al. Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial. JACC Heart Fail. 2024 Apr 3;
Selvaraj, Senthil, et al. “Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial.JACC Heart Fail, Apr. 2024. Pubmed, doi:10.1016/j.jchf.2024.02.018.
Selvaraj S, Patel S, Sauer AJ, McGarrah RW, Jones P, Kwee LC, Windsor SL, Ilkayeva O, Muehlbauer MJ, Newgard CB, Borlaug BA, Kitzman DW, Shah SJ, Shah SH, Kosiborod MN, PRESERVED-HF Investigators. Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial. JACC Heart Fail. 2024 Apr 3;
Journal cover image

Published In

JACC Heart Fail

DOI

EISSN

2213-1787

Publication Date

April 3, 2024

Location

United States

Related Subject Headings

  • 3201 Cardiovascular medicine and haematology
  • 1102 Cardiorespiratory Medicine and Haematology