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Randomized Controlled Trial
. 2024 Jun;12(6):999-1011.
doi: 10.1016/j.jchf.2024.02.018. Epub 2024 Apr 17.

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

Senthil Selvaraj  1 , Shachi Patel  2 , Andrew J Sauer  3 , Robert W McGarrah  1 , Philip Jones  2 , Lydia Coulter Kwee  4 , Sheryl L Windsor  2 , Olga Ilkayeva  5 , Michael J Muehlbauer  4 , Christopher B Newgard  4 , Barry A Borlaug  6 , Dalane W Kitzman  7 , Sanjiv J Shah  8 , Svati H Shah  1 , Mikhail N Kosiborod  9 ; PRESERVED-HF Investigators
Affiliations
Randomized Controlled Trial

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

Senthil Selvaraj et al. JACC Heart Fail. 2024 Jun.

Abstract

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).

Keywords: SGLT2i; acylcarnitine; branched-chain amino acids; heart failure with preserved ejection fraction; ketone bodies; metabolomics.

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Conflict of interest statement

Funding Support and Author Disclosures PRESERVED-HF was an investigator-initiated trial funded by AstraZeneca and conducted by Saint Luke’s Mid America Heart Institute independent of the funding source. The PRESERVED-HF metabolomics substudy was funded by the Edna and Fred L. Mandel Jr Foundation seed grant (to Dr Selvaraj) and support from National Institutes of Health grants K23HL161348 (to Dr Selvaraj), R01HL160689 (to Dr McGarrah), and P30DK124723 (to Dr Newgard). Dr Borlaug was supported in part by R01 HL128526, R01 HL162828, and U01 HL160226, from the National Institutes of Health, and W81XWH2210245, from the United States Department of Defense. Dr Kitzman was supported in part by National Institutes of Health grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272. Dr Selvaraj has received research support from the National Heart, Lung, and Blood Institute (K23HL161348), the Doris Duke Charitable Foundation (#2020061), the American Heart Association (#935275), the Mandel Foundation, the Duke Heart Center Leadership Council, the Institute for Translational Medicine and Therapeutics, and the Foundation for Sarcoidosis Research; and has served on advisory boards for AstraZeneca. Dr Sauer has performed consulting, advising, or has received research funding from Abbott, Boston Scientific, Biotronik, Bayer, Amgen, CSK Vifor, Acorai, Story Health, General Prognostics, Impulse Dynamics, and Edwards Lifesciences. Dr McGarrah has been a consultant for AstraZeneca and M3; and has received research funding from Eli Lilly. Dr Newgard is a member of the Eli Lilly Global Diabetes Advisory Board. Dr Borlaug has received research support from the National Institutes of Health and the United States Department of Defense, as well as research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Janssen, Merck, and Novo Nordisk; and is a named inventor (US Patent No. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Kitzman has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer Ingelheim, Novo Nordisk, Rivus, and St. Luke’s Medical Center; has received grant support from Novartis, AstraZeneca, Bayer, Pfizer, Novo Nordisk, Rivus, and St. Luke’s Medical Center; and owns stock in Gilead Sciences. Dr S.J. Shah has received support from research grants from the National Institutes of Health (U54 HL160273, R01 HL140731, and R01 HL149423), Pfizer, and AstraZeneca; and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Corvia, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, Ultromics, and United Therapeutics. Dr S.H. Shah has received research funding through a sponsored Research Agreement to Duke University from AstraZeneca, Lilly, Verily, and nference; and is co-inventor on unlicensed patents held by Duke University. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; is a consultant for and/or on the advisory board of 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has stock options from Artera Health and Saghmos Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1:
Figure 1:. Heatmap of Correlation Between Baseline Metabolite Levels and Changes in Trial Endpoints.
Heatmap cluster correlation matrix is depicted for the relationship between changes in several trial endpoints (KCCQ-OSS, KCCQ-CSS, NT-proBNP, weight, and 6-minute walk test distance) with baseline metabolite levels. See Supplementary Table 1 for metabolite abbreviations. CSS, clinical summary score; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OSS, overall summary score.
Figure 2:
Figure 2:. Heatmap of Correlation Between Changes in Metabolites and Changes in Trial Endpoints.
Heatmap cluster correlation matrix is depicted for the relationship between changes in several trial endpoints (KCCQ-OSS, KCCQ-CSS, NT-proBNP, weight, and 6-minute walk test distance) with changes in metabolites from baseline to follow-up. See Supplementary Table 1 for metabolite abbreviations. CSS, clinical summary score; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OSS, overall summary score.
Figure 3:
Figure 3:. Differences in Metabolites Levels with Dapagliflozin versus Placebo in DEFINE-HF and PRESERVED-HF.
The placebo-adjusted, 12-week differences in metabolite levels that were differentially affected by dapagliflozin treatment in DEFINE-HF are shown in comparison with PRESERVED-HF. Depicted values include the mean placebo-adjusted differences in metabolite levels with the corresponding 95% confidence intervals for each study. DEFINE-HF, Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction; PRESERVED-HF, Dapagliflozin in PRESERVED Ejection Fraction Heart Failure. Created with BioRender.com.
Central Illustration:
Central Illustration:. Targeted Metabolites, Cardiometabolic Endpoints, and Influence of Dapagliflozin in HFpEF
AC, acylcarnitines; BCAA, branched-chain amino acids; HFpEF, heart failure with preserved ejection fraction; CSS, clinical summary score; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OSS, overall summary score; 6MWD, 6-minute walk distance; PRESERVED-HF, Dapagliflozin in PRESERVED Ejection Fraction Heart Failure. Created with BioRender.com.
See this image and copyright information in PMC

References

    1. Nassif ME, Windsor SL, Borlaug BA et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med 2021;27:1954–1960. - PMC - PubMed
    1. Vaduganathan M, Docherty KF, Claggett BL et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet 2022. - PubMed
    1. Hahn VS, Petucci C, Kim MS et al. Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction. Circulation 2023;147:1147–1161. - PMC - PubMed
    1. Schiattarella GG, Altamirano F, Tong D et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature 2019;568:351–356. - PMC - PubMed
    1. Selvaraj S, Fu Z, Jones P et al. Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction: DEFINE-HF. Circulation 2022. - PMC - PubMed

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