{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:14:16Z","timestamp":1790802856122,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis\u2013defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      The mean age was 66\u00b111 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis\u2013derived metabolite factors (which were comprised of ketone and short-\/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate &gt;500 \u03bcM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      <jats:sub>interaction<\/jats:sub>\n                      &gt;0.10), whereas the ketogenic effect diminished at higher LVEF (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      <jats:sub>interaction<\/jats:sub>\n                      =0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique Identifiers: NCT03030235 and NCT02653482.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.124.011980","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T05:00:31Z","timestamp":1729227631000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":30,"title":["Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction"],"prefix":"10.1161","volume":"17","clinical-trial-number":[{"clinical-trial-number":"nct02653482","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03030235","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8418-7623","authenticated-orcid":true,"given":"Senthil","family":"Selvaraj","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.S., R.W.M., R.J.M., S.H.S.)."},{"name":"Duke Molecular Physiology Institute, Duke University, Durham, NC (S.S., R.W.M., L.C.K., O.I., M.J.M., C.B.N., S.H.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shachi","family":"Patel","sequence":"additional","affiliation":[{"name":"Saint Luke\u2019s Mid America Heart Institute, Kansas City, MO (S.P., A.J.S., P.J., S.L.W., M.N.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9268-2795","authenticated-orcid":true,"given":"Andrew J.","family":"Sauer","sequence":"additional","affiliation":[{"name":"Saint Luke\u2019s Mid America Heart Institute, Kansas City, MO (S.P., A.J.S., P.J., S.L.W., M.N.K.)."},{"name":"University of Missouri-Kansas City (A.J.S., M.N.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6693-7152","authenticated-orcid":true,"given":"Robert W.","family":"McGarrah","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Duke University Medical 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