Metabolic and Pharmacokinetic Profiling of a Ketone Ester by Background SGLT2 Inhibitor Therapy in HFrEF
Growing evidence supports therapeutic ketosis in heart failure with reduced ejection fraction, though uncertainty exists regarding use with SGLT2i and dose-dependent effects. In a phase I trial of 2 ketone ester (KE) doses in 20 heart failure with reduced ejection fraction participants, stratified by background SGLT2i, the authors detailed pharmacokinetic parameters, noting rapid ketosis and short half-life. KE was associated with lower non-esterified fatty acid, branched-chain amino acids, and most acylcarnitines (except C2 and C4-OH, which increased); differences were observed by SGLT2i and KE dose. Increases in heart rate and decreases in systolic blood pressure, pH, and bicarbonate were generally transient. KE ingestion induces rapid changes in key metabolic pathways, differentially affected by SGLT2i (fatty acid metabolism) and KE dose (ketone metabolism). Hemodynamic effects were transient and irrespective of dose or SGLT2i. (Ketone Pharmacokinetic Study in HFrEF; NCT05757193).
Authors
- Kenneth B. Margulies (ORCID: https://orcid.org/0000-0002-8093-4465)
- Michael J. Muehlbauer (ORCID: https://orcid.org/0000-0003-1501-0706)
- Lacey D. Taylor
- Lydia Coulter Kwee (ORCID: https://orcid.org/0000-0002-6997-8571)
- Svati H. Shah (ORCID: https://orcid.org/0000-0002-3495-2830)
- Daniel P. Kelly (ORCID: https://orcid.org/0000-0002-3811-9491)
- Senthil Selvaraj (ORCID: https://orcid.org/0000-0001-8418-7623)
- M He (ORCID: https://orcid.org/0009-0000-4329-4852)
- Payman L. Zamani (ORCID: https://orcid.org/0000-0002-9345-5834)
- Olga Ilkayeva (ORCID: https://orcid.org/0000-0002-9779-0883)
- Marat Fudim (ORCID: https://orcid.org/0000-0002-8671-7007)
- Robert John Mentz (ORCID: https://orcid.org/0000-0002-3222-1719)
- Melissa Hurdle
- Christoph P. Hornik (ORCID: https://orcid.org/0000-0001-7056-8759)
- W. Todd Cade (ORCID: https://orcid.org/0000-0002-2329-7623)
- Chetan B. Patel (ORCID: https://orcid.org/0000-0002-3990-5689)
- Adam D. DeVore (ORCID: https://orcid.org/0000-0002-4679-2221)
- Elizabeth J. Thompson
- C. B. Newgard
- Stephanie Milosovic
Institutions
- Duke University (US)
- Hospital of the University of Pennsylvania (US)
- Clinical Research Institute (US)
- Duke Medical Center (US)
- Duke University Hospital (US)
Publication Details
- Journal
- JACC Basic to Translational Science
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1016/j.jacbts.2024.10.014
- Citations
- 4
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 1.31
Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases