Metabolic and Pharmacokinetic Profiling of an Exogenous Ketone Ester by Background SGLT2 Inhibitor Therapy in Heart Failure with Reduced Ejection

Growing evidence supports ketosis in HFrEF, though uncertainty exists regarding use with SGLT2i and dose-dependent effects. In a phase I trial of two KE doses in 20 HFrEF participants, stratified by background SGLT2i, we detailed pharmacokinetic parameters, noting rapid ketosis and short half-life. KE was associated with lower NEFA, BCAA, and most acylcarnitines (except C2/C4-OH). Increases in heart rate and decreases in SBP, 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/SGLT2i.