Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.

backgroundMechanisms 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.

methodsMetabolomic 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-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points.

resultsThe mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (

conclusionsSGLT2is 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. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482.