ArticleJournal of the American Heart Association2026
Ketone Body Metabolism and Sodium Glucose Cotransporter 2 Inhibitor Response in Heart Failure With Ischemic Cause: A Precision Medicine Approach Using Metabolomics Integration With Global Burden of Disease Population Data Across Diverse Genetic Backgrounds.
Article in Journal of the American Heart Association, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundHeart failure with ischemic cause is associated with substantial cardiovascular mortality. SGLT2 (sodium glucose cotransporter 2) inhibitors demonstrate cardiovascular benefits, but interindividual response variability remains poorly understood. We investigated the relationship between baseline ketone body metabolism and SGLT2 inhibitor response in heart failure with ischemic cause across diverse genetic backgrounds.
methodsWe analyzed metabolomics data from 3847 patients with heart failure with ischemic cause across 23 countries (2020-2024). Ketone body metabolites (β-hydroxybutyrate, acetoacetate, acetone) were quantified by liquid chromatography-mass spectrometry. SGLT2 inhibitor response was assessed via a composite end point including cardiovascular mortality, heart failure hospitalization, and kidney function decline. Analyses included multivariate Cox regression, machine learning (Random Forest, Extreme Gradient Boosting), and Mendelian randomization, integrating Global Burden of Disease 2021 data across 5 genetic ancestry groups.
resultsBaseline β-hydroxybutyrate inversely correlated with SGLT2 inhibitor outcomes (r=-0.67,
conclusionsBaseline ketone body metabolism is strongly associated with SGLT2 inhibitor outcomes in heart failure with ischemic cause, with marked interancestry variability. Metabolomic profiling may inform precision medicine approaches to therapeutic decision-making, pending prospective validation.
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