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 Backg

Background Heart 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. Methods We 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. Results Baseline β‐hydroxybutyrate inversely correlated with SGLT2 inhibitor outcomes (r=−0.67, P <0.001). The lowest ketone tertile demonstrated superior outcomes (hazard ratio [HR], 0.58 [95% CI, 0.51–0.66], P <0.001), and the highest tertile showed elevated risk (HR, 1.58 [95% CI, 1.39–1.79], P <0.001). East Asian populations exhibited 34.24% higher baseline ketone levels (2.47±0.83 versus 1.84±0.61 mmol/L, P <0.001) with attenuated treatment benefit versus European ancestry. Machine learning models achieved area under the receiver operating characteristic curve of 0.8245 (95% CI, 0.8012–0.8478) predicting individual outcomes from baseline metabolomic profiles. Conclusions Baseline 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.