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.
Full Paper - https://doi.org/10.1161/JAHA.125.048427
Mendelian randomization (hypothesis generating) of epidemiology (a systematic review of epidemiology is still only as strong as the epidemiology itself, so not at all) in patients with heart failure on sglt2's. Lower ketone bodies had better HF outcomes, but also along ethnic lines (so other variables could account for it as well)
Not that these populations were not doing ketogenic eating patterns, or low carb, just their background ketone levels in their typical diet while on sglt2s, so high carb
But that doesn't follow also from the paper
So its possible the sglt2 is interfering with ketone use (hence the ketone build up in a high carb diet), resulting in their negative outcomes, but their opinion is against ketones in general.
Even if you take this epidemiology as truth - are you a east asian taking a sglt2 alongside a high carb diet while maintaining ketone levels > 2.25mmol/l?
The next research question is : how would a high carb diet with sglt2 inhibitors compare against a ketogenic diet without sglt2 inhibitors in IHF? i.e. are the benefits from the slgt2 based on ketone metabolism? we don't know. The east-asian's might also have non-impaired ketogenic metabolism without the sglt2s.