The effect of empagliflozin on ketone bodies in patients with heart failure with reduced ejection fraction (Empire HF)

Abstract Background The thrifty-substrate hypothesis suggests that Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors increase plasma levels of ketone bodies and create a salutary switch in myocardial fuel metabolism. Purpose We investigated the effect of SGLT2 inhibitor on plasma beta-hydroxybutyrate in patients with heart failure and reduced ejection fraction (HFrEF). Method This is a post hoc analysis of the Empagliflozin in Heart Failure Patients with Reduced Ejection Fraction (Empire HF) trial, an investigator-initiated, double-blind, randomized, placebo-controlled trial which enrolled 190 stable HFrEF patients with a left ventricular ejection fraction (LVEF) of ≤40%. Patients were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo. Analyses were performed in patients with complete data using a linear-mixed effect-model with log-transformed beta-hydroxybutyrate, adjusted for baseline beta-hydroxybutyrate value, age, sex, and type 2 diabetes. Results A total of 188 (99%) patients had available data. The groups were well-matched with respect to baseline characteristics. Mean age was 64 (SD, 11) years; LVEF was 29 (SD, 8) %, 13% had type 2 diabetes, New York Heart Association (NYHA) class II was found in 78%. Median plasma levels of beta-hydroxybutyrate were 0.10 (inter quartile range (IQR) 0.05–0.18) mmol/l at baseline, and 0.11(IQR 0.07–0.2) mmol/l at follow-up in the empagliflozin group. In the placebo group, baseline and at follow-up concentrations were 0.10 (0.06–0.17) mmol/l and 0.09 (0.05–0.15) mmol/l, respectively. Empagliflozin increased plasma levels of beta-hydroxybutyrate compared to placebo (adjusted between-groups treatment effect; Ratio of change 1.45 [95%confidence interval (CI); 1.12–1.87], p = 0.005 (Figure 1). The effect of empagliflozin on beta-hydroxybutyrate outcomes was consistent across multiple subgroups analyses including baseline median age, sex, N-terminal-pro B-type natriuretic peptide (NT-proBNP) cut-off 600 pg/mL, treatment with sacubitril–valsartan or beta-blockers, measured glomerular filtration rate (GFR) level, hemoglobin A1c (HbA1c) level, and concomitant type 2 diabetes (all P interaction>0.05). Conclusion In patients with HFrEF, predominantly without diabetes, short-term treatment with empagliflozin increased the levels of beta-hydroxybutyrate. The absolute changes were modest and the exact contribution of ketone bodies to the cardiovascular benefits of SGLT2 inhibitors requires further clarification.Figure 1Table 1