Circulating Ketone Body Levels in Acute Heart Failure Treated With Empagliflozin

Circulating ketone body concentrations are significantly higher during acute decompensated heart failure and unaffected by empagliflozin.

During acute decompensated heart failure (HF) vs after stabilization, circulating ketone body concentrations, particularly acetone, are significantly higher, and these concentrations in patients with acute HF are unaffected by empagliflozin treatment. These are among the analysis findings published in the Journal of Cardiac Failure.

Investigators aimed to test the hypothesis that patients with acute decompensated HF have increased ketogenesis and that higher circulating ketone body concentrations will be found during acute cardiac decompensation than after stabilization. The secondary endpoint was additional increases in circulating ketone body concentrations with SGLT2-inhibitors.

They initiated a post-hoc analysis that included 79 patients (≥18 years of age; median age, 76 years [IQR, 68-83]) from the EMPA-RESPONSE-AHF trial ( Identifier: NCT03200860) hospitalized with acute HF between 2017 and 2019. EMPA-RESPONSE-AHF was a randomized double-blind, placebo controlled, multicenter study. Patients (34% women) given placebo were compared with those treated with sodium-dependent glucose-cotransporter protein 2 inhibitor empagliflozin for 30 days. Baseline and 5 other time point measurements (after 24, 48, 72, and 96 hours and after 30 days) were recorded for acetoacetate, plasma concentrations of ketone bodies acetone, and β-hydroxybutyrate.

Group demographics and vital clinical signs at baseline were similar. Higher heart rates, higher left ventricular ejection fraction (P =.042), a higher prevalence of atrium fibrillation/-flutter (P =.012), and higher NT-pro BNP concentrations (P =.036) were noted in patients with higher baseline total ketone body (TKB) concentrations.

Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared to after stabilization.

The investigators found median TKB concentrations gradually decreased from baseline 251 (IQR, 178-377) µmol/L to 202 [IQR, 156-240] µmol/L at day 30 (P =.041). They observed acetone decreased from baseline 60 (IQR, 34-94) µmol/L to 30 (IQR, 21-42) µmol/L at day 30 (P <.001). They noted higher acetone concentrations correlated with higher N-terminal pro b-type natriuretic peptide (NT-pro BNP) levels (r=0.234; P =.039).

They found greater risk of HF rehospitalizations, in-hospital worsening HF, and all-cause death after 30 days was univariately associated with baseline higher acetone concentration. Acetone was no longer an independent predictor for this combined outcome following adjustment for sex and age.

The investigators noted higher heart rate was associated with higher β-hydroxybutyrate concentrations (r=0.243; P =.031) and with higher TKB (r=0.237; P =.035). They found no significant associations between NT-pro BNP and TKB, β-hydroxybutyrate, or acetoacetate.

Acetoacetate and β-hydroxybutyrate remained stable throughout analysis. Patients treated with empagliflozin or placebo throughout analysis experienced no difference in circulating ketone bodies.

Analysis limitations include that the patient measurements were taken in a fed state which may mask the ketolytic effect of empagliflozin treatment. The sample size is also underpowered and no distinction is made between patients with HF with persevered or reduced ejection fraction.

The investigators believe their results suggest ketone body metabolism is activated during acute HF episodes. “Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared to after stabilization,” the study authors wrote. “Empagliflozin did not affect ketone body concentrations in our study.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Voorrips SN, Boorsma EM, Beusekamp JC, et al. Longitudinal changes in circulating ketone body levels in patients with acute heart failure: a post hoc analysis of the EMPA-Response-AHF Trial. J Card Fail. Published online October 14, 2022. doi:10.1016/j.cardfail.2022.09.009