Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial

Cardiovasc Diabetol. 2024 Apr 27;23(1):145. doi: 10.1186/s12933-024-02221-2.

Abstract

Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium.

Methods: This post hoc analysis of the EMMY trial investigated the changes in serum β-hydroxybutyrate (3-βOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-βOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio).

Results: The mean 3-βOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-βOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-βOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-βOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-βOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant.

Conclusion: This post hoc analysis showed that SGLT2i increased 3-βOHB levels after AMI compared to placebo. Higher baseline 3-βOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-βOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-βOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.

Keywords: 3-βOHB; Beta-hydroxybutyrate; Clinical Trial; Empagliflozin; Ketone body; SGLT2 inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Randomized Controlled Trial
  • Multicenter Study

MeSH terms

  • 3-Hydroxybutyric Acid* / blood
  • Aged
  • Benzhydryl Compounds* / therapeutic use
  • Biomarkers* / blood
  • Female
  • Glucosides* / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain* / blood
  • Peptide Fragments* / blood
  • Sodium-Glucose Transporter 2 Inhibitors* / adverse effects
  • Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
  • Stroke Volume / drug effects
  • Time Factors
  • Treatment Outcome
  • Ventricular Function, Left* / drug effects

Substances

  • empagliflozin
  • Sodium-Glucose Transporter 2 Inhibitors
  • Biomarkers
  • Benzhydryl Compounds
  • Glucosides
  • Natriuretic Peptide, Brain
  • Peptide Fragments
  • pro-brain natriuretic peptide (1-76)
  • 3-Hydroxybutyric Acid