Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

Q: What are the key findings of this study?

Empagliflozin significantly improved systolic function in wild-type mice with post-infarct heart failure (ΔEF +9.9% vs -11.6% with saline), a benefit that was abolished in BDH1 or FGF21 knockout mice.

Q: What is the clinical evidence from this study?

Population: Post-myocardial infarction heart failure (n=60). Intervention: Empagliflozin vs. Saline. Primary outcome: Change in left ventricular ejection fraction (ΔEF).

Q: What does this research mean for the field?

Empagliflozin improves post-myocardial infarction systolic function by activating a liver-heart metabolic axis that depends on liver-derived FGF21 and cardiomyocyte BDH1-mediated ketone oxidation. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Dao‐Fu Dai; Inés Martins; Nastaran Daneshgar; Meng Gao; Benjamin Rodriguez; Mohd Mabood Khan; Antentor Hinton; Peter A. Crawford; Chad E. Grueter

doi:10.3390/cells15161478

August 18, 2026CellsOpen Access

Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

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Key result

Empagliflozin improves post-infarct LVEF by ~22% in mice via BDH1 and FGF21 pathways.

n=60

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Why the study?

SGLT2 inhibitors improve outcomes in heart failure, but the underlying mechanisms remain incompletely understood.

Does empagliflozin improve post-infarct heart failure in mice through the FGF21 and ketone body oxidation pathway?

Key Points

To determine whether empagliflozin improves post-myocardial infarction heart failure by activating hepatic fibroblast growth factor-21 (FGF21) and promoting cardiomyocyte ketone body oxidation.
Myocardial infarction was induced via left anterior descending artery ligation in wild-type, cardiomyocyte-specific BDH1-knockout, and hepatocyte-specific FGF21-knockout mice.
Following confirmation of reduced ejection fraction, mice were randomized to empagliflozin (10 mg/kg/day) or saline vehicle for 4 weeks with blinded echocardiographic assessments.
In vitro assays in HepG2 liver cells and human induced pluripotent stem cell-derived cardiomyocytes evaluated cellular mechanisms and gene expression.
Saline-treated wild-type mice exhibited progressive systolic dysfunction (ΔEF: −11.6 ± 6.3%), whereas empagliflozin-treated wild-type mice showed significant functional recovery (ΔEF: 9.9 ± 4.3%).
Empagliflozin-mediated cardiac recovery was completely abolished in cardiomyocyte-specific BDH1-knockout mice (ΔEF: −10.5 ± 2.8%) and in hepatocyte-specific FGF21-knockout mice.
Empagliflozin significantly decreased myocardial fibrosis area in wild-type mice (p = 0.03), but failed to reduce fibrosis in BDH1-knockout mice.

Structured PICO

Does empagliflozin improve post-infarct heart failure in mice through the FGF21 and ketone body oxidation pathway?

P

Population

Approximately 60 male mice aged 8-12 weeks with induced myocardial infarction and LVEF < 0.65, randomized to empagliflozin or saline and followed for 4 weeks.

I

Intervention

Empagliflozin 10 mg/kg/day via intraperitoneal injection or gavage for 1 to 4 weeks (in vivo); Empagliflozin 10 μM or 50 μM for 8 to 48 hours (in vitro).

C

Comparator

Saline vehicle (in vivo) or saline control (in vitro).

O

Outcome

Change in left ventricular ejection fraction (ΔEF) at 4 weeks post-treatment, measured by conscious transthoracic echocardiography.surrogate

Main Result

Absolute Event Rate: 9.9% vs -11.6%

Empagliflozin improves post-infarct cardiac function by activating a liver-heart metabolic axis that requires hepatic FGF21 production and cardiomyocyte BDH1-mediated ketone oxidation.

Limitations

Experiments were performed primarily in murine models and human cell models, requiring further validation in patient populations.
Detailed signaling mechanisms between hepatic FGF21 and cardiac BDH1 are incompletely understood.
Metabolic flux analysis for β-hydroxybutyrate and acetoacetate was not performed.
HepG2 cells may differ from primary hepatocytes with respect to metabolic regulation.
It remains unclear whether similar mechanisms contribute to the beneficial effects of other SGLT2 inhibitors.
Performed primarily in murine models and human cell models, requiring further validation in patient populations and other types of heart failure
Detailed signaling mechanisms are incompletely understood
Lack of reliable metabolic flux analysis for β-hydroxybutyrate and acetoacetate in sick mice
HepG2 cells may differ from primary hepatocytes with respect to metabolic regulation and FGF21 production
Unclear whether similar mechanisms contribute to the beneficial effects observed with other members of the SGLT2 inhibitor class

Ask about this paper

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Implication

Empagliflozin's post-MI systolic benefit requires FGF21 and cardiomyocyte BDH1 in mice; leaves open translation of this axis to human HF therapy.

Abstract

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure, but the mechanisms remain incompletely understood. Metabolic remodeling has been proposed as a key mediator. Methods and Results: Myocardial infarction (MI) was induced in cardiomyocyte-specific BDH1 knockout (BDH1-KO) wild-type (WT) mice and in liver-specific Fibroblast Growth Factor-21 knockout (FGF21-KO) mice. Following confirmation of reduced ejection fraction (EF), mice were randomized to empagliflozin (Empa, 10 mg/kg/day) or saline. After 4 weeks, untreated WT mice demonstrated progressive systolic dysfunction (ΔEF: −11.6 ± 6.3%), whereas Empa-treated WT mice showed significant improvement (ΔEF: 9.9 ± 4.3%). This benefit was completely abolished in BDH1-KO mice (ΔEF: −10.5 ± 2.8%) or FGF21-KO mice, suggesting that FGF21 regulation and cardiomyocyte ketone oxidation are required for Empa cardioprotection. In WT and hepatocyte-specific FGF21-KO mice, 1 week of Empa treatment increased cardiac BDH1 expression in WT but not FGF21-deficient mice. In human iPSC-cardiomyocytes, FGF21 induced BDH1 expression, whereas Empa had no direct effect on BDH1. In HepG2 liver cells, Empa increased both FGF21 and BDH1 expression. Conclusions: Empa activates the liver–heart metabolic axis. Loss of cardiomyocyte BDH1 or FGF21 production by the liver abolishes Empa-mediated improvement in post-MI cardiac function, identifying FGF21/ketone metabolism as a key mechanism of SGLT2 inhibitor cardioprotection.

Discussion

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Cite This Study

Dai et al. (2026) studied Post-myocardial infarction heart failure (n=60). Empagliflozin vs. Saline was evaluated on Change in left ventricular ejection fraction (ΔEF). Empagliflozin significantly improved systolic function in wild-type mice with post-infarct heart failure (ΔEF +9.9% vs -11.6% with saline), a benefit that was abolished in BDH1 or FGF21 knockout mice.

synapsesocial.com/papers/6a86b5978a91293e6a1ccf81 https://doi.org/10.3390/cells15161478

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Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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