SGLT2i Therapy Prevents Anthracycline-Induced Cardiotoxicity in a Large Animal Model by Preserving Myocardial Energetics.

Summary

In a randomized large-animal model, empagliflozin preserved LVEF (57.5% vs 47.0% control) and eliminated AIC events at 20 mg while enhancing ketone utilization and preserving myocardial energetics and mitochondrial integrity. Effects were dose-dependent and consistent across imaging, metabolomics, and ultrastructure.

Key Findings

• Empagliflozin 20 mg preserved LVEF (median 57.5%) versus doxorubicin control (47.0%), P=0.027.
• AIC events occurred in 0% (20 mg), 50% (10 mg), and 72% (control), indicating dose-dependent protection.
• Mechanistic readouts showed increased myocardial ketone uptake, preserved energetics by MRS, and improved mitochondrial structure and respiration.

Clinical Implications

Empagliflozin prophylaxis may protect high-risk patients receiving anthracyclines; dose selection (e.g., 20 mg) and timing merit clinical testing with safety monitoring.

Limitations

• Preclinical (porcine) data; external validity to humans uncertain
• Single anthracycline regimen and female animals may limit generalizability

Future Directions

Randomized clinical trials to test SGLT2i prophylaxis in patients receiving anthracyclines, with biomarker and imaging substudies to validate energetic mechanisms.