SGLT2 Inhibitors Modulate Mitochondrial Peptides and Cellular Stress in Diabetic Heart Failure

Diabetic heart failure is a complex condition characterized by impaired cardiac function and metabolic dysregulation. SGLT2 inhibitors like empagliflozin and dapagliflozin have demonstrated significant cardioprotective benefits in these patients, extending beyond their glucose-lowering effects. However, the precise mechanisms underlying these broader benefits, particularly their influence on mitochondrial-derived peptides like humanin and MOTS-c, and their impact on cellular stress pathways such as nitrosative stress and ferroptosis, remain incompletely understood.

The study revealed significant modulations in the measured parameters following treatment with SGLT2 inhibitors. Patients receiving empagliflozin or dapagliflozin showed a marked increase in serum levels of both humanin and MOTS-c, mitochondrial-derived peptides known for their protective roles. Furthermore, the treatment significantly reduced markers associated with nitrosative stress, indicating a decrease in oxidative damage. The most important finding was the substantial attenuation of ferroptosis parameters, suggesting a protective effect against iron-dependent cell death in the cardiac tissue of these vulnerable patients. These beneficial changes were consistently observed across both empagliflozin and dapagliflozin groups compared to baseline or control, highlighting a shared mechanism of action beyond glycemic control.