Effects of empagliflozin and dapagliflozin on serum humanin, MOTS-c levels, nitrosative stress, and ferroptosis parameters in diabetic patients with heart failure

Sodium-glucose cotransporter 2 (SGLT2) inhibitors produce cardioprotective effects on heart failure (HF), even in the absence of diabetes. However, the underlying mechanisms of this cardioprotective effect remain unexplored. The purpose of this study was to examine the effects of SGLT2 inhibitors on serum MOTS-c, humanin levels, nitrosative stress, and ferroptosis parameters in diabetic patients with HF with reduced ejection fraction (HFrEF). A total of 74 adult diabetic patients with HFrEF and 37 healthy controls were included in this prospective study. Half of the patients were using SGLT2 inhibitors (empagliflozin or dapagliflozin) for at least two months. Serum nitric oxide and 3-nitrotyrosine levels were markedly higher in diabetic patients with HFrEF than the control (P < 0.001), but these elevations were inhibited with SGLT2 inhibitors. Although SGLT2 inhibitors had no marked effect on humanin levels, they significantly augmented MOTS-c levels when compared to the control. SGLT2 inhibitors augmented GPX4 but inhibited ACSL4 levels when compared to diabetic patients with HF. However, TFRC levels were increased in the patient group (P < 0.001 for all) but not modified with SGLT2 inhibitors. Our results suggest that increased nitrosative stress is significantly depressed by SGLT2 inhibitors. This study was the first to show that SGLT2 inhibitors can stimulate MOTS-c, but not humanin, in diabetic patients with HFrEF. SGLT2 inhibitors reduced ferroptosis through elevation of GPX4 and suppression of ACSL4 levels. Our data suggest that SGLT2 inhibitors could produce cardioprotective effects through relieving ferroptosis, inhibiting nitosative stress, and stimulating mitochondrial MOTS-c release.