SGLT2 independent effects of the SGLT2 inhibitor empagliflozin Focus on the heart

This thesis explores how sodium glucose cotransporter 2 inhibitors (SGLT2i), particularly empagliflozin (EMPA), reduce cardiovascular risk by investigating their effects on cardiac infarction, hypertrophy, and heart failure (HF). SGLT2i demonstrate significant cardiovascular benefits across diabetic and non-diabetic populations, possibly through off-target effects. The study has reviewed EMPA's acute impact on cardiac physiology, focusing on ion homeostasis, inflammation, oxidative stress, and metabolism. It also investigates EMPA's effects on cardiac metabolism in diabetic hearts, revealing reduced lactate generation and augmented α-ketoglutarate synthesis. EMPA directly inhibits the cardiac sodium hydrogen exchanger 1 (NHE1), albeit with varying results in different experimental setups. Additionally, EMPA attenuates cardiac hypertrophy by inhibiting NHE1 and the RSK pathway. Furthermore, preclinical research and observational studies highlight SGLT2i's role in reducing infarct size, independent of SGLT2 expression. In a murine HF model, EMPA's protective effects involve NHE1, nitric oxide (NO), and interconnected pathways, independent of SGLT2. Notably, EMPA's benefits in HF are not solely reliant on SGLT2 expression. Lastly, the thesis explores how EMPA protects against HF by improving cardiac metabolism, independently of SGLT2. It reveals that EMPA's metabolic alterations precede its mechanical benefits, suggesting SGLT2-independent mechanisms at play. These findings contribute to understanding the multifaceted cardioprotective effects of EMPA and SGLT2i, paving the way for further research in cardiovascular disease management.