Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence

Abstract

Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II (Ang II), the main mediator of the renin-angiotensin-aldosterone system (RAAS), also contributes to CVD by promoting ROS production. Reduced activity of sirtuins, a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High sirtuin levels and AMPK signaling stimulate hypoxia-inducible factor 1 beta (HIF-1β), which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. SGLT2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on all of these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increases mitochondrial efficiency, reduces oxidative stress and inflammation, and strengthens tissues. These findings suggest that SGLT2 inhibitors have great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs, however, rigorous research is needed to validate these preliminary findings.