Antioxidant Effects of SGLT2 Inhibitors on Cardiovascular-Kidney-Metabolic (CKM) Syndrome

The cardiovascular-kidney-metabolic (CKM) syndrome was recently conceptualized to provide a holistic framework for diagnosing and treating the full spectrum of key age-associated interrelated conditions: overweight/obesity, type 2 diabetes mellitus, acute and chronic kidney disease, and cardiovascular disease. This conceptualization resulted from epidemiological associations, advances in our understanding of shared and interrelated pathogenic mechanisms, and observations that several drug families improved outcomes in all three components of CKM. Sodium/glucose cotransporter 2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) enhance all CKM spectrum components, although their efficacy varies against specific components. However, the modified mechanisms by these drugs beyond glycemic control in CKM syndrome are poorly understood. We now deeply review the available literature regarding the impact of SGLT2i on oxidative stress and antioxidant defenses in preclinical and clinical studies of type 2 diabetes mellitus, acute and chronic kidney disease, cardiovascular disease, and CKM syndrome. Evidence suggests that SGLT2i may have a secondary antioxidant effect that reduces the vicious cycle of tissue injury-inflammation-tissue injury, even in organs distant from the primary injury.