Beyond their metabolic effect, sodium–glucose cotransporter-2 (SGLT-2) inhibitors reduce the risk of heart failure and have cardiovascular and nephroprotective effects, yet their exact mechanism of action remains unclear. This prospective study included 40 patients with type 2 diabetes whose physician initiated SGLT-2 inhibitor therapy. Prior to and 4 weeks after the initiation of SGLT-2 inhibitors, in addition to routine clinical and laboratory measurements, hydroxyl free radical and neuropathic evaluations were performed. Body weight, body mass index (BMI), fasting glucose, fructosamine, and albuminuria decreased significantly, whereas red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), and platelet count increased significantly. Urinary o-tyrosine/p-tyrosine and (m-tyrosine+o-tyrosine)/p-tyrosine ratios were significantly reduced, suggesting diminished hydroxyl free radical production. Patients with neuropathy, identified by abnormal baseline current perception threshold (CPT) values, showed significant improvements. Significant correlations between RBCs, platelet parameters, albuminuria, and hydroxyl free radical markers disappeared after SGLT-2 treatment and changes in hydroxyl free radical markers correlated positively with CPT changes. Our results suggest that short-term SGLT-2 inhibition recalibrates metabolic, hematologic, renal, and neuropathic endpoints simultaneously, presumably through attenuating abnormal ortho- and meta-tyrosine incorporation into signaling proteins. Further studies are required to confirm long-term durability and examine whether additional strategies, such as supplementation of the physiological p-tyrosine, could amplify these benefits.

Beyond their metabolic effect, SGLT-2 inhibitors reduce the risk of heart failure and have cardiovascular and nephroprotective effects, yet their exact mechanism of action remains unclear. This prospective study included 40 patients with type 2 diabetes whose physician initiated SGLT-2 inhibitor therapy. Prior to and after 4 weeks of the initiation of use of SGLT-2 inhibitors, in addition to routine clinical and laboratory measurements, hydroxyl free radical and neuropathic evaluations were performed. Body weight, BMI, fasting glucose, fructosamine, and albuminuria decreased significantly, whereas RBC count, hemoglobin, hematocrit, MCV, and platelet count increased significantly. Urinary o-tyrosine/p-tyrosine and (m-tyrosine+o-tyrosine)/p-tyrosine ratios were significantly reduced, suggesting diminished hydroxyl free radical production. Patients with neuropathy measured by the abnormal baseline CPT (current perception threshold) values showed significant improvements. Significant correlations between RBC, platelet parameters, albuminuria and hydroxyl free radical markers disappeared after SGLT-2-treatment, and changes of hydroxyl free radical markers correlated positively with CPT changes. Our results suggest that short-term SGLT-2 inhibition simultaneously recalibrates metabolic, hematologic, kidney and neuropathic endpoints, potentially through attenuating abnormal ortho- and meta-tyrosine incorporation into signaling proteins. Further studies are required to confirm long-term durability and examine whether additional strategies such as supplementation of the physiological p-tyrosine could amplify these benefits.