The Physiological and Cardiovascular Effects of Empagliflozine in Type 2 Diabetes

Recently it was shown that in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) who received Empagliflozine as compared with placebo had a lower rate of death from cardiovascular causes, non-fatal MI, or non-fatal strokes as well as death from any cause and hospitalization for heart failure Empagliflozine is a selective inhibitor of renal sodium-glucose co-transporters (SGLTs) that has been approved for treatment of type 2 diabetes. It is associated with weight loss, reduction in blood pressure without an increase in heart rate, and improves markers of arterial stiffness and vascular resistance, visceral adiposity, albuminuria and urate.

Renal sodium-glucose cotransporter (SGLT2) resides in the proximal tubule (PT).The latter is anatomically exposed to the initial glomerular filtrate. Therefore the proximal tubule (PT) cells play a variety of roles amongst which are receptor mediated protein endocytosis, reabsorption of sodium, glucose and phosphate At steady state approximately 85% of the filtered phosphate Pi load is reabsorbed by the kidney through sodium phosphate transporters found in the apical membrane of the proximal tubule cells.

These transporters are also affected by fibroblast growth factor 23 (FGF23). Fibroblast growth factor 23 (FGF23) is a hormone that is mainly secreted by osteocytes and osteoblasts in bone, and the levels of FGF23 increase significantly at the very early stages of chronic kidney disease (CKD) and may play a critical role in mineral ion disorders and bone metabolism in these patients.

Recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralization instead of producing a systematic effect. It augments phosphaturia by affecting sodium phosphate co transporters: mainly :NaP2a Fibroblast growth factor 23 (FGF23) FGF23 binds to a receptor complex consisting of FGFR1, 3 or 4 and α Klotho and activates ERK1/2 leading to internalization and degradation of NaP2a.

Klotho a transmembrane protein identified as an aging suppressor protein , expressed mainly in the distal tubule and to a lesser extent in the PTC serves as a co-receptor along with FGF receptor in the binding of FGF23 in the DCT It is found mainly in kidney distal tubular epithelium, parathyroid gland, epithelial cells of the choroid plexus in the brain and human vascular tissue .Recently it was demonstrated in the PCT as well.