Effect of Empagliflozin on Urinary Excretion of Adenosine and on Markers of Osteocyte Function and Glomerular Damage in Diabetic and Non-diabetic Patients With Chronic Kidney Disease

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of orally drugs for the treatment of type 2 diabetes. These drugs decrease plasma glucose levels by inhibiting its reabsorption in the proximal tubules of the kidney. They have an attractive clinical efficacy profile, including glycemic control, weight loss, and lowering blood pressure. SGLT2 inhibitors have also been reported to reduce the risk of severe adverse cardiovascular events and progression of diabetic kidney disease. SGLT2 is expressed in the kidney, while its expression in other tissues is most likely negligible or absent.

SGLT2 dilates the supply vessels to the glomerulus thereby promoting hyperfiltration. In animal models SGLT2 has been shown to reduce the excretion of macular dense adenosine, which may contribute to the excessive glomerular filtration rate as a result of vasodilation of the afferent vessels. Adenosine, unlike other vascular regions, increases the tension in the walls of the vessels supplying blood to the glomerulus. The role of adenosine in humans in this regard is poorly defined, although treatment with empagliflozin has recently been shown to increase the urinary excretion of adenosine in type 1 diabetic patients with controlled hyperglycemia. Our working hypothesis is that the SGLT2 inhibitor empagliflozin may reduce the hyperfiltration of residual nephrons by increasing adenosine production, which affects the contraction of the afferent arterioles, and this effect occurs in various types of nephropathy.

In addition, it has been described that SGLT2 inhibitors may affect individual parameters of calcium-phosphate metabolism, leading to changes in bone mineral density and an increase in bone resorption marker SGLT2 inhibitors also stimulate renal, proximal phosphate reabsorption. Increased phosphate reabsorption triggers the secretion of fibroblast growth factor 23 (FGF23). FGF23 inhibits the production of 1,25-dihydroxyvitamin D (the biologically active form of vitamin D), which reduces the absorption of calcium from the gastrointestinal tract, thereby stimulating the secretion of parathyroid hormone (PTH). In the conducted studies, it was found that SGLT2 inhibitors increase the concentration of serum phosphorus, FGF23 in the plasma and PTH in the plasma, while lowering the level of 1,25-dihydroxyvitamin D.