Sodium phosphate cotransporter 2a inhibitors: potential therapeutic uses

Targeting sodium phosphate cotransporter 2a (Npt2a) offers a novel strategy for treating hyperphosphatemia in chronic kidney disease (CKD). Here we review recent studies on the efficacy of Npt2a inhibition, its plasma phosphate (P(i))-lowering effects, as well as potential “off-target” beneficial effects on cardiovascular consequences. RECENT FINDINGS: Two novel Npt2a-selective inhibitors (PF-06869206 and BAY-767) have been developed. Pharmacological Npt2a inhibition shows a significant phosphaturic effect and consequently lowers plasma P(i) and parathyroid hormone (PTH) levels regardless of CKD. However, plasma fibroblast growth factor 23 (FGF23), a master regulator of P(i) homeostasis, shows inconsistent responses between these two inhibitors (no effect by PF-06869206 vs. reduction by BAY-767). In addition to the effects on P(i) homeostasis, Npt2a inhibition also enhances urinary excretions of Na(+), Cl(−), and Ca(2+), which is recapitulated in animal models with reduced kidney function. The effect of Npt2a inhibition by BAY-767 on vascular calcification has been studied, with positive results showing that oral treatment with BAY-767 (10 mg kg(−1)) attenuated the increases in plasma P(i) and Ca(2+) content in the aorta under the setting of vascular calcification induced by a pan-FGF receptor inhibitor. Together, Npt2a inhibition offers a promising therapeutic approach for treating hyperphosphatemia and reducing cardiovascular complications in CKD. SUMMARY: Npt2a inhibition significantly increases urinary P(i) excretion and lowers plasma P(i) and PTH levels; moreover, it exerts pleiotropic “off-target” effects, providing a novel treatment for hyperphosphatemia and exhibiting beneficial potential for cardiovascular complications in CKD.