Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis

Abstract

Background and objectives The sodium glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin is a novel drug for the treatment of diabetes mellitus. Recent studies suggest that SGLT-2 inhibitors affect phosphate homeostasis, but their effects on phosphate-regulating hormones in patients with diabetic kidney disease are still unclear. Design, setting, participants, & measurements We performed a post-hoc analysis of a double-blind, randomized, crossover trial in patients with type 2 diabetes with early-stage diabetic kidney disease on stable reninangiotensin-aldosterone system blockade, with an albumin-to-creatinine ratio between 100 and 3500 mg/g, eGFR$45 ml/min per 1.73 m 2 , and glycosylated hemoglobin$7.2% and ,11.4%. Patients were randomized to dapagliflozin 10 mg/d or placebo during consecutive 6-week study periods, separated by a 6-week wash-out. We investigated effects on circulating phosphate, calcium, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH] 2 D) levels. Results Thirty-one patients (age 62 years; 23% female) were analyzed. Compared with placebo, dapagliflozin increased serum phosphate by 9% (95% confidence interval, 4% to 15%; P=0.002), PTH increased by 16% (3% to 30%; P=0.01), FGF23 increased by 19% (0.3% to 42%; P=0.05), and serum 1,25(OH) 2 D decreased by 212% (225% to 4%; P=0.12). Calcium and 25(OH)D were unaffected. We found no correlation between changes in markers of phosphate homeostasis and changes in eGFR or 24-hour albumin excretion during dapagliflozin treatment. Conclusions Dapagliflozin increases serum phosphate, plasma PTH, and FGF23. This effect was independent of concomitant changes in eGFR or 24-hour albumin excretion.

Mineral and Electrolyte Disorders With SGLT2i Therapy

“…Low calcitriol levels are, in turn, responsible for high PTH levels directly via reduced feedback inhibition, and indirectly by reducing dietary calcium absorption (Fig. C) . The combination of decreased 1,25(OH)2D and increased PTH and FGF‐23 levels likely contribute to the increased fracture risk associated with SGLT2is.…”

“…These complex feedback pathways may account for the large standard deviation of 1,25‐dihydroxyvitamin D and PTH reported in different studies. This may preclude the prediction of the net effect of SGLT2is on mineral metabolism as well as the long term clinical consequences also considering that changes in phosphate homeostasis may persist over the treatment period …”

“…Hence, the increase in plasma FGF-23 was a physiological response to the increase in serum phosphorus, which possibly explains the decrease in plasma 1,25-dihydroxyvitamin D. (51) The result of a secondary analysis of a crossover doubleblinded, placebo-controlled trial further corroborates this hypothesis. Indeed, De Jong and colleagues (52) reported on small albeit significant increases in serum phosphate (9%), FGF-23 (19%), and PTH (16%) in a cohort of 31 patients with T2D complicated by CKD stages 2 to 4 and albuminuria who were treated with dapagliflozin for 6 weeks. Notably, these changes were mirrored by a significant 12% decrease in 1,25-dihydroxyvitamin D; no effect on tubular reabsorption of phosphate and serum calcium was noted.…”

“…Notably, these changes were mirrored by a significant 12% decrease in 1,25-dihydroxyvitamin D; no effect on tubular reabsorption of phosphate and serum calcium was noted. (52) To reconcile available evidence, it is plausible that the primary trigger of the changes of mineral metabolism following SGLT2is entails the increased phosphate-dependent sodium reabsorption in the proximal tubule caused by decreased glucose-dependent sodium reabsorption. By inhibiting the cotransport of both Na + and glucose, SGLT2is increase Na + availability in the regions of the proximal tubule where NaPi-2a and NaPi-2c are expressed and modulate renal phosphate handling.…”

“…2C). (51,52) The combination of decreased 1,25(OH)2D and increased PTH and FGF-23 levels likely contribute to the increased fracture risk associated with SGLT2is.…”