SGLT2 Inhibitor Increases Serum Phosphate, PTH, and FGF23

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Study supports the hypothesis that altered tubular phosphate handling drives the increase in serum phosphate during SGLT2 inhibition.
Study supports the hypothesis that altered tubular phosphate handling drives the increase in serum phosphate during SGLT2 inhibition.

Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases serum phosphate as well parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), new study findings confirm.

Martin H. de Borst, MD, PhD, of University Medical Center Groningen in The Netherlands, and colleagues conducted a post-hoc analysis of the double-blind, randomized, crossover IMPROVE trial. Thirty-one patients with type 2 diabetes and early-stage nephropathy (i.e., albumin-to-creatinine ratio 100 to 3500 mg/g and estimated glomerular filtration rate 45 mL/min/1.73 m2 or higher) on a stable dose of ACE inhibitors or angiotensin receptor blockers were assigned to dapagliflozin 10 mg/day or placebo for 6 weeks, then switched to the alternate treatment for 6 weeks following a wash-out period.

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Dapagliflozin significantly increased serum phosphate by 9%, PTH by 16%, and FGF23 by 19%, and decreased 1,25(OH)2D by 12%, according to results published in the Clinical Journal of the American Society of Nephrology. Calcium and 25(OH)D did not fluctuate. Investigators found that these effects on mineral metabolism markers did not relate to changes in kidney function or albuminuria.

“Our findings support effects of dapagliflozin on phosphate homeostasis independent of its effect on kidney function,” Dr de Borst and his colleagues stated. “The long-term persistence of these effects and their potential clinical effects in patients with more advanced CKD should be further investigated.”

The effects of SGLT2 inhibitors on bone and mineral homeostasis are likely a class effect, according to the researchers. These drugs appear to promote tubular sodium/phosphate cotransport. Rises in PTH and FGF23 possibly reflect a compensatory response. It is unclear whether these findings indicate a safety signal.

Study limitations include the small sample size, short duration, and lack of information on dietary phosphorus intake and urinary calcium.

Reference

de Jong MA, Petrykiv SI, Laverman GD, et al. Effects of dapagliflozin on circulating markers of phosphate homeostasis. Clin J Am Soc Nephrol. 14:66-73. DOI:10.2215/CJN.04530418

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