Possible adverse effects of SGLT2 inhibitors on bone - PubMed (original) (raw)

Possible adverse effects of SGLT2 inhibitors on bone

Simeon I Taylor et al. Lancet Diabetes Endocrinol. 2015 Jan.

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Conflict of interest statement

Conflicts of interest

SIT was previously employed by and currently owns restricted stock in the Bristol-Myers Squibb Company. In addition, he is a paid consultant and adviser for the following companies: Aegerion Pharmaceuticals, Inc.; Ambrx, Inc.; Calibrium, LLC; Genkyotex, S.A.; Isis Pharmaceuticals, Inc.; Nimbus Discovery, LLC; Yabao Pharmaceutical Co., Ltd.; and Cadila Healthcare Limited. Neither JEB nor KIR have any conflicts of interest to report.

Figures

Figure 1

Figure 1. Proposed mechanisms whereby SGTL2 inhibitors exert adverse effects on bone

Panel A: Published data demonstrate that SGLT2 inhibitors increase serum phosphate levels,, probably by promoting renal tubular phosphate reabsorption. Because of the action of SGLT2 inhibitors to decrease Na+ transport, this increases the electrochemical gradient for Na+, thereby driving increased co-transport of phosphate and Na+. In human studies, phlorizin (a non-selective SGLT1/ SGLT2 inhibitor) decreased phosphate clearance by an average of ~80% during the first hour after phlorizin administration. Furthermore, phlorizin promotes phosphate reabsorption in perfused proximal convoluted tubules. This is likely the mechanism of the observed SGLT2 inhibitor-induced increase in serum phosphate. Panel B: Increased levels of serum phosphate are predicted to increase secretion of PTH by the parathyroid gland. Either directly or indirectly (e.g., mediated by effects of PTH), the increased serum phosphate has the potential to increase FGF23 secretion by osteocytes in bone.– The effect of phosphate to promote PTH secretion is believed to be mediated, at least in part, by the effect of increased phosphate levels to decrease levels of free ionized Ca++. Both PTH and FGF23 promote phosphaturia by decreasing renal tubular reabsorption of phosphate. In contrast, the two hormones exert opposite effects upon 1α-hydroxylation of 25-hydroxyvitamin D – with PTH increasing and FGF23 decreasing 1,25-dihydroxyvitamin D formation.

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