Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study

Abstract

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors, the newest class of oral therapies approved for type 2 diabetes (T2D), decrease plasma glucose levels by inhibiting renal proximal tubular glucose reabsorption (1). These drugs have attractive clinical efficacy profiles, including glycemic control, weight loss, and decreased blood pressure. SGLT2 inhibitors have also been reported to decrease the risks of major adverse BACKGROUND. Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health.

Mineral and Electrolyte Disorders With SGLT2i Therapy

“…According to these findings, the increase in serum phosphate in response to canagliflozin administration was caused by a significant increase in renal tubular reabsorption of phosphate. 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.…”

“…According to these findings, the increase in serum phosphate in response to canagliflozin administration was caused by a significant increase in renal tubular reabsorption of phosphate. 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 …”

“…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 …”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…To more specifically evaluate serum bone mineral homeostasis, a single‐blind, placebo‐controlled, cross‐over study conducted in 25 hospitalized patients, examining short‐term exposure to canagliflozin (300 mg/day for 5 days), demonstrated increases in serum phosphorus (+16%), plasma FGF23 (+20%), and PTH (+25%), while decreasing 1,25 (OH) 2 vitamin D (−10%) . Moreover, FGF23 and phosphorus levels were correlated .…”