Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis

Myles Wolf, Geoffrey A Block, Glenn M Chertow, Kerry Cooper, Bruno Fouqueray, Sharon M Moe, Yan Sun, Holly Tomlin, Marc Vervloet, Rainer Oberbauer, Myles Wolf, Geoffrey A Block, Glenn M Chertow, Kerry Cooper, Bruno Fouqueray, Sharon M Moe, Yan Sun, Holly Tomlin, Marc Vervloet, Rainer Oberbauer

Abstract

Background: Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown.

Methods: To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide.

Results: Etelcalcetide reduced FGF23 [median % change (quartile 1-quartile 3)] from baseline to the end of the trial significantly more than placebo [-56% (-85 to -7) versus +2% (-40 to +65); P <0.001] and cinacalcet [-68% (-87 to -26) versus -41% (-76 to +25); P <0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide.

Conclusion: These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium.

Keywords: FGF23; PTH; calcimimetics; hemodialysis; secondary hyperparathyroidism.

© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

FIGURE 1
FIGURE 1
Changes in FGF23 in the randomized controlled trials of (A) etelcalcetide versus placebo and (B) etelcalcetide versus cinacalcet. Median percent change (quartile 1, quartile 3) = median percent change from baseline to Week 27.
FIGURE 2
FIGURE 2
Changes in FGF23 according to concomitant vitamin D treatment in trials of (A) etelcalcetide versus placebo and (B) etelcalcetide versus cinacalcet. Median percent change (quartile 1–quartile 3) = median percent change from baseline to Week 27. Spearman correlation coefficients (r) and P-values on the figure panels summarize and compare the within-group associations between percent change from baseline to Week 27 in FGF23 according to whether vitamin D dose was or was not increased. Results below the figure panels summarize between-group comparisons stratified by the change in vitamin D dosing.
FIGURE 3
FIGURE 3
Changes in FGF23 according to concomitant increases in dialysate calcium concentration in trials of (A) etelcalcetide versus placebo and (B) etelcalcetide versus cinacalcet. Median (quartile 1, quartile 3) = median percent change from baseline to week 27. Spearman correlation coefficients (r) and P-values on the figure panels summarize and compare the within-group associations between percent change from baseline to Week 27 in FGF23 according to whether dialysate calcium was or was not increased. Results below the figure panels summarize between-group comparisons stratified by the change in dialysate calcium.
FIGURE 4
FIGURE 4
Changes in FGF23 according to concomitant increases in calcium supplementation in trials of (A) etelcalcetide versus placebo and (B) etelcalcetide versus cinacalcet. Median percent change (quartile 1, quartile 3) = median percent change from baseline to Week 27. Spearman correlation coefficients (r) and P-values on the figure panels summarize and compare the within-group associations between percent change from baseline to Week 27 in FGF23 according to whether calcium supplementation was or was not increased. Results below the figure panels summarize between-group comparisons stratified by the change in calcium supplementation.

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