Etelcalcetide Is Effective at All Levels of Severity of Secondary Hyperparathyroidism in Hemodialysis Patients

Abstract

Introduction: Calcimimetics improve parameters of secondary hyperparathyroidism (sHPT) but are mostly initiated when patients have severe disease, potentially limiting effectiveness. We evaluated the effects of etelcalcetide on lowering intact parathyroid hormone, calcium, and phosphate at different disease severity levels.

Methods: This analysis examined data from 2 parallel, phase 3, randomized, placebo-controlled, 26-week trials conducted in 1023 adult (≥18 years old) patients with sHPT on maintenance hemodialysis. Etelcalcetide effects by baseline intact parathyroid hormone stratum (<600, 600-1000, and >1000 ng/l) on mean percentage change in intact parathyroid hormone; changes in calcium and phosphate; and achieving serum intact parathyroid hormone ≤300 ng/l, phosphate <1.78 mmol/l, and both combined, were assessed.

Results: Etelcalcetide reduced serum intact parathyroid hormone by a similar percentage across baseline strata. A similar proportion achieved >30% intact parathyroid hormone reduction across strata for the etelcalcetide arms. Parathyroid hormone increased modestly in each placebo-group stratum, most prominently in the lowest stratum. Serum calcium and phosphate concentrations decreased across strata in etelcalcetide-treated patients, with the most pronounced reductions in patients with highest baseline parathyroid hormone. However, the proportion of patients achieving parathyroid hormone, phosphate, and both targets was highest in the lowest baseline parathyroid hormone stratum, where etelcalcetide dose requirements were lowest. Etelcalcetide dose requirement was lowest among patients in the lowest intact parathyroid hormone stratum.

Conclusion: Etelcalcetide effectively lowered serum intact parathyroid hormone, calcium, and phosphate, irrespective of the severity of secondary hyperparathyroidism. The ability to achieve target goals was greatest, and dose requirement smallest, when etelcalcetide was initiated among patients with the lowest level of disease severity.

Keywords: calcium; chronic kidney disease; hemodialysis; mineral metabolism; parathyroid hormone; phosphate.

Figures

Graphical abstract

Figure 1

Efficacy of etelcalcetide (ETEL) at attaining laboratory targets for (a) intact parathyroid hormone (PTH) >30% reduction, (b) PTH ≤ 300 pg/ml, (c) P < 5.5 mg/dl, and (d) both PTH ≤ 300 pg/ml and P < 5.5 mg/dl, during the efficacy-assessment phase (EAP). Patients with no PTH and/or P measurement during the EAP were considered as not achieving the endpoint. PBO, placebo; P, phosphate.

Figure 2

Weekly vitamin D receptor activators (VDRA) and etelcalcetide (ETEL) dose during the efficacy-assessment phase (EAP) by baseline intact parathyroid hormone (PTH) strata. Data presented as median, 25th percentile and 75th percentile (box) and minimum maximum dose (whiskers). VDRA dose is presented as i.v. paricalcitol equivalents. PBO, placebo.

References

1. 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group KDIGO 2017 Clinical Practice Guideline Update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD) Kidney Int Suppl. 2017;7:1–59.
   2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017;7:1-59.
2. 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group KDIGO Clinical Practice Guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int Suppl. 2009;113:S1–S130.
   2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO Clinical Practice Guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130.
3. 1. Bover J., Ureña P., Ruiz-Garcia C. Clinical and practical use of calcimimetics in dialysis patients with secondary hyperparathyroidism. Clin J Am Soc Nephrol. 2016;11:161–174.
   2. Bover J, Ureña P, Ruiz-Garcia C, et al. Clinical and practical use of calcimimetics in dialysis patients with secondary hyperparathyroidism. Clin J Am Soc Nephrol. 2016;11:161-174.
4. 1. Frãzao J., Rodriguez M. Secondary hyperparathyroidism disease stabilization following calcimimetic therapy. NDT Plus. 2008;1(suppl 1):i12–i17.
   2. Frazao J, Rodriguez M. Secondary hyperparathyroidism disease stabilization following calcimimetic therapy. NDT Plus. 2008;1(suppl 1):i12-i17.
5. 1. Block G.A., Bushinsky D.A., Cunningham J. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: two randomized clinical trials. JAMA. 2017;317:146–155.
   2. Block GA, Bushinsky DA, Cunningham J, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: two randomized clinical trials. JAMA. 2017;317:146-155.
6. 1. Frazao J.M., Messa P., Mellotte G.J. Cinacalcet reduces plasma intact parathyroid hormone, serum phosphate and calcium levels in patients with secondary hyperparathyroidism irrespective of its severity. Clin Nephrol. 2011;76:233–243.
   2. Frazao JM, Messa P, Mellotte GJ, et al. Cinacalcet reduces plasma intact parathyroid hormone, serum phosphate and calcium levels in patients with secondary hyperparathyroidism irrespective of its severity. Clin Nephrol. 2011;76:233-243.
7. 1. Sudhaker Rao D., Han Z.H., Phillips E.R. Reduced vitamin D receptor expression in parathyroid adenomas: implications for pathogenesis. Clin Endocrinol (Oxf) 2000;53:373–381.
   2. Sudhaker Rao D, Han ZH, Phillips ER, et al. Reduced vitamin D receptor expression in parathyroid adenomas: implications for pathogenesis. Clin Endocrinol (Oxf). 2000;53:373-381.
8. 1. Block G., Do T.P., Collins A.J. Co-trending of parathyroid hormone and phosphate in patients receiving hemodialysis. Clin Nephrol. 2016;85:142–151.
   2. Block G, Do TP, Collins AJ, et al. Co-trending of parathyroid hormone and phosphate in patients receiving hemodialysis. Clin Nephrol. 2016;85:142-151.
9. 1. Almaden Y., Hernandez A., Torregrosa V. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol. 1998;9:1845–1852.
   2. Almaden Y, Hernandez A, Torregrosa V, et al. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol. 1998;9:1845-1852.
10. 1. Li J., Molnar M.Z., Zaritsky J.J. Correlates of parathyroid hormone concentration in hemodialysis patients. Nephrol Dial Transplant. 2013;28:1516–1525.
    2. Li J, Molnar MZ, Zaritsky JJ, et al. Correlates of parathyroid hormone concentration in hemodialysis patients. Nephrol Dial Transplant. 2013;28:1516-1525.
11. 1. Frãzao J.M., Braun J., Messa P. Is serum phosphorus control related to parathyroid hormone control in dialysis patients with secondary hyperparathyroidism? BMC Nephrol. 2012;13:76.
    2. Frazao JM, Braun J, Messa P, et al. Is serum phosphorus control related to parathyroid hormone control in dialysis patients with secondary hyperparathyroidism? BMC Nephrol. 2012;13:76.
12. 1. Block G.A., Klassen P.S., Lazarus J.M. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208–2218.
    2. Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208-2218.
13. 1. Cooper K., Quarles D., Kubo Y. Relationship between reductions in parathyroid hormone and serum phosphorus during the management of secondary hyperparathyroidism with calcimimetics in hemodialysis patients. Nephron Clin Pract. 2012;121:c124–c130.
    2. Cooper K, Quarles D, Kubo Y, et al. Relationship between reductions in parathyroid hormone and serum phosphorus during the management of secondary hyperparathyroidism with calcimimetics in hemodialysis patients. Nephron Clin Pract. 2012;121:c124-c130.
14. 1. Zitt E., Fouque D., Jacobson S.H. Serum phosphorus reduction in dialysis patients treated with cinacalcet for secondary hyperparathyroidism Results mainly from parathyroid hormone reduction. Clin Kidney J. 2013;6:287–294.
    2. Zitt E, Fouque D, Jacobson SH, et al. Serum phosphorus reduction in dialysis patients treated with cinacalcet for secondary hyperparathyroidism Results mainly from parathyroid hormone reduction. Clin Kidney J. 2013;6:287-294.
15. 1. Kravietz A.M., Buicko J.L., Parreco J.P. Thirty-day readmissions following parathyroidectomy: evidence from the National Readmissions Database, 2013–2014. Am J Otolaryngol. 2018;39:82–87.
    2. Kravietz AM, Buicko JL, Parreco JP, et al. Thirty-day readmissions following parathyroidectomy: evidence from the National Readmissions Database, 2013-2014. Am J Otolaryngol. 2018;39:82-87.
16. 1. Li J.G., Xiao Z.S., Hu X.J. Total parathyroidectomy with forearm auto-transplantation improves the quality of life and reduces the recurrence of secondary hyperparathyroidism in chronic kidney disease patients. Medicine (Baltimore) 2017;96:e9050.
    2. Li JG, Xiao ZS, Hu XJ, et al. Total parathyroidectomy with forearm auto-transplantation improves the quality of life and reduces the recurrence of secondary hyperparathyroidism in chronic kidney disease patients. Medicine (Baltimore). 2017;96:e9050.
17. 1. Brunelli S.M., Dluzniewski P.J., Cooper K. Management of serum calcium reductions among patients on hemodialysis following cinacalcet initiation. Pharmacoepidemiol Drug Saf. 2015;24:1058–1067.
    2. Brunelli SM, Dluzniewski PJ, Cooper K, et al. Management of serum calcium reductions among patients on hemodialysis following cinacalcet initiation. Pharmacoepidemiol Drug Saf. 2015;24:1058-1067.
18. 1. Puccini M., Ceccarelli C., Meniconi O. Near total parathyroidectomy for the treatment of renal hyperparathyroidism. Gland Surg. 2017;6:638–643.
    2. Puccini M, Ceccarelli C, Meniconi O, et al. Near total parathyroidectomy for the treatment of renal hyperparathyroidism. Gland Surg. 2017;6:638-643.
19. 1. Yajima A., Ogawa Y., Takahashi H.E. Changes of bone remodeling immediately after parathyroidectomy for secondary hyperparathyroidism. Am J Kidney Dis. 2003;42:729–738.
    2. Yajima A, Ogawa Y, Takahashi HE, et al. Changes of bone remodeling immediately after parathyroidectomy for secondary hyperparathyroidism. Am J Kidney Dis. 2003;42:729-738.
20. 1. Florescu M.C., Islam K.M., Plumb T.J. Calcium supplementation after parathyroidectomy in dialysis and renal transplant patients. Int J Nephrol Renovasc Dis. 2014;7:183–190.
    2. Florescu MC, Islam KM, Plumb TJ, et al. Calcium supplementation after parathyroidectomy in dialysis and renal transplant patients. Int J Nephrol Renovasc Dis. 2014;7:183-190.