review Cinacalcet for secondary hyperparathyroidism: from improved mineral levels to improved mortality? M.G. Vervloet1*, P.W.G. du Buf-Vereijken2, B-J. Potter van Loon3, N. Manamley4, L.J.M. Reichert5, P.J.H. Smak Gregoor6 1Department of Nephrology, VU University Medical Centre, Amsterdam, the Netherlands, 2Department of Internal Medicine, Amphia Hospital, Breda, the Netherlands, 3Department of Internal Medicine, St Lucas Andreas Hospital, Amsterdam, the Netherlands, 4Amgen Limited UK, Cambridge, United Kingdom, 5Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands, 6Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands, *corresponding author: tel.: +31 (0)20-4442673, fax: +31 (0)20-4442675; e-mail: [email protected] abstraCt Keywords Secondary hyperparathyroidism is an almost inevitable Cinacalcet, CKD-MBD, dialysis, secondary hyperpara- complication of advanced kidney failure. The introduction thyroidism, ECHO of the calcimimetic cinacalcet for the treatment of secondary hyperparathyroidism in patients on dialysis was based on its ability to reduce elevated levels of parathyroid introduction hormone (PTH). Subsequent clinical studies confirmed the beneficial effects of cinacalcet on biochemical parameters Secondary hyperparathyroidism is a frequent complication reflecting mineral disturbances and bone disease. In of chronic kidney disease (CKD).1 Levels of parathyroid this review we summarise the impact of cinacalcet on hormone (PTH) increase as CKD progresses, thus biochemical, intermediate and clinical outcomes. We also there is a high prevalence of secondary hyperpara- present previously unpublished mineral metabolism data thyroidism among patients with end-stage renal disease.2 from 144 Dutch dialysis patients treated with cinacalcet Hypocalcaemia, vitamin D deficiency, and hyperphos- who participated in the pan-European ECHO observational phataemia, all hallmarks of CKD, are physiological stimuli study. Although secondary hyperparathyroidism tended for PTH secretion.3 Moreover, during CKD expression to be more severe in our Dutch cohort, compared with the of the vitamin D receptor, the calcium-sensing receptor entire ECHO cohort, cinacalcet was nevertheless effective and Klotho on parathyroid glands declines, thereby in reducing PTH in these patients. Two recent clinical abolishing the inhibitory effects of 1,25-dihydroxyvitamin studies evaluated, respectively, the efficacy of cinacalcet D, calcium and fibroblast growth factor 23 (FGF-23) on in improving the intermediate endpoint of cardiovascular PTH production and secretion.2,4-7 All these factors lead calcifications (ADVANCE trial), and its impact on clinical to hyperplasia of the parathyroid glands, which, once outcomes, including all-cause mortality and cardiovascular established, is generally irreversible.8 Originally, PTH events (EVOLVE trial). The ADVANCE trial provided was considered to be an indicator of renal bone disease, evidence that cinacalcet may indeed improve calcification but it is a poor predictor of bone histology, especially in in both large arteries and cardiac valves. The EVOLVE trial, advanced CKD,9 unless levels of alkaline phosphatase however, did not meet its clinical primary endpoint (time are also considered along with PTH.10 In end-stage renal to all-cause mortality, myocardial infarction, hospitalisation disease, PTH was found to be associated with mortality. for unstable angina, heart failure or a peripheral vascular This association, after multivariate adjustment, showed event), although secondary and sensitivity analysis a U-shaped curve for studies using both cross-sectional suggested a beneficial effect. The clinical implications of data and evolution of values over time,11-14 with increased these important studies are also addressed in this review. mortality at both high and low PTH levels. Unfortunately, © Van Zuiden Communications B.V. All rights reserved. september 2013, vol. 71, no 7 348 there is no consistency across these studies regarding (CKD-MBD).25,26,38 As the controlled setting of prospective the optimal level of PTH in end-stage renal disease, and clinical trials can differ substantially from everyday for this reason, the recently published Kidney Disease clinical practice, it was encouraging that similar levels of Improving Global Outcomes (KDIGO) guidelines could improvement in calcium, phosphorus, and especially PTH, only suggest preventing PTH levels from moving outside were achieved in the ECHO observational study (Evaluation extreme ranges (2 to 9 times the upper limit of normal of the Clinical Use of Mimpara® in Haemodialysis and range).15 Apart from the epidemiological association that Peritoneal Dialysis Patients, an Observational Study).27,39 exists between levels of PTH and mortality in patients with secondary hyperparathyroidism, two additional lines of evidence suggest a contributory role for elevated PTH Dutch experien Ce: t He e CHo levels in the causal pathway to adverse clinical events. STUdy Firstly, patients with primary hyperparathyroidism (who do not have uraemia), have increased mortality, mainly The ECHO study was a one-year observational study due to cardiovascular complications,16 including left among European dialysis patients receiving cinacalcet ventricular hypertrophy.17 Secondly, as the PTH receptor (n=1865). Detailed descriptions of the methodology used is present on cardiomyocytes and vascular smooth muscle have been published previously.27 In short, all dialysis cells,18 elevated PTH levels may lead to changes in the patients at participating centres who were prescribed functioning of these cells, including disturbances in cinacalcet at the decision of their treating physician were calcium channels and energy handling. eligible for inclusion in the analysis. They were followed Treatment options for secondary hyperparathyroidism from six months prior to initiation of cinacalcet, until 12 aim to prevent hyperphosphataemia and hypocalcaemia, months afterwards. There was no treatment algorithm while correcting 1,25-hydroxyvitamin D deficiency.19,20 provided. The main outcome parameter was the proportion These include active vitamin D sterols,21-24 the calcimimetic of patients who attained target levels for PTH, phosphate, cinacalcet,25-27 (in dialysis patients), combinations of and calcium. both,28,29 phosphate binders15,30 and surgery.31 Although As there were important differences across the 12 countries parathyroidectomy can effectively lower PTH, it is that participated in the ECHO study, we conducted associated with postoperative hypocalcaemia,32 and can a separate analysis of the 144 participants from the induce prolonged irreversible hypoparathyroidism.33 The latter is associated with increased mortality.34 The use of parathyroidectomy is declining,35 and a detailed discussion is beyond the scope of this review paper. figure 1. Evolution of intact parathyroid hormone The present review summarises the subsequent effects (iPTH) in Dutch patients treated with cinacalcet in of cinacalcet on biochemical endpoints, intermediate the ECHO observational study. During the observation TM endpoints including bone mineral density (BMD) period KDOQI guidelines were followed, aiming at PTH levels between 16-32 pmol/l and arterial calcification, and finally on hard clinical endpoints. We also present previously unpublished mineral 2b metabolism data from 144 Dutch dialysis patients treated 140 Cinacalcet 2,5 Cinacalcet with cinacalcet who participated in a pan-European 120 observational study. We conclude with a discussion on the 2 implications of these new data for clinical practice. 100 1,5 80 60 CinaCalCet 1 40 SerumP (mmol/l) The calcimimetic agent cinacalcet hydrochloride Serum iPTH (pmol/l) 0,5 (Mimpara®, Amgen Inc, Thousand Oaks, CA, USA) was 20 approved in the Netherlands in 2005 for the treatment of Median (Q1, Q3) -34 -49 -58 Median (Q1, Q3) -9 -5 -9 0 % change from baseline (-59, -7) (-70, -13) (-76, -22) 0 % change from baseline (-22, 6) (-22, 17) (-26, 11) secondary hyperparathyroidism in patients with stage 5 -6 months Baseline 3 months 6 months 12 months -6 months Baseline 3 months 6 months 12 months CKD on dialysis. This class of drugs acts by increasing the n = 123 n = 142 n = 133 n = 126 n = 88 n = 91 n = 144 n = 118 n = 101 n = 73 sensitivity of the calcium-sensing receptor to extracellular calcium ions, inhibiting the release of PTH.36,37 In phase Median (Q1, Q3) Median (Q1, Q3) KDOQI™ recommended targets KDOQI™ recommended targets III clinical trials, cinacalcet improved achievement of target levels for the metabolic abnormalities associated K2cDOQitM= Kidney disease outcomes Quality initiative; Q = quartile. 2d Cinacalcet Cinacalcet with chronic kidney disease-mineral and bone disorders 3 6,5 2,8 5,5 ) 2 /l Vervloet, et al. Cinacalcet in secondary hyperparathyroidism. 2 2,6 4,5 september 2013, vol. (mmol/l) 71, no 7 Ca axP (mmol 349 2,4 3,5 Serum Serum C 2,2 2,5 Median (Q1, Q3) -7 -5 -3 Median (Q1, Q3) -20 -10 -15 2 % change from baseline (-14, -1) (-12, 3) (-14, 0,3) 1,5 % change from baseline (-33, -3) (-29, 8) (-36, 4) -6 months Baseline 3 months 6 months 12 months -6 months Baseline 3 months 6 months 12 months n = 81 n = 142 n = 104 n = 92 n = 71 n = 79 n = 142 n = 99 n = 87 n = 68 Median (Q1, Q3) Median (Q1, Q3) KDOQI™ recommended targets KDOQI™ recommended targets Netherlands (80% on haemodialysis, the remainder on effeCt on inter Mediate peritoneal dialysis). The Dutch participants generally had endpoints