Cinacalcet in Patients with Chronic Kidney Disease: A Cumulative Meta-Analysis of Randomized Controlled Trials

Palmer, Suetonia C.; Nistor, Ionuţ; Craig, Jonathan C.; Pellegrini, Fabio; Messa, Piergiorgio; Tonelli, Marcello; Covic, Adrian; Strippoli, Giovanni F.M.

doi:10.1371/journal.pmed.1001436

Cited by 124 publications

(80 citation statements)

References 41 publications

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“…The CASR is one of the first GPCRs for which an allosteric activator, the calcimimetic cinacalcet, has been developed and approved for therapeutic use in humans (37,38,39,40) to treat primary and secondary hyperparathyroidism (41,42). In addition, cinacalcet has been used for treatment of hyperparathyroidism related to hereditary vitamin D-resistant rickets (43) and X-linked hypophosphatemia (44).…”

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Mayr¹,

Schnabel²,

Dörr³

et al. 2016

European Journal of Endocrinology

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The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper-or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper-and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

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Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Mayr¹,

Schnabel²,

Dörr³

et al. 2016

European Journal of Endocrinology

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“…Second, the EVOLVE RCT did not reach its clinical primary composite end point after an unadjusted intentionto-treat (ITT)-based analysis (Table1) (13). These results were supported by a recent meta-analysis, mainly driven by this negative EVOLVE primary result, which included other heterogeneous studies with different designs (59). Thus, a recent European Renal Association-European Dialysis and Transplant Association position statement did not recommend the routine use of calcimimetic therapy to improve survival in patients with CKD stage 5D and biochemical evidence of SHPT (30).…”

Section: Cinacalcet Use In Patients With Ckd Treated By Dialysismentioning

confidence: 84%

“…Previous meta-analyses have confirmed that calcimimetic treatment effectively improves significant biochemical parameters of SHPT and enables more patients to achieve common targets (65,66). Other studies and metaanalyses have confirmed that cinacalcet has a significant beneficial effect in preventing parathyroidectomy and hypercalcemia (13,49,59,(65)(66)(67)(68)(69), but these studies also found that cinacalcet increases nausea, vomiting, and hypocalcemia, with relative risks of 2.02 (95% CI, 1.45 to 2.81), 1.97 (95% CI, 1.73 to 2.24), and 6.98 (95% CI, 5.10 to 9.53), respectively (59). Therefore, these are the problems that nephrologists encounter more frequently with the clinical use of cinacalcet, together with PTH oversuppression (5).…”

Section: Cinacalcet Use In Patients With Ckd Treated By Dialysismentioning

confidence: 98%

Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism

Bover

Ureña

Ruiz-García

et al. 2016

Clinical Journal of the American Society of Nephrology

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CKD and CKD-related mineral and bone disorders (CKD-MBDs) are associated with high cardiovascular and mortality risks. In randomized clinical trials (RCTs), no single drug intervention has been shown to reduce the high mortality risk in dialysis patients, but several robust secondary analyses point toward important potential beneficial effects of controlling CKD-MBD-related factors and secondary hyperparathyroidism. The advent of cinacalcet, which has a unique mode of action at the calcium-sensing receptor, represented an important step forward in controlling CKD-MBD. In addition, new RCTs have conclusively shown that cinacalcet improves achievement of target levels for all of the metabolic abnormalities associated with CKD-MBD and may also attenuate the progression of vascular and valvular calcifications in dialysis patients. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Tolerance of cinacalcet is limited by frequent secondary side effects such as nausea, vomiting, hypocalcemia and oversuppression of parathyroid hormone, which may cause some management difficulties, especially for those lacking experience with the drug. Against this background, this review aims to summarize the results of studies on cinacalcet, up to and including the publication of the recent ADVANCE and EVOLVE RCTs, as well as recent post hoc analyses, and to offer practical guidance on how to improve the clinical management of the most frequent adverse events associated with cinacalcet, based on both currently available information and personal experience. In addition, attention is drawn to less common secondary effects of cinacalcet treatment and advisable precautions.

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“…Indeed, a recent meta-analysis indicated a reduced need for parathyroidectomy in patients treated with cinacalcet. 107 Nonetheless, these encouraging findings are preliminary and deserve further investigation to be verified.…”

Section: Cinacalcet and Bone Density Fractures And Parathyroidectomymentioning

confidence: 86%

Review of cinacalcet hydrochloride in the management of secondary hyperparathyroidism

Yousaf

Charytan

2013

Renal Failure

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Cinacalcet is the first Food and Drug Administration-approved calcimimetic for the treatment of secondary hyperparathyroidism in dialysis patients. It is effective in improving control of parathyroid hormone, serum calcium, phosphorus, and calcium-phosphorus product. The calcium-lowering effect of cinacalcet overcomes the limitations of standard therapy associated hypercalcemia. There is evidence to suggest that cinacalcet has important clinical implications, which extend beyond its relevance in the treatment of secondary hyperparathyroidism. This review summarizes the evidence regarding the role of cinacalcet in the treatment of secondary hyperparathyroidism, disrupted bone mineral metabolism, cardiovascular disease, and mortality. In addition, the cost implications of cinacalcet are briefly explored.

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Cinacalcet in Patients with Chronic Kidney Disease: A Cumulative Meta-Analysis of Randomized Controlled Trials

Abstract: Giovanni Strippoli and colleagues report findings of a systematic review and meta-analysis examining the benefits and harms of calcimimetic therapy in adults with chronic kidney disease.

Cited by 124 publications

References 41 publications

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism

Review of cinacalcet hydrochloride in the management of secondary hyperparathyroidism

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