In high- to moderate-quality evidence from 16 randomized controlled trials involving 6,988 patients, routine cinacalcet (30 to 180 mg/d) therapy in people with CKD stage 5D decreases PTH concentrations (281 ng/l [32 pmol/l]), reduces hypercalcemia, and infrequently prevents surgical parathyroidectomy, but has little or no effect on all-cause mortality, has imprecise effects on cardiovascular death, and is associated commonly with adverse effects including hypocalcemia, nausea, vomiting, and diarrhea. On average, routinely treating 1,000 people for 1 y has no effect on mortality, might prevent three patients from experiencing surgical parathyroidectomy, and leads to approximately 60 and 150 patients experiencing hypocalcemia and nausea, respectively. Evidence in people with CKD stages 3–5 is scant and generally low or very low quality. Because of lower absolute risks of parathyroidectomy in earlier stages of CKD, the benefits of cinacalcet identified in dialysis populations are likely to be smaller if generalized to people with CKD stages 3–5. Data for recipients of a kidney transplant and those treated with peritoneal dialysis were largely absent.
Although it remains possible that routine cinacalcet prescribing has a beneficial effect on all-cause mortality, consistent treatment effects across all the available studies providing data suggest that, at best, any benefit for mortality is likely to be small. Given that lag censoring analyses for outcomes (where data were censored 6 mo after patients stopped using the study drug) were reported as prespecified secondary analyses in the EVOLVE trial 
and suggested a potential benefit for cinacalcet on total mortality (hazard ratio, 0.83 [95% CI, 0.73 to 0.96]), it might be argued that additional trials of cinacalcet are now needed or that cinacalcet lowers mortality. However, we suggest that, given that lag censoring approaches were secondary analyses and that overall data for mortality in this meta-analysis are high-quality according to GRADE criteria, additional placebo-controlled trials of cinacalcet are very unlikely to change the confidence in the size and direction of the treatment estimates we observed. By contrast, given the low- to very-low-quality evidence currently available for people with CKD stages 3–5, and the lack of available data to allow analysis of whether treatment effects differ by stage of CKD, additional trial data for this specific group of patients would be informative.
Notably, the trials contributing to the analyses all sought to investigate the use of cinacalcet as “routine” or “first line” therapy for elevated PTH levels. Their findings therefore do not exclude the possibility that cinacalcet may afford benefits in the treatment of elevated PTH levels resistant to treatment with vitamin D compounds and phosphate binders. The generally negative findings of existing trials on patient-level end points have resulted in clinical practice guideline recommendations that suggest that cinacalcet should be used when serum parathyroid levels are very high, other treatments have been ineffective, and surgical parathyroidectomy is contraindicated 
. However, the specific use of cinacalcet in this clinical setting has not been adequately evaluated in randomized trials, and, in particular, outcomes and adverse events after parathyroidectomy versus cinacalcet have not been studied.
Before the development of cinacalcet, vitamin D compounds were the mainstay of therapy to normalize perturbed PTH concentrations in CKD, which if left unchecked lead to painful fractures, bone deformity, and generalized osteopenia. In a now familiar sequence of events in nephrology, although vitamin D therapy was effective for improving a surrogate outcome (lower serum PTH levels) and was associated with lower mortality in nonrandomized studies 
, subsequent randomized trials did not clearly demonstrate beneficial effects of vitamin D compounds on cardiovascular events or death for people with CKD 
. Similarly, while cinacalcet was shown 10 y ago to markedly improve surrogate outcomes (both serum PTH and calcium by phosphorus product levels) in people with CKD 
, and observational analyses suggest an association between cinacalcet treatment and improved all-cause and cardiovascular mortality 
, until recently, randomized trial evidence systematically evaluating the effect of cinacalcet on clinical outcomes was not available. Despite this vacuum of high-quality evidence for patient-centered end points and cumulative data indicating frequent side effects including hypocalcemia, nausea, or vomiting, cinacalcet has become the most expensive drug cost and the eighth most frequently prescribed drug for Medicare Part D enrolled dialysis patients in the United States, and year-on-year prescribing costs are increasing rapidly in the United Kingdom 
This meta-analysis shows that, although its use is widespread and costly, cinacalcet provides small absolute benefits for parathyroidectomy, provides no reductions in mortality, and frequently leads to adverse gastrointestinal effects that may adversely influence nutrition and quality of life in these patients. Importantly, the effects of cinacalcet treatment on all-cause mortality, parathyroidectomy, hypocalcemia, and nausea were all identifiable before the EVOLVE trial 
was released in late 2012, and the EVOLVE trial has now largely only increased our confidence in treatment effects. The EVOLVE trial has additionally provided us with important data for cardiovascular mortality, showing that benefits of therapy on this outcome are lower than cumulatively estimated by earlier trials. The EVOLVE trial was needed to provide certainty and high-quality data that routine cinacalcet use provides little or no benefit for adults treated with dialysis; monitoring of prescribing data post-EVOLVE may now reveal a fall in the prescribing costs and frequency of routine cinacalcet administration in parallel with the high-quality evidence available, although questions will remain as to why prescribing costs became so high in the context of insufficient cumulated evidence over the last decade. As with vitamin D compounds previously, the pathway from drug development to clinical use for cinacalcet reminds us that relying on surrogate end points and nonrandomized studies to evaluate treatment efficacy for new interventions is likely to result in unreliable estimates of clinical effectiveness. This, in turn, leads to extensive use of interventions that do not improve population outcomes and unnecessarily increase healthcare expenditure.
The treatment effect we observed for cinacalcet on fracture (RR, 0.53) was similar in magnitude to, but less certain than, the risk estimate observed in a pooled analysis of four similarly designed randomized, double-blind, placebo-controlled trials of cinacalcet enrolling 1,184 participants with CKD stage 5D and intact PTH concentrations of 300 ng/l or more, in which the RR of fracture was 0.46 (95% CI, 0.22–0.95) 
. It was unclear in that publication which trials were included in the pooled analysis, from which data for extended treatment in two trials including about half the randomized participants were included. It is possible that cinacalcet lowers the risk of fracture, but at this time, treatment estimates based on published trial data summarized by meta-analysis are imprecise and lower quality.
The current evidence for cinacalcet in this systematic review is consistent with the UK National Health Service National Institute for Health and Clinical Excellence guidance recommending that cinacalcet should not be used for the routine treatment of elevated serum PTH levels in people with CKD and should be limited to people with elevated PTH concentrations refractory to standard therapy, with a normal or high serum calcium concentration, and
in whom surgical parathyroidectomy is contraindicated because the risks of surgery outweigh the benefits 
. The data also support the current US Food and Drug Administration approval for cinacalcet, which is restricted to patients with CKD stage 5D who have secondary hyperparathyroidism, although benefits of treatment in this setting are limited to prevention of surgical parathyroidectomy and avoidance of hypercalcemia 
. At this time, however, the available randomized evidence for cinacalcet does not support the current Kidney Disease: Improving Global Outcomes clinical practice guidelines suggesting that people with CKD treated with dialysis and elevated or rising PTH levels (beyond two to nine times the upper normal limit) receive vitamin D compounds or calcimimetics or a combination to decrease serum PTH levels to within the suggested range 
Although based on a peer-reviewed protocol and conducted using methods developed by the Cochrane Collaboration, our review has limitations that should be considered. First, data for cinacalcet therapy were largely limited to adults with CKD stage 5D. Insufficient data were available to determine whether treatment effects differed according to severity of CKD. Second, data for recipients of a kidney transplant were absent, although as in other stages of CKD, cinacalcet use may provide benefits outweighing treatment hazards for people requiring parathyroidectomy in whom surgical therapy is contraindicated. Third, due to a relative absence of trials in patients receiving peritoneal dialysis, treatment estimates for this specific group are uncertain. Finally, because of the lack of head-to-head data in available trials, the comparative effectiveness of cinacalcet versus vitamin D compounds for patient-level outcomes remains uncertain.
In conclusion, cinacalcet therapy provides small reductions in the risk of surgical parathyroidectomy but has little or no effect on all-cause mortality and uncertain effects on cardiovascular death for people with CKD and is commonly associated with nausea and vomiting. Routine use of cinacalcet therapy in people with CKD does not appear warranted, and benefits may be limited to preventing parathyroidectomy in the small number of patients for whom surgery is contraindicated. Additional trials in patients with CKD stage 5D are unlikely to change the estimates of treatment effects for cinacalcet.