Review of cinacalcet hydrochloride in the management of secondary hyperparathyroidism

Abstract

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.

• Bone disease
• calcium
• cardiovascular disease
• end-stage renal disease
• parathyroid hormone
• vascular calcification

Introduction

Secondary hyperparathyroidism (SHPT) with elevated serum parathyroid hormone levels (PTH) due to hypertrophy and hyperplasia of the parathyroid glands is a common complication that develops in the early stages of chronic kidney disease (CKD) with increasing frequency and severity as CKD progresses.1–3 Although the specific sequence and triggers are not fully defined, SHPT presumably develops as a consequence of rising serum phosphorus concentrations and Fibroblast Growth Factor 23 (FGF23) levels,4–6 decreased 1, 25 hydroxy vitamin D production by the kidney and decreasing serum calcium levels which in turn stimulate increased synthesis and release of PTH. The increased serum PTH may lead to the development of renal osteodystrophy.7,8 Moreover, persistently elevated levels of PTH, phosphorus, and calcium-phosphorus product may predispose to vascular and soft tissue calcification and are associated with significant morbidity, diminished quality of life, and mortality.9–13

The management of SHPT has primarily consisted of dietary phosphate restriction, phosphate binders, active vitamin D analogues such as calcitriol, paricalcitol, doxercalciferol, alfacalcidol, oxacalcitriol, and falecalcitriol and in severe cases parathyroidectomy (referred to hereafter as standard therapy). In April 2004, a calcimimetic known as cinacalcet was approved for the treatment of SHPT in dialysis patients.

Cinacalcet, a novel phenylalkylamine type II calcimimetic, suppresses PTH synthesis and release by the parathyroid glands, by potentiating the stimulation of calcium sensing receptors (CaSR) by extracellular calcium. Hence, CaSR-dependent PTH secretion is suppressed even in the presence of low calcium when cinacalcet is used. Cinacalcet has a half-life of 30–40 hours and reaches a steady-state plasma concentration in 7 days. It leads to a mean reduction of approximately 40% or more in PTH levels from baseline and the maximum reduction in PTH levels are achieved within 2–4 hours of each dose of cinacalcet.14,15 The optimal dose of cinacalcet ranges from 30 mg to a maximum of 180 mg once daily, with most patients responding to a dose of 30–60 mg per day. Similar efficacy of cinacalcet in reducing PTH levels is seen regardless of CKD stage or modality of dialysis15–17 and this effect is sustained for at least up to 3 years.18,19 Long-term combination of cinacalcet with standard therapy has been shown to reduce parathyroid hyperplasia.20

Safety profile

Cinacalcet is well tolerated and the common adverse events reported in the literature have been mild to moderate and include mainly gastrointestinal disturbances such as nausea, vomiting, diarrhea, constipation, and transient hypocalcemia.21 Severe and symptomatic hypocalcemia and hypophosphatemia similar to hungry bone syndrome associated with rapid correction of severe chronic hyperparathyroidism has been reported rarely.22,23 A recent meta-analysis of 15 randomized controlled trials investigating the efficacy and safety of cinacalcet showed no statistically significant difference in all adverse events or all-cause mortality in the cinacalcet groups versus control therapy groups.24 However, the episodes of hypocalcemia, nausea, vomiting, diarrhea, and upper respiratory tract infections were significantly increased in the cinacalcet group.24

Cinacalcet and KDOQI/KDIGO guidelines

Elevated bone and mineral parameters have been identified as independent predictors of cardiovascular and all-cause mortality.9,10,25 The greatest risk of mortality is associated with PTH levels greater than 600 pg/mL, phosphorus levels greater than 7.0 mg/dL, and calcium levels greater than 10 mg/dL.12,26 The survival benefit apparent with more strictly controlled biochemical parameters of SHPT led to the development of Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines.27 The KDOQI guidelines recommended controlling PTH between 150 and 300 pg/mL, phosphorus between 3.5 and 5.5 mg/dL, corrected calcium between 8.4 and 9.5 mg/dL, and calcium-phosphorus product below 55 mg²/dL².

The relatively narrow therapeutic ranges for bone and mineral metabolism parameters defined by KDOQI have been a matter of debate and were recently revised by the Kidney Disease: Improving Global Outcomes (KDIGO) in 2009 to account for the lack of standardization of the PTH assays in addition to the recognition of the relevant clinical evidence that has accumulated since the development of KDOQI targets.28 The new recommendations have widened the target PTH ranges by nearly two to nine times the upper normal limit of PTH defined by the specific assay used which reflect a revised PTH range of approximately 130–600 pg/mL.29

The consistent achievement of KDOQI goals for bone and mineral metabolism has been difficult with standard therapy, with a large proportion of patients exhibiting persistent and refractory SHPT.30–33 Not surprisingly, only about 6.6% and 10.9% of dialysis patients simultaneously met KDOQI targets for PTH, phosphorus, calcium, and calcium-phosphorus product levels in 2003 and 2004, respectively.32 Presumably, this is related to the fact that attempts to suppress serum PTH with increasing doses of active vitamin D analogues are limited by the development of hypercalcemia and worsening hyperphosphatemia.33 The likelihood of developing hypercalcemia with active Vitamin D analogues is further increased by the concomitant use of calcium-containing phosphate binders. In contrast, cinacalcet while suppressing PTH levels simultaneously reduces serum calcium and phosphorus levels thereby adequately controlling not only PTH but also calcium, phosphorus, and calcium-phosphorus product and this effect may be sustained for up to 3 years.12,15,19,34–36 The calcium- and phosphorus-lowering effect of cinacalcet enables the addition or increment of vitamin D therapy to further facilitate PTH suppression.

In 2005, Moe et al. reported improvement in achieving KDOQI goals with the use of cinacalcet with standard therapy.37 This effect was sustained in patients receiving cinacalcet plus stable standard therapy without increases in serum calcium or phosphorus at Week 100.18 This finding was confirmed by subsequent studies. The OPTIMA (Open-Label, Randomized Study Using Cinacalcet to Improve Achievement of KDOQI Targets in Patients with End-Stage Renal Disease) study revealed that a treatment regimen, which includes cinacalcet, is more effective in achieving KDOQI goals with respect to PTH, calcium, phosphorus, and calcium-phosphorus product than standard therapy alone.38 Similarly, ECHO trial (Evaluation of the Clinical Use of Cinacalcet (Mimpara®) in Hemodialysis and Peritoneal Dialysis Patients: an Observational Study) also supported a key role of cinacalcet in meeting KDOQI targets.39 Yet, the IMPACT study results revealed superiority of paricalcitol with or without cinacalcet compared to the combination of cinacalcet and low-dose vitamin D in reducing iPTH levels to KDOQI targets with little alteration in calcium levels in patients undergoing hemodialysis.40 Cinacalcet use has also been associated with lower doses of phosphate binders in addition to controlling bone profile parameters within KDOQI ranges.33 The addition of cinacalcet increased the proportion of dialysis patients achieving PTH ≤300 pg/mL in the ACHIEVE study.41 A recent meta-analysis has confirmed that the KDOQI goals for bone metabolism are now increasingly being achieved with the addition of cinacalcet to the standard therapy.21 Importantly, cinacalcet use has enabled simultaneous attainment of all four KDOQI bone and mineral targets, which has been shown to improve survival in 22,937 hemodialysis patients.42

Cinacalcet, phosphorus control, and FGF23

As renal function declines, dietary phosphorus begins to accumulate in the body. This is initially compensated by decreased tubular reabsorption which is regulated by PTH and FGF23. Both PTH and FGF23 (251 amino acid phosphaturic hormone) increase the fractional renal excretion of phosphorus. However, these adaptive responses are compromised when GFR falls below 20 mL/min/1.73 m² and hyperphosphatemia ensues.

Traditionally, hyperphosphatemia has been treated with dietary restrictions and phosphate binders. In predialysis patients, dietary protein restriction is commonly recommended because it may slow the progression of CKD and decrease phosphorus intake. Short-term control of SHPT has been reported with dietary phosphate restrictions.43,44 However, dietary interventions have limited success due to adherence issues, improper nutritional labeling, and susceptibility to malnutrition.45–48

On the other hand, vitamin D therapy often exacerbates hyperphosphatemia via increased intestinal phosphate absorption. Therefore, concomitant use of phosphate binders is usually indicated with vitamin D therapy. Numerous trials have shown efficacies of different phosphate binders in reducing phosphorus levels while improving bone and calcification outcomes.49 Although a concurrent reduction in PTH and FGF23 levels has also been reported with use of phosphate binders, their effect on FGF23 levels remains controversial.50–52 Moreover, progression of vascular calcification may be accelerated with calcium-based phosphate binders.52 Indeed, the presence of hypercalcemia restricts initiation or dose increases of calcium-based phosphate binders. The use of all phosphate binders in general is often limited due to poor compliance, intolerability, and cost. By contrast, cinacalcet use is associated with reduced phosphorus levels as well as lower requirement of phosphate binders in dialysis patients.53,54 Phosphorus levels decline in parallel with cinacalcet-induced PTH suppression presumably due to decreased mobilization or increased uptake of phosphorus by bone consequent to suppressed PTH.53 This is a sharp contradistinction to worsening hyperphosphatemia observed when vitamin D therapy is used alone. Because vitamin D therapy enhances phosphorus absorption and phosphate binders can only prevent intestinal phosphorus absorption, this particular effect of cinacalcet stands distinguished and useful in the treatment of SHPT. Moreover, the reduced PTH-driven phosphorus efflux from bone may be sustained long term in those treated with cinacalcet and vitamin D.55

It has been assumed that phosphorus-lowering effect of cinacalcet mainly stems from the suppression of PTH and its phosphaturic effect on renal tubules.53 However, cinacalcet-induced reduction in FGF23 levels may also be partially responsible.56

It is important to note that phosphorus-lowering effects of cinacalcet have not been observed in CKD stages 3 and 4 clinical trials. In fact, 4-week cinacalcet therapy led to increased serum phosphorus levels (greater than 4.7 mg/dL) in a phase II trial of predialysis population.16 In another phase II trial, serum phosphorus levels rose from 4.1 mg/dL at baseline to 4.9 mg/dL after 16 week cinacalcet therapy which necessitated either initiation of a phosphate binder or phosphate binder dose increase in 30% of patients.57 Cinacalcet-associated hyperphosphatemia was later confirmed in a phase III trial which reported a 21% increase in phosphorus in cinacalcet group versus 6% in controls.58 These findings raise concerns about reducing PTH with cinacalcet at the expense of worsening hyperphosphatemia and hypocalcemia in CKD 3 and 4 patients. Although only speculative, cinacalcet-associated hyperphosphatemia seen in predialysis population may result from cinacalcet-related suppression of PTH and FGF23 levels which in turn reduce urinary phosphate excretion.58,59 The phosphaturic effect of PTH and FGF23 levels is insignificant in dialysis patients and this may explain the phosphorus-lowering effect of cinacalcet in this specific population. It is not clear whether cinacalcet-induced PTH suppression leads to decreased FGF23 levels or other mechanisms are involved.

Cardiovascular morbidity and mortality

Cardiovascular disease represents the leading cause of mortality in ESRD patients.60 Arterial disease and left ventricular hypertrophy, the two main culprits responsible for increased cardiovascular mortality, are frequently encountered in the ESRD population.

Changes in the vascular structures are known to occur with aging but the process is accelerated in ESRD due to altered hemodynamics, endocrine perturbations, and the process of vascular calcification. SHPT-associated biochemical abnormalities not only strongly predict cardiovascular morbidity and mortality but are also linked to the process of cardiovascular calcification.12,61–67 Vascular calcification reflects an increased deposition of calcium in the tunica intima and tunica media of arterial vessels. Tunica intima calcification is a risk factor of atherosclerotic disease and is associated with arterial stenotic lesions while tunica medial calcification leads to arterial stiffness and left ventricular hypertrophy consequent to the increased afterload. Left ventricular hypertrophy ultimately leads to diastolic dysfunction, congestive heart failure, arrhythmias, and sudden death. Furthermore, cardiac valves may also accumulate calcium deposits, which is 5 to 10 times more common in dialysis patients compared to the general population.68

Therefore, the highly prevalent and rapidly progressive burden of cardiovascular calcification is integral to the pathogenesis of cardiovascular disease and is an important determinant of cardiovascular and all cause mortality in ESRD patients.11,69–72

Cinacalcet and vascular calcification and cardiovascular outcomes

A small study of hemodialysis patients demonstrated a tendency for regression of coronary artery calcification in those who received cinacalcet.73 Likewise, the ADVANCE study (a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis) shared findings of lower vascular and cardiac valve calcification scores in patients receiving cinacalcet plus low-dose vitamin D analogues compared to flexible doses of vitamin D analogues alone.74 Moreover, significantly reduced arterial stiffness was evident in 21 patients receiving cinacalcet for 12 months in another observational study.75

Cardiovascular-related hospitalization and mortality was shown to be significantly lower in cinacalcet-treated patients versus those treated with standard therapy alone.12,76 An all-cause and cardiovascular survival benefit was also noted by Block et al. in an observational study of 19,186 patients.77 However, the first placebo-controlled randomized trial, Evaluation of Cinacalcet HCl to Lower Cardiovascular Events (EVOLVE), investigating the impact of cinacalcet therapy on hard clinical outcomes including myocardial infarction, stroke, heart failure, hospitalization for unstable angina, peripheral vascular event, parathyroidectomy, fracture, and death failed to show a survival benefit in the cinacalcet group compared to the placebo group.78 There was also no risk reduction in cardiovascular events in the cinacalcet group.78 Thus, a definitive beneficial effect of cinacalcet therapy on cardiovascular outcomes remains speculative. Additional studies are needed to investigate the effect of cinacalcet treatment of vascular calcification, left ventricular hypertrophy, and cardiovascular outcomes.

More recently, FGF23, expressed in bone and connective tissues, has been identified as a powerful predictor of vascular calcification and mortality in hemodialysis patients.79–84 FGF23-induced left ventricular hypertrophy was evident in vitro85 and increased levels of FGF23 were independently associated with left ventricular hypertrophy in 162 CKD patients.86 Similarly, but independently of PTH, FGF23 stimulates phosphorus excretion via klotho-FGFR1 complex located in the kidneys.87 FGF23 decreases calcitriol synthesis by inhibiting 1 ∝ hydroxylase,88–90 which is opposite to the effect of PTH. FGF23 and PTH levels are regulated via feedback mechanism such that FGF23 decreases PTH gene expression, secretion, and parathyroid cell proliferation while PTH increases FGF23 expression. Lavi-Mashayoff et al. demonstrated that PTH is necessary for the high levels of FGF23 seen early in the course of kidney failure due to high adenine-phosphorus diet in rats.91 Parathyroidectomy prevented and corrected the increase in FGF23 levels in kidney failure rats80 and in 15 CKD patients with secondary hyperparathyroidism.92

The FGF23-PTH loop is disturbed in the setting of CKD such that FGF23 fails to suppress parathyroids due to downregulation of klotho-FGFR1 because both FGF23 and PTH levels are increased. Emerging evidence suggests that FGF23 may not only act as a biomarker of phosphate toxicity but also mediate direct toxicity to the heart.93 CKD patients also exhibit a deficiency of klotho, which is a coreceptor for FGF23. Klotho was shown to be an early biomarker of CKD and also appears to preserve renal function and mitigate vascular calcification by inhibiting the uptake of phosphate by vascular smooth muscle.94

It is, therefore, hypothesized that optimal control of calcium, phosphorus, CaxP, PTH, and FGF23 levels which may be accomplished with cinacalcet treatment may reduce cardiovascular morbidity and mortality in ESRD patients.

Cinacalcet, FGF23-Klotho axis, and cardiovascular calcification

FGF23 levels were significantly lower in the cinacalcet with low-dose vitamin D versus control group on flexible doses of vitamin D analogues in the ACHIEVE study.95 The reduction in FGF-23 in the cinacalcet with low-dose vitamin D group could be attributed to the lower doses of vitamin D because vitamin D can elevate FGF-23 levels.96 Koizumi et al. also reported reduced levels of FGF23 in 55 hemodialysis patients who received cinacalcet.97 This possible mechanism for a beneficial effect of cinacalcet on vascular calcification and cardiovascular outcomes awaits further investigation.

Cinacalcet and bone density, fractures, and parathyroidectomy

Cortical bone density inversely correlates with PTH levels in hemodialysis patients98 and a decrease in bone density increases the risk for fracture-related hospitalization.12 PTH greater than 900 pg/mL was associated with an increased risk for any new fracture in the Dialysis Outcomes and Patterns Study (DOPPS) compared to a PTH falling between 150 and 300 pg/mL.99 The study by Danese et al. also indicates an association, albeit weak, of increased risk for hip and vertebral fractures and PTH concentration.100

Definitive evidence that cinacalcet-induced PTH suppression may attenuate or reverse bone loss and decrease the incidence of fractures is lacking. Bone histology parameters were assessed by Yajima et al. and indicated an increased mineralized bone volume in four hemodialysis patients who received cinacalcet for 52 weeks.101 A small multi-center study of 10 hemodialysis patients demonstrated an increase of 2% in mineral density of proximal femur without similar effect on lumbar spine mineral density after 6 months of treatment with cinacalcet.102 In the study by Ishimura et al., 1-year treatment with cinacalcet resulted in reduced radius bone mineral density loss in 61 chronic hemodialysis patients.103 Another study looking at bone histology after 1 year of cinacalcet versus standard therapy reported a reduction in bone turnover and marrow fibrosis in 19 patients treated with cinacalcet.104

The relative risk of fractures was seen to be significantly reduced in the cinacalcet group compared to those treated with standard therapy alone in a post hoc analysis from four placebo-controlled randomized controlled trials.76 The pooled data also showed a much smaller relative risk of parathyroidectomy in the cinacalcet group versus standard therapy.76 Although the four trials were not designed or powered for the evaluation of clinical outcomes, the pooled data suggest a role for cinacalcet in improving such clinical events. In a 6-month observational study in Japan, cinacalcet prevented parathyroidectomy in 80% of patients who had indications for parathyroidectomy.105 However, the indications for parathyroid intervention in this study of 61 patients were much more aggressive than guidelines practiced elsewhere.105 Cinacalcet, by reducing PTH to 250 pg/mL in 48% of patients with PTH range of 500 to 800 pg/mL and in 20% of patients with >800 pg/mL, eliminated indications for parathyroidectomy in Japanese patients.106 Therefore, the marked PTH-lowering effects of cinacalcet are sometimes referred to as “medical parathyroidectomy.” 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.

Cinacalcet and cost analysis

The evaluation of the economic implications of cinacalcet in the treatment of SHPT has produced mixed results worldwide. In hemodialysis patients, the direct drug costs of treating SHPT with intravenous calcitriol averaged $80.20 per patient per week ($4170 per year) versus $278.46 per patient per week ($14,480 per year) for treatment with cinacalcet in 2007.108 A cost analysis performed on cinacalcet versus parathyroidectomy as treatment for uncontrolled SHPT suggests that cinacalcet therapy is most cost-effective only for patients who are to remain on dialysis for 7.25 ± 0.25 months or less.109 Recently, simulation model developed using ADVANCE trial data showed that cinacalcet use in SHPT management may be cost-effective compared to standard therapy in the United States.110 Moreover, a cost analysis performed by Ray et al. suggests that the costs can be reduced if cinacalcet is started early when PTH rises above 300 pg/mL versus late in the course when PTH levels are more severely deranged.111 Another cost analysis derived from the OPTIMA trial data also appears to favor cost-effectiveness of cinacalcet in five European countries, despite differences in healthcare systems and economic wealth.112 This is contrary to the previous UK-based report113 and ACHIEVE trial data-based simulation model, which found that cinacalcet therapy was more costly.114 Rogerri et al. analyzed FARO study data and suggested that paricalcitol treatment alone was significantly less expensive than combined with cinacalcet regardless of baseline severity and control of SHPT.115 A cost analysis from Japan generated incremental cost-effectiveness ratio (ICER) of $352,631/QALY gained and $21,613/QALY gained with cinacalcet use in patients who were eligible and ineligible for parathyroidectomy, respectively.116 It is important to note that the indication for parathyroidectomy was defined as a PTH greater than 500 pg/mL for more than 6 months in this cost analysis model.

Although cinacalcet is an expensive drug and its cost-effectiveness remains controversial, a cost re-analysis will be warranted to incorporate new data related to cardiovascular health and long-term clinical outcomes in dialysis patients.

Conclusion

Cinacalcet is a safe and effective addition to the armamentarium for the treatment of secondary hyperparathyroidism. In appropriate patients it may replace, supplement or enhance standard therapeutic approaches for the management of SHPT. Future studies are required to define the underlying mechanisms of the apparent pleiotropic effects of cinacalcet on the cardiovascular system. The full and definitive impact of cinacalcet on clinical outcomes remains to be established.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Chaim Charytan is a recipient of research support from Amgen, Abbot, American Regent Laboratories, Dynavax, Mitsubishi and Fibrogen.