Calcimimetics in End Stage Renal Disease

Management of CKD-MBD

Treatment for CKD-MBD generally starts with counseling about a low-phosphorus diet and phosphate binders to limit gastrointestinal phosphorus absorption (3–5). Clinically meaningful reductions in serum phosphorus levels can also be achieved by increasing weekly dialysis time. Next, calcitriol or another active vitamin D agent is typically started to reduce parathyroid hormone (PTH) levels to goal. Neither the Kidney Disease Outcomes Quality Initiative nor the Kidney Disease Improving Global Outcomes (KDIGO) guidelines give preference to any specific active vitamin D agent.

Cinacalcet is often started when adequate PTH control is not achieved with the above measures or if worsening hyperphosphatemia or hypercalcemia complicates therapy. Cinacalcet, the first calcimimetic medication approved by the Food and Drug Administration (FDA) as a treatment for secondary hyperparathyroidism, is effective in decreasing PTH, calcium, and phosphorus levels, and it has reduced the need for parathyroidectomy (6, 7). Cinacalcet acts by binding to the calcium-sensing receptor of the parathyroid gland, “mimicking” the effect of calcium and decreasing PTH levels.

A new intravenous calcimimetic, etelcalcetide, has recently been approved by the FDA. In the phase 3 trial, the primary efficacy end point (achieving more than a 30% reduction from baseline in mean predialysis PTH levels during weeks 20 to 27) was achieved, proving noninferiority of etelcalcetide to cinacalcet (Table 1). In addition, the secondary end point, a more than 50% reduction of PTH levels, was achieved more frequently in the etelcalcetide group (8).

Table 1.

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Notably, nausea and vomiting occurred at similar rates between etelcalcetide and cinacalcet, indicating a possible centrally mediated mechanism. Etelcalcetide is associated with a higher incidence of hypocalcemia; however, few patients developed related symptoms, including muscle cramping and parasthesias (8).

Etelcalcetide is a dialyzable peptide that must be given posthemodialysis to avoid drug removal. It has not been tested in patients on peritoneal dialysis or home hemodialysis.

New KDIGO guidelines, released in July 2017, do not change the target PTH level, which remains within two to nine times the upper limit of normal for the assay (9). The work group did not prioritize any PTH-lowering treatment (calcimimetics, calcitriol, or other active vitamin D agents), suggesting that all were suitable as first-line drugs.

Cinacalcet, cardiovascular disease, and mortality

Early randomized, placebo-controlled trials showed a reduction in the risk of cardiovascular hospitalization with cinacalcet use (10). The Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) Trial randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or placebo (11). Participants were followed for up to 64 months, with a primary composite end point of time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event.

The unadjusted intention to treat analysis of the primary composite end point was not significantly different between the two groups (relative hazard, 0.93; 95% confidence interval, 0.85 to 1.02; p = 0.11). Differences in baseline characteristics, including older age in the cinacalcet arm and initiation of commercially available cinacalcet or parathyroidectomy in the placebo arm, may have attenuated the differences between the two groups.

A secondary analysis comparing older versus younger EVOLVE Trial participants revealed a significant reduction in the primary composite outcome in participants ≥65 years old, although an observational study showed conflicting results (12, 13).

Cinacalcet, fractures, and parathyroidectomy

Dialysis patients have a higher incidence of fractures, with increased morbidity and mortality compared with the general population (14). Secondary hyperparathyroidism is a major contributor to bone disease in ESRD, and treatment with cinacalcet improves histopathologic changes seen on bone biopsy (15). In the EVOLVE Trial, the effect of cinacalcet on clinical fracture was not statistically significant (relative hazard, 0.89; 95% confidence interval, 0.75 to 1.07) (11). However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16% to 29% (16). Furthermore, parathyroidectomy occurred in 7% of cinacalcet-treated patients and 14% of placebo-treated patients (relative hazard, 0.44; 95% confidence interval, 0.36 to 0.54). Independent predictors of parathyroidectomy included younger age, female gender, geographic region, and absence of history of peripheral vascular disease (11).

Challenges and new developments

There are multiple practical challenges to current successful calcimimetic prescribing. Prescribers often encounter barriers owing to insurance prior authorization policies. Cinacalcet often comes at significant patient cost under Medicare Part D, and some patients are unable to afford copays. The wholesale annual cost of cinacalcet dosed at 30 to 60 mg per day ranges from $10,000 to $19,400, respectively. Gastrointestinal side effects of cinacalcet also limit patient adherence.

Dialysis facilities already provide dietary phosphorus restriction counseling and active vitamin D agents.

In January 2018, dialysis providers became responsible for providing both cinacalcet and etelcalcetide for Medicare patients and likely, many private insurers as well. This represents an opportunity to address many of the practical prescribing issues noted here.

In conclusion:

• Management of CKD-MBD in ESRD includes dietary phosphorus restriction, phosphate binders, active vitamin D agents, and calcimimetics.

• Cinacalcet use is associated with lower rates of parathyroidectomy and possibly, fewer bone fractures.

• Data on the effect of cinacalcet on cardiovascular disease and mortality remain uncertain.

• Compared with cinacalcet, etelcalcetide more effectively lowers PTH, with a similar incidence of nausea and vomiting but higher rates of hypocalcemia.

• Physicians will need to individualize CKD-MBD care by carefully evaluating the value and benefit against the risks and costs of different approaches as dialysis facilities began taking on the provision of calcimimetics in January 2018.