Calcium Sensing Receptor Activators: A Decade of Study, A Bright Future

Secondary hyperparathyroidism is common in dialysis patients due to impaired vitamin D activation. An article published in the 2015 issue of Seminars in Dialysis surveys the past decade’s findings about use of calcium sensing receptor activators—also called calcimimetics—in this population. Oral cinacalcet (Sensopar, first approved in 2004) is the only drug available in this class, but multiple agents are in development.

Cinacalcet is commonly used with other hypercalcemia medications such as vitamin D analogs and phosphate binders. The ECHO study showed that more patients achieved the study’s primary endpoint (a parathyroid hormone level decrease greater than 30%) with cinacalcet than with a vitamin D analog alone. Most patients who receive cinacalcet have had dialysis for years but studies have only shown cinacalcet’s efficacy in patients with shorter dialysis histories (eg, 3 to 12 months).

Vascular calcification-induced aortic valve stenosis—a common concern in dialyzed hyperphosphatemic patients—can lead to acute myocardial infarction, hospitalization for unstable angina, congestive heart failure, and peripheral vascular events. Calcium sensing receptor activators prevent vascular calcification, but the EVOLVE trial failed to show that they reduced cardiovascular event incidence.

However, several issues related to the study may have affected the outcomes. Many participants discontinued the drug in the placebo arms. In addition, many patients originally assigned to the control group received cinacalcet because their secondary hyperparathyroidism was inadequately controlled. Medication adherence was hampered by adverse effects. Notably, patients receiving cinacalcet were less likely to have a parathyroidectomy or severe unremitting hyperparathyroidism.

Cinacalcet has been used clinically in kidney transplant-induced hypercalcemia as well. Small studies have shown efficacy but cinacalcet lacks randomized controlled trials or FDA approval in this population.

The calcium-sensing receptor is a key management target when dialysis patients develop secondary hyperparathyroidism. The evidence, since cinacalcet’s approval in 2004, is promising for the development of better-tolerated calcium sensing receptor activators. Researchers believe that intravenous formulations would decrease nausea and vomiting, which are common causes of medication non-adherence and discontinuation.