Calcimimetics and outcomes in CKD

Abstract

In the past decade, several experimental studies demonstrated an inhibitory effect of calcimimetics on the progression of vascular calcification in animals with chronic kidney disease (CKD), in keeping with the expression of the calcium-sensing receptor (CaR) in vascular tissue. In addition, calcimimetics were also found to prevent the arterial remodeling caused by CKD and to slow the progression of atherosclerosis in uremic rats and mice, respectively. The mode of action of these CaR modulators could be both via a better control of secondary hyperparathyroidism and direct effects on the vessel wall. Two main clinical trials, ADVANCE and EVOLVE, recently evaluated in patients with CKD stage 5D the effects of the calcimimetic cinacalcet on the progression of vascular calcification and hard cardiovascular outcomes, respectively. Both trials missed their respective primary end point by intent-to-treat analysis although by other prespecified analyses, including adjustment for baseline characteristics, there was strong suggestive evidence in favor of reductions in risk, in agreement with numerous experimental studies. Further clinical trials are needed to settle this issue definitively.

Pharmacokinetics, Pharmacodynamics, and Safety of the Novel Calcimimetic Agent Evocalcet in Healthy Japanese Subjects: First-in-Human Phase I Study

“…Treatment of SHPT includes dietary restriction of phosphorus and the prescription of phosphate binders, and/or active vitamin D products. Calcimimetics are an emerging therapy for SHPT in CKD [ 8 – 10 ], allosterically modifying calcium-sensing receptors (CaSR) to reduce PTH secretions [ 11 ].…”

Prospective cohort study: Cinacalcet-mediated lowering of PTH level and cardiovascular disease mortality in younger Korean patients with stage 5 CKD at a Korean secondary hospital

“…1,2 When combined with abnormal serum level of phosphorus, high serum level of PTH has been associated with an increased risk of CVD mortality and all-cause mortality in patients with CKD. [10][11][12][13][14] Moreover, the studies have focused on varied target levels of biochemicals and hormones. [7][8][9] It has been difficult to determine the true effect of cinacalcet on mortality because previous studies have exhibited highly variable baseline levels of biochemicals and hormones, in addition to wide variations in patient age and glomerular filtration rate (GFR).…”

“…[7][8][9] It has been difficult to determine the true effect of cinacalcet on mortality because previous studies have exhibited highly variable baseline levels of biochemicals and hormones, in addition to wide variations in patient age and glomerular filtration rate (GFR). [10][11][12][13][14] Moreover, the studies have focused on varied target levels of biochemicals and hormones. Therefore, several potential factors could explain the discrepancies between findings from various observational studies and randomized control trials (RCTs).…”

Emerging drugs for secondary hyperparathyroidism

“…However, clinical data reveal that paricalcitol treatment can be associated with elevations in serum calcium and phosphorus, and a significant minority of patients treated with paricalcitol experience hypercalcemia, which may promote vascular calcification [56]. Calcimimetics, such as cinacalcet, lower PTH levels and reduce serum calcium and phosphorus compared to vitamin D [30,38,73,74] and cinacalcet plus low-dose calcitriol analogs has been shown to reduce serum FGF-23 more than calcitriol analogs alone [75]. However, cinacalcet is administered orally and has been associated with gastrointestinal AEs in~30% of patients and hypocalcemia in 7% [38].…”