The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Michihito Wada - One of the best experts on this subject based on the ideXlab platform.
-
effectiveness of Cinacalcet treatment for secondary hyperparathyroidism on hospitalization results from the mbd 5d study
PLOS ONE, 2019Co-Authors: Shinji Asada, Michihito Wada, Kazuki Yoshida, Shingo Fukuma, Takanobu Nomura, Yoshihiro Onishi, Noriaki Kurita, Masafumi Fukagawa, Shunichi Fukuhara, Tadao AkizawaAbstract:Objectives To elucidate the effect of Cinacalcet use on all-cause and cause-specific hospitalization outcomes using a prospective cohort of maintenance hemodialysis patients. Methods We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism and examined baseline characteristics as well as longitudinal changes. All patients were Cinacalcet-naive at study enrollment. Further, we used a marginal structural model to account for time-varying confounders on Cinacalcet initiation and hospitalization outcomes, and an Andersen-Gill–type recurrent event model to account for any recurring events of hospitalization in the outcome analysis using the weighted dataset. Results Among the 3,276 patients, Cinacalcet treatment was initiated in 1,384 patients during the entire follow-up. Cinacalcet users were slightly younger, included more patients with chronic glomerulonephritis and fewer patients with diabetes, were more likely to have a history of parathyroidectomy, and were more often used receiving vitamin D receptor activator, phosphate binders, and iron supplements. The overall hospitalization analysis yielded a hazard ratio (HR) of 0.97 (95% confidence interval [CI]: 0.80, 1.18). A trend toward a mild protective association was observed for cardiovascular-related hospitalizations (HR: 0.85; 95% CI: 0.64, 1.14). In the subgroup analysis, a protective association was seen due to Cinacalcet use for infection-related hospitalizations in the lowest intact parathyroid hormone group (HR: 0.36; 95% CI: 0.14, 0.95). Conclusions Cinacalcet initiation in patients on maintenance hemodialysis had no effect on all-cause and cause-specific hospitalizations. Although the overall association was statistically not significant, Cinacalcet may have a protective association on cardiovascular-related hospitalization in all patients and infection-related hospitalization in patient with low intact parathyroid hormone.
-
a novel calcimimetic agent evocalcet mt 4580 khk7580 suppresses the parathyroid cell function with little effect on the gastrointestinal tract or cyp isozymes in vivo and in vitro
PLOS ONE, 2018Co-Authors: Takehisa Kawata, Shin Tokunaga, Miki Murai, Nami Masuda, Waka Haruyama, Youji Shoukei, Yutaka Hisada, Tetsuya Yanagida, Hiroshi Miyazaki, Michihito WadaAbstract:Cinacalcet hydrochloride (Cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, Cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, Cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to Cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than Cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than Cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to Cinacalcet, an oral calcimimetic agent, with a wider safety margin.
-
A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.
PloS one, 2018Co-Authors: Takehisa Kawata, Shin Tokunaga, Miki Murai, Nami Masuda, Waka Haruyama, Youji Shoukei, Yutaka Hisada, Tetsuya Yanagida, Hiroshi Miyazaki, Michihito WadaAbstract:Cinacalcet hydrochloride (Cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, Cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, Cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to Cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than Cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than Cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to Cinacalcet, an oral calcimimetic agent, with a wider safety margin.
-
Cinacalcet suppresses calcification of the aorta and heart in uremic rats
Kidney international, 2008Co-Authors: Takehisa Kawata, Nobuo Nagano, Masaki Obi, Sonoe Miyata, Chika Koyama, Nami Kobayashi, Sachiko Wakita, Michihito WadaAbstract:High serum parathyroid hormone levels are associated with vascular calcification. Cinacalcet is a calcimimetic agent that inhibits parathyroid hormone secretion and is used to treat patients with secondary hyperparathyroidism. Here we measured the effects of oral Cinacalcet on calcification of the aorta and heart in rats with a remnant kidney (5/6 nephrectomy) model of uremia that were fed a high-phosphate diet containing lactose to accelerate the process of aortic calcification. Alizarin red staining showed that the smooth muscle in the aortic arch of rats with a remnant kidney was calcified. The tissue levels of calcium and phosphorus in the aorta and hearts of these rats were significantly increased compared to sham-operated rats. Expression of the osteoblastic lineage genes osteocalcin, osteopontin and runt-related gene 2 were also increased in the aorta of these rats. Cinacalcet suppressed these calcification-related changes by reducing serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Parathyroidectomy also suppressed calcification in this model. We suggest that Cinacalcet inhibits calcification of the aorta and heart in uremic patients with secondary hyperparathyroidism by decreasing serum parathyroid hormone levels.
-
Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism
Kidney international, 2005Co-Authors: Matthew Colloton, Michihito Wada, Gerald Miller, Edward Shatzen, Catherine Stehman-breen, David L. Lacey, David MartinAbstract:Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism . Background Secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) is a physiologic response to kidney failure characterized by elevated serum parathyroid hormone (PTH) levels and parathyroid gland enlargement. Calcimimetic agents acting through allosteric modification of the calcium-sensing receptor (CaR) can attenuate parathyroid hyperplasia in rats with secondary HPT. The present study explores the effects of the calcimimetic Cinacalcet HCl on parathyroid hyperplasia, apoptosis, and PTH secretion in a rat model of secondary HPT. Methods Cinacalcet HCl was gavaged daily (1, 5, or 10 mg/kg) for 4 weeks starting 6 weeks post-5/6 nephrectomy. After dosing, hyperplasia was determined using parathyroid weight and proliferating cell nuclear antigen (PCNA) immunochemistry. Apoptosis was determined using in situ techniques. Serum PTH (1–34) and blood chemistries were determined throughout the course of the study. Results Administration of Cinacalcet HCl (5 or 10 mg/kg) significantly reduced the number of PCNA-positive cells and decreased parathyroid weight compared with vehicle-treated 5/6 nephrectomized rats. There was no difference in apoptosis from Cinacalcet HCl–treated or vehicle-treated animals. Serum PTH and blood ionized calcium levels decreased in Cinacalcet HCl–treated animals compared with vehicle-treated controls. Conclusion The results confirm previous work demonstrating that calcimimetic agents attenuate the progression of parathyroid hyperplasia in subtotally nephrectomized rats, extending earlier observations to now include Cinacalcet HCl. These results support a role for the CaR in regulating parathyroid cell proliferation. Therefore, Cinacalcet HCl may represent a novel therapy for improving the management of secondary HPT.
Masafumi Fukagawa - One of the best experts on this subject based on the ideXlab platform.
-
effectiveness of Cinacalcet treatment for secondary hyperparathyroidism on hospitalization results from the mbd 5d study
PLOS ONE, 2019Co-Authors: Shinji Asada, Michihito Wada, Kazuki Yoshida, Shingo Fukuma, Takanobu Nomura, Yoshihiro Onishi, Noriaki Kurita, Masafumi Fukagawa, Shunichi Fukuhara, Tadao AkizawaAbstract:Objectives To elucidate the effect of Cinacalcet use on all-cause and cause-specific hospitalization outcomes using a prospective cohort of maintenance hemodialysis patients. Methods We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism and examined baseline characteristics as well as longitudinal changes. All patients were Cinacalcet-naive at study enrollment. Further, we used a marginal structural model to account for time-varying confounders on Cinacalcet initiation and hospitalization outcomes, and an Andersen-Gill–type recurrent event model to account for any recurring events of hospitalization in the outcome analysis using the weighted dataset. Results Among the 3,276 patients, Cinacalcet treatment was initiated in 1,384 patients during the entire follow-up. Cinacalcet users were slightly younger, included more patients with chronic glomerulonephritis and fewer patients with diabetes, were more likely to have a history of parathyroidectomy, and were more often used receiving vitamin D receptor activator, phosphate binders, and iron supplements. The overall hospitalization analysis yielded a hazard ratio (HR) of 0.97 (95% confidence interval [CI]: 0.80, 1.18). A trend toward a mild protective association was observed for cardiovascular-related hospitalizations (HR: 0.85; 95% CI: 0.64, 1.14). In the subgroup analysis, a protective association was seen due to Cinacalcet use for infection-related hospitalizations in the lowest intact parathyroid hormone group (HR: 0.36; 95% CI: 0.14, 0.95). Conclusions Cinacalcet initiation in patients on maintenance hemodialysis had no effect on all-cause and cause-specific hospitalizations. Although the overall association was statistically not significant, Cinacalcet may have a protective association on cardiovascular-related hospitalization in all patients and infection-related hospitalization in patient with low intact parathyroid hormone.
-
Head-to-head comparison of the new calcimimetic agent evocalcet with Cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism.
Kidney international, 2018Co-Authors: Masafumi Fukagawa, Ryutaro Shimazaki, Tadao AkizawaAbstract:Secondary hyperparathyroidism (SHPT) leads to cardiovascular calcification, which affects survival and quality of life in patients with chronic kidney disease. Cinacalcet is used to control SHPT, but it may induce gastrointestinal symptoms, resulting in lower adherence and insufficient dosages. Therefore, a need exists to develop new calcimimetics that cause fewer gastrointestinal symptoms. Here we conducted a phase 3, randomized, double-blind, double-dummy trial for a head-to-head comparison of the efficacy and safety of evocalcet, a new oral calcimimetic, to the established Cinacalcet. Japanese patients with SHPT on hemodialysis were randomized to receive evocalcet or Cinacalcet (317 patients each) for 30 weeks. The primary efficacy endpoint was non-inferiority of evocalcet to Cinacalcet in the proportion of patients achieving a mean intact parathyroid hormone level of 60 to 240 pg/mL from week 28 to 30 (non-inferiority margin, -15%, per protocol set analyses). In the evocalcet and Cinacalcet groups, 72.7% and 76.7%, respectively, achieved the target intact parathyroid hormone level (between-group difference: -4.0% [95% confidence interval -11.4%, 3.5%], for non-inferiority). The incidence of gastrointestinal-related adverse events was 18.6% and 32.8%, respectively (between-group difference: -14.2% [-20.9%, -7.5%], significant for superiority). Thus, the non-inferiority of evocalcet to Cinacalcet in suppressing intact parathyroid hormone with fewer gastrointestinal-related adverse events was demonstrated. Hence, evocalcet may be a favorable alternative to existing calcimimetics for management of SHPT.
-
effects of secondary hyperparathyroidism treatment on improvement in anemia results from the mbd 5d study
PLOS ONE, 2016Co-Authors: Motoko Tanaka, Kazuki Yoshida, Shingo Fukuma, Masafumi Fukagawa, Shunichi Fukuhara, Kazutaka Matsushita, Tadao AkizawaAbstract:Objectives Anemia is an important prognostic factor in hemodialysis patients. It has been reported that parathyroidectomy ameliorates anemia and reduces the requirement of postoperative erythropoiesis-stimulating agents. The objective of this study was to assess the effect of Cinacalcet, which is considered as a pharmacological parathyroidectomy, on anemia in hemodialysis patients. Methods We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism; the criteria were: intact parathyroid hormone concentrations ≥ 180 pg/mL or use of an intravenous or oral vitamin D receptor activator. All patients were Cinacalcet-naive at study enrollment. The main outcome measure was achievement of the target hemoglobin level (≥10.0 g/dL), which was measured repeatedly every 6 months. Cinacalcet exposure was defined as cumulative time since initiation. Both conventional longitudinal models and marginal structural models were adjusted for confounding factors. Results Among 3,201 Cinacalcet-naive individuals at baseline, Cinacalcet was initiated in 1,337 individuals during the follow up. Cinacalcet users were slightly younger; included more patients with chronic glomerulonephritis and fewer with diabetes; were more likely to have a history of parathyroidectomy; and were more often on activated vitamin D agents, phosphate binders, and iron supplements. After adjusting for both time-invariant and time-varying potential confounders, including demographics, comorbidities, comedications, and laboratory values, each additional 6-month duration on Cinacalcet was associated with a 1.1-fold increase in the odds of achieving the target hemoglobin level. Conclusions Cinacalcet may improve anemia in chronic hemodialysis patients with secondary hyperparathyroidism, possibly through pathways both within and outside the parathyroid hormone pathways. Further investigations are warranted to delineate the roles of Cinacalcet not only in the management of chronic kidney disease–mineral and bone disorder but also in anemia control.
-
pth dependence of the effectiveness of Cinacalcet in hemodialysis patients with secondary hyperparathyroidism
Scientific Reports, 2016Co-Authors: Tadao Akizawa, Shingo Fukuma, Yoshihiro Onishi, Noriaki Kurita, Masafumi Fukagawa, Takuhiro Yamaguchi, Masahide Mizobuchi, Alan R Ellis, Alan M Brookhart, Takeshi HasegawaAbstract:Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined Cinacalcet’s effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relationships between Cinacalcet initiation and important clinical outcomes. To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders. Over a mean of 33 months, Cinacalcet was more effective in patients with more severe SHPT. In patients with iPTH ≥500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29–0.82). For a composite of cardiovascular hospitalization and mortality, the association was not statistically significant, but the IRR was 0.67 (95% CI: 0.43–1.06). These findings indicate that decisions about using Cinacalcet should take into account the severity of SHPT.
-
prescription patterns and mineral metabolism abnormalities in the Cinacalcet era results from the mbd 5d study
Clinical Journal of The American Society of Nephrology, 2012Co-Authors: Masafumi Fukagawa, Shingo Fukuma, Yoshihiro Onishi, Tadao Akizawa, Takuhiro Yamaguchi, Takeshi Hasegawa, Kiyoshi Kurokawa, Shunichi FukuharaAbstract:Summary Background and objectivesPrescription patterns for hemodialysis patients with secondary hyperparathyroidism have varied widely since market introduction of Cinacalcet. This study examined associations between prescription patterns and subsequent laboratory values. Design, setting, participants, & measurements Using a Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients subcohort, 1716 prevalent hemodialysis patients (4048 sets for repeated measures between January 2008 and July 2009) with an intact parathyroid hormone (iPTH) level .180 pg/ml who used intravenous vitamin D receptor activator (VDRA) without Cinacalcet were selected. Prescription patterns were defined based on Cinacalcet administration (starting or not) and VDRA dosage change (decreased [,225%], stable [225% to 25%], or increased [.25%]). Proportion differences (PDs) were determined for decreasing iPTH levels by at least one category (,180, 180–299, 300–499, and $500 pg/ml) and for achieving target phosphorus (3.5–6.0 mg/dl) and calcium (8.4–10.0 mg/dl) levels, adjusting for potential confounders. Results The starting Cinacalcet and increased VDRA patterns were associated with decreasing iPTH levels (PD, 0.25 and 0.13; 95% confidence intervals [95% CIs], 0.19–0.31 and 0.09–0.17, respectively); combination use had an additive association (PD, 0.34; 95% CI, 0.20–0.42). The starting Cinacalcet and decreased VDRA combination was associated with simultaneously achieving target phosphorus (PD, 0.12; 95% CI: 0.04–0.20) and calcium (PD, 0.09; 95% CI, 0.01–0.17) levels.
Geoffrey A Block - One of the best experts on this subject based on the ideXlab platform.
-
dosing of etelcalcetide vs Cinacalcet for secondary hyperparathyroidism reply
JAMA, 2017Co-Authors: Geoffrey A Block, Glenn M ChertowAbstract:In Reply Dr Hai and colleagues are concerned that the starting dose of etelcalcetide was 5 mg (not the lowest dose) whereas the starting dose of Cinacalcet was 30 mg (the lowest dose). This clinical trial, using a double-dummy active control, dosed Cinacalcet in strict accordance with the approved package insert and in a manner consistent with previous clinical trials of similar duration using similar biochemical end points.1,2 Our finding of a mean decrease in PTH of approximately 40% over 26 weeks in patients treated with Cinacalcet is similar to findings of the phase 3 trials with Cinacalcet (43% decrease in mean PTH over 26 weeks).1 The dosing of etelcalcetide was approved by the US Food and Drug Administration. Because Cinacalcet and etelcalcetide are different drugs, there is no a priori reason to believe that their dosing schemes should be identical.
-
effect of etelcalcetide vs Cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism a randomized clinical trial
Publisher, 2017Co-Authors: Geoffrey A Block, Tilman B Drueke, Markus Ketteler, Kevin J Martin, John Cunningham, Bastian Dehmel, Sunfa Cheng, David A Bushinsky, Reshma Kewalramani, Sharon M MoeAbstract:Importance Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects. Objective To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic Cinacalcet. Design, Setting, and Participants A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral Cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015. Interventions Etelcalcetide intravenously and oral placebo (n = 340) or oral Cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily. Main Outcomes and Measures The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting. Results The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to Cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive Cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was −10.5% (95% CI, −17.5% to −3.5%, P for noninferiority, P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to Cinacalcet ( P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%). Conclusions and Relevance Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to Cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety. Trial Registration clinicaltrials.gov Identifier:NCT1896232
-
Cinacalcet dialysate calcium concentration and cardiovascular events in the evolve trial
PMC, 2016Co-Authors: Patrick H Pun, Jürgen Floege, Tilman B Drueke, Glenn M Chertow, Safa Abdalla, Geoffrey A Block, Ricardo Correarotter, Bastian Dehmel, William G Goodman, Charles A HerzogAbstract:Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to Cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of Cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the Cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of Cinacalcet on the outcomes examined. The effects of Cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.
-
the effects of Cinacalcet on blood pressure mortality and cardiovascular endpoints in the evolve trial
Author, 2016Co-Authors: Tara I Chang, Jürgen Floege, Tilman B Drueke, Safa Abdalla, Gerard M London, Geoffrey A Block, Ricardo Correarotter, Charles A Herzog, Kenneth W Mahaffey, Sharon M MoeAbstract:Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive Cinacalcet or placebo. We sought to examine whether the effect of Cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether Cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to Cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to Cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of Cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks Cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of Cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.
-
effects of Cinacalcet on fracture events in patients receiving hemodialysis the evolve trial
Journal of The American Society of Nephrology, 2015Co-Authors: Sharon M Moe, Jürgen Floege, Glenn M Chertow, Patrick S Parfrey, Safa Abdalla, Gerard M London, Geoffrey A Block, Ricardo Correarotter, Charles A Herzog, Kenneth W MahaffeyAbstract:Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that Cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive Cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to Cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (Cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial Cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of Cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, Cinacalcet did not reduce the rate of clinical fracture. 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%–29%.
Glenn M Chertow - One of the best experts on this subject based on the ideXlab platform.
-
incidence predictors and therapeutic consequences of hypocalcemia in patients treated with Cinacalcet in the evolve trial
Kidney International, 2018Co-Authors: Jürgen Floege, Kate Tsirtsonis, Jan Iles, Tilman B Drueke, Glenn M Chertow, Patrick S ParfreyAbstract:The calcimimetic Cinacalcet is used to treat secondary hyperparathyroidism in patients receiving dialysis, and asymptomatic hypocalcemia is often observed following its initiation. Here we investigated the incidence, predictors and therapeutic consequences of hypocalcemia by a post hoc analysis of the randomized, double-blind, placebo-controlled EValuation Of Cinacalcet Hydrochloride Therapy to Lower CardioVascular Events (EVOLVE) trial. Hypocalcemia was classified as mild (total serum calcium 8.0–8.39 mg/dL), moderate (7.5–7.99 mg/dL) or severe (under 7.5 mg/dL). At least one episode of hypocalcemia developed within 16 weeks after the first administered dose among 58.3% of 1938 patients randomized to Cinacalcet versus 14.9% of 1923 patients randomized to placebo. Hypocalcemia in the Cinacalcet group was severe in 18.4% of the patients versus 4.4% in the placebo group. Severe hypocalcemia following administration of Cinacalcet was associated with higher baseline plasma parathyroid hormone, lower corrected total serum calcium, higher serum alkaline phosphatase, geographic region (patients from Latin America and Russia had a higher risk relative to the United States) and higher body mass index. The median Cinacalcet dose immediately prior to the first hypocalcemic episode was 54-58 mg/day and similar in the three hypocalcemia categories. In the majority of patients, hypocalcemia resolved spontaneously within 14 days without modification of background therapy. Among patients who received an intervention, the most common was an increase in the active vitamin D sterol dose. Thus, the occurrence of hypocalcemia is frequent following initiation of Cinacalcet and the likelihood of developing hypocalcemia was related to the severity of secondary hyperparathyroidism. Hypocalcemia was generally asymptomatic and self-limited.
-
dosing of etelcalcetide vs Cinacalcet for secondary hyperparathyroidism reply
JAMA, 2017Co-Authors: Geoffrey A Block, Glenn M ChertowAbstract:In Reply Dr Hai and colleagues are concerned that the starting dose of etelcalcetide was 5 mg (not the lowest dose) whereas the starting dose of Cinacalcet was 30 mg (the lowest dose). This clinical trial, using a double-dummy active control, dosed Cinacalcet in strict accordance with the approved package insert and in a manner consistent with previous clinical trials of similar duration using similar biochemical end points.1,2 Our finding of a mean decrease in PTH of approximately 40% over 26 weeks in patients treated with Cinacalcet is similar to findings of the phase 3 trials with Cinacalcet (43% decrease in mean PTH over 26 weeks).1 The dosing of etelcalcetide was approved by the US Food and Drug Administration. Because Cinacalcet and etelcalcetide are different drugs, there is no a priori reason to believe that their dosing schemes should be identical.
-
Cinacalcet dialysate calcium concentration and cardiovascular events in the evolve trial
PMC, 2016Co-Authors: Patrick H Pun, Jürgen Floege, Tilman B Drueke, Glenn M Chertow, Safa Abdalla, Geoffrey A Block, Ricardo Correarotter, Bastian Dehmel, William G Goodman, Charles A HerzogAbstract:Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to Cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of Cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the Cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of Cinacalcet on the outcomes examined. The effects of Cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.
-
economic evaluation of Cinacalcet in the united states the evolve trial
Value in Health, 2015Co-Authors: Vasily Belozeroff, Glenn M Chertow, Patrick S Parfrey, Christopher N Graham, Bastian Dehmel, Andrew BriggsAbstract:Abstract Background Previous economic evaluations of Cinacalcet in patients with secondary hyperparathyroidism (sHPT) relied on the combination of surrogate end points in clinical trials and epidemiologic studies. Objectives The objective was to conduct an economic evaluation of Cinacalcet on the basis of the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial from a US payer perspective. Methods We developed a semi-Markov model to assess the cost-effectiveness of Cinacalcet in addition to conventional therapy, compared with conventional therapy alone, in patients with moderate-to-severe sHPT receiving hemodialysis. We used treatment effect estimates from the unadjusted intent-to-treat (ITT) analysis and prespecified covariate-adjusted ITT analysis as our main analyses. We assessed model sensitivity to variations in individual inputs and overall decision uncertainty through probabilistic sensitivity analyses. Results The incremental cost-effectiveness ratio (ICER) for Cinacalcet was $61,705 per life-year and $79,562 per quality-adjusted life-year (QALY) gained using the covariate-adjusted ITT analysis. Probabilistic sensitivity analysis suggested a 73.2% chance of the ICER being below a willingness-to-pay threshold of $100,000. Treatment effects from unadjusted ITT analysis yielded an ICER of $115,876 per QALY. The model was most sensitive to the treatment effect on mortality. Conclusions In the unadjusted ITT analysis, Cinacalcet does not represent a cost- effective use of health care resources when applying a willingness-to-pay threshold of $100,000 per QALY. When using the covariate-adjusted ITT treatment effect, which represents the least biased estimate, however, Cinacalcet is a cost-effective therapy for patients with moderate-to-severe sHPT on hemodialysis.
-
effects of Cinacalcet on fracture events in patients receiving hemodialysis the evolve trial
Journal of The American Society of Nephrology, 2015Co-Authors: Sharon M Moe, Jürgen Floege, Glenn M Chertow, Patrick S Parfrey, Safa Abdalla, Gerard M London, Geoffrey A Block, Ricardo Correarotter, Charles A Herzog, Kenneth W MahaffeyAbstract:Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that Cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive Cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to Cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (Cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial Cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of Cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, Cinacalcet did not reduce the rate of clinical fracture. 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%–29%.
Takehisa Kawata - One of the best experts on this subject based on the ideXlab platform.
-
a novel calcimimetic agent evocalcet mt 4580 khk7580 suppresses the parathyroid cell function with little effect on the gastrointestinal tract or cyp isozymes in vivo and in vitro
PLOS ONE, 2018Co-Authors: Takehisa Kawata, Shin Tokunaga, Miki Murai, Nami Masuda, Waka Haruyama, Youji Shoukei, Yutaka Hisada, Tetsuya Yanagida, Hiroshi Miyazaki, Michihito WadaAbstract:Cinacalcet hydrochloride (Cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, Cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, Cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to Cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than Cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than Cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to Cinacalcet, an oral calcimimetic agent, with a wider safety margin.
-
A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.
PloS one, 2018Co-Authors: Takehisa Kawata, Shin Tokunaga, Miki Murai, Nami Masuda, Waka Haruyama, Youji Shoukei, Yutaka Hisada, Tetsuya Yanagida, Hiroshi Miyazaki, Michihito WadaAbstract:Cinacalcet hydrochloride (Cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, Cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, Cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to Cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than Cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than Cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to Cinacalcet, an oral calcimimetic agent, with a wider safety margin.
-
Cinacalcet suppresses calcification of the aorta and heart in uremic rats
Kidney international, 2008Co-Authors: Takehisa Kawata, Nobuo Nagano, Masaki Obi, Sonoe Miyata, Chika Koyama, Nami Kobayashi, Sachiko Wakita, Michihito WadaAbstract:High serum parathyroid hormone levels are associated with vascular calcification. Cinacalcet is a calcimimetic agent that inhibits parathyroid hormone secretion and is used to treat patients with secondary hyperparathyroidism. Here we measured the effects of oral Cinacalcet on calcification of the aorta and heart in rats with a remnant kidney (5/6 nephrectomy) model of uremia that were fed a high-phosphate diet containing lactose to accelerate the process of aortic calcification. Alizarin red staining showed that the smooth muscle in the aortic arch of rats with a remnant kidney was calcified. The tissue levels of calcium and phosphorus in the aorta and hearts of these rats were significantly increased compared to sham-operated rats. Expression of the osteoblastic lineage genes osteocalcin, osteopontin and runt-related gene 2 were also increased in the aorta of these rats. Cinacalcet suppressed these calcification-related changes by reducing serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Parathyroidectomy also suppressed calcification in this model. We suggest that Cinacalcet inhibits calcification of the aorta and heart in uremic patients with secondary hyperparathyroidism by decreasing serum parathyroid hormone levels.