Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis

Abstract

Background-Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. Methods and Results-This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99). Conclusions-Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23are associated with lower rates of cardiovascular death and major cardiovascular events. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

“…FGF23 concentrations were reduced by ≥50% in 50% versus 15% in patients randomized to cinacalcet versus placebo, respectively. 91 By week 20, neutralization of FGF23 was associated with a significantly reduced risk of cardiovascular mortality, SCD, and heart failure and in the primary composite end point (ie, time to death or a first nonfatal cardiovascular event [myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event]). Reductions in the risk of all-cause mortality, myocardial infarction, unstable angina, peripheral vascular event, stroke, fracture, and parathyroidectomy were not statistically significant.…”

Is north Indian population changing it craniofacial form? A study of secular trends in craniometric indices and its relation to sex and ancestry estimation

“…A broad face is usually associated with a brachycephal and similarly a long face is associated with long head or dolichocephalic. Though this is a harmonic relation between the head and the face, but not universal in occurrence [82]. For example, the Armenoids (a subtype of Caucasoid ancestry) who possess long and relatively narrow faces along with relatively short and broad heads.…”

“…The modern people are generally orthognathous, only a few of them may show a little prognathism. Among the human population, the Mongoloids and some white people show slight or moderate alveolar prognathism but facial prognathism is almost absent in them [82].…”

Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis

“…Sixty-four percent of patients assigned to cinacalcet had $30% reduction in serum FGF-23 concentrations from baseline to week 20 compared with 28% of the placebo group (29). Among patients randomly assigned to cinacalcet, a $30% reduction in FGF-23 was associated with a significant reduction in the composite CV end point (relative hazard, 0.82; 95% CI, 0.69 to 0.98) (29). This nonrandomized analysis generates the hypothesis that FGF-23 plays a role in the pathogenesis of CV events in CKD and the deleterious effects of FGF-23 might be ameliorated by cinacalcet.…”

“…From 2007 to 2011, accumulating data in patients with advanced CKD and ESRD showed that serum fibroblast growth factor-23 (FGF-23) concentrations were elevated and were associated with mortality, left ventricular hypertrophy, and CV events independent of serum phosphate, PTH, and a variety of demographic and other clinical factors (27,28). Sixty-four percent of patients assigned to cinacalcet had $30% reduction in serum FGF-23 concentrations from baseline to week 20 compared with 28% of the placebo group (29). Among patients randomly assigned to cinacalcet, a $30% reduction in FGF-23 was associated with a significant reduction in the composite CV end point (relative hazard, 0.82; 95% CI, 0.69 to 0.98) (29).…”