F-06 : cardiovascualr complications
F- 06 : metabolic complications
C- 05 : Hyperphospatemia
Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in
Hemodialysis. The Evaluation of Cinacalcet HCl Therapy to Lower
Cardiovascular Events (EVOLVE) Trial
Journal : Circulation
Year : 2015 / Month : July
Volume : 132
Pages : 27-39
DOI: 10.1161/CIRCULATIONAHA.114.013876
Sharon M. Moe, MD;
Glenn M. Chertow, MD, MPH;
Patrick S. Parfrey, MD;
Yumi Kubo, MS;
Geoffrey A. Block, MD;; Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial
Investigators*
+ Author Affiliations
From Indiana University School of Medicine and Roudebush Veterans Administration Medical Center,
Indianapolis (S.M.M.); Stanford University School of Medicine, Palo Alto, CA (G.M.C., K.W.M.); Health
Sciences Center, St. John’s, NL, Canada (P.S.P.); Amgen Inc, Thousand Oaks, CA (Y.K., M.S., B.D.,
W.G.G.); Denver Nephrology, CO (G.A.B.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador
Zubirán, Mexico City, Mexico (R.C.-R.); Inserm Unit 1088, UFR Médecine/Pharmacie, Université de
Picardie, Amiens, France (T.B.D.); University of Minnesota, Minneapolis (C.A.H.); Hôpital Manhès,
Paris, France (G.M.L.); University College London, London, UK (D.C.W.); and Universitätsklinikum der
RWTH Aachen, Germany (J.F.).
Correspondence to Sharon M. Moe, MD, Indiana University School of Medicine, 950 W Walnut St, R2202, Indianapolis, IN 46202. E-mail smoe@iupui.edu
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
FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.
Key Words: arrhythmias, cardiac
ventricular remodeling
calcium
death, sudden, cardiac
renal insufficiency, chronic
COMMENTS
Elevated levels of fibrobast growth factor 23 (FGF-23) are associated with cardiovascular and all-cause
mortality in patients with kidney disease. A secondary analysis of the EVOLVE trial reports that
cinacalcet-induced reductions in FGF-23 were associated with a reduced risk of cardiovascular events
in patients with secondary hyperparathyroidism on dialysis.
Disordered mineral metabolism, including secondary hyperparathyroidism and hyperphosphataemia,
contributes to vascular calcification, which is associated with cardiovascular events and death.
Fibroblast growth factor 23 (FGF-23)—an important hormonal regulator of circulating phosphate and
calcitriol that is produced by osteocytes and osteoblasts—has also been implicated in poor
cardiovascular disease (CVD) outcomes and increased all-cause mortality among patients with CKD
and end-stage renal disease (ESRD).3 The question of whether reducing FGF-23 levels or inhibiting
FGF-23 activity improves outcomes in patients with kidney disease has led to studies of various
therapies that target FGF-23 levels, including phosphate binders, calcimimetics and FGF-23neutralization antibodies.
Together with its co-receptor Klotho, FGF-23 induces renal phosphate excretion by reducing the activity
of the sodium–phosphate cotransporter in the renal proximal tubule. FGF-23 is also a negative
regulator of calcitriol and parathyroid hormone (PTH). Levels of FGF-23 increase early in the course of
CKD5 (well before other abnormalities of mineral metabolism such as secondary hyperparathyroidism
manifest) to compensate for phosphate retention in the setting of reduced glomerular filtration rate and
nephron mass. As kidney function decreases, FGF-23 levels progressively rise and are highest among
patients on dialysis. Large epidemiologic studies of CKD and ESRD populations show a strong
relationship between high circulating FGF-23 levels and left ventricular hypertrophy (LVH) , CVD and
all-cause mortality.
This study shows that treatment with the calcimimetic cinacalcet significantly reduced serum FGF-23
levels in patients with secondary hyperparathyroidism on haemodialysis, and that these treatmentinduced reductions in FGF-23 levels were associated with reduced rates of cardiovascular death and
major cardiovascular events, including heart failure and sudden cardiac death.
This study provides the first evidence that lowering FGF-23 levels might improve clinical outcomes in
patients on chronic dialysis, and provides proof-of-principle that.
Pr. Jacques CHANARD
Professor of Nephrology