Cinacalcet, FGF23 and Cardiovascular Disease in Hemodialysis: The EVOLVE Trial

Moe SM, Chertow GM, Parfrey PS et al., EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial Investigators.
Circulation. 2015 Jun 9. pii: CIRCULATIONAHA.114.013876. [Epub ahead of print]

Background

Mineral metabolism is aberrant in early stages of chronic kidney disease (CKD) [1], as illustrated by elevations in the serum concentrations of fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH) in patients with estimated glomerular filtration rate (eGFR) of 50 ml/min/1.73m2. As CKD progresses, levels of both hormones continue to rise, possibly in an attempt to maintain normal concentrations of phosphate and calcium in serum.
In patients with CKD, elevated serum FGF23 levels are associated with mortality [2], progression of CKD [2,3], left ventricular hypertrophy [4,5] and CV events [6.7], irrespective of phosphate and PTH levels and several demographic and clinical factors.
FGF23 is strongly elevated in patients with end-stage renal disease (ESRD) receiving dialysis, which is associated with poor survival [8-10] and ventricular hypertrophy [11]. Animal research also suggests a direct role for FGF23 in CV disease.
Preliminary studies have suggested that the calcimimetic cinacalcet can reduce FGF23 levels in patients on dialysis [13,14], but it is unknown whether this would improve outcomes. This post-hoc analysis of the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial assessed the effect of treatment with cinacalcet on serum FGF23 and the impact of FGF23 reduction on CV outcomes in 3883 patients with secondary hyperparathyroidism receiving haemodialysis.

Main results

• At week 20, FGF23 had decreased from 5555 to 2255 pg/mL in patients randomised to cinacalcet, and from 5600 to 5580 pg/mL in placebo-treated patients (P<0.001).
• More patients randomised to cinacalcet (64% vs. 28% on placebo) showed FGF23 reductions >30% or >50% (50% vs. 15%, P<0.001 for both comparisons). The reduction seen in patients receiving cinacalcet did not depend on whether or not patients also received calcitriol or other vitamin D sterols.
• In patients randomised to cinacalcet, a >30% reduction in FGF23 between baseline and week 20 was associated with a lower relative risk of the primary composite endpoint of CV mortality, sudden cardiac death and heart failure (HR: 0.82, 95%CI: 0.69-0.98, P=0.03).
  A >50% reduction gave a similarly reduced risk reduction (HR: 0.81, 95%CI: 0.68-0.96, P=0.01).
• Patients randomised to placebo who had a >30% reduction in FGF23 did not show a reduction in CV events.

Conclusion

This study shows that the calcimimetic cinacalcet not only reduces serum PTH, but also FGF23. This decrease in FGF23 levels is associated with reduced risk of CV mortality and selected CV events such as heart failure and sudden death. It remains to be determined whether the observed associations are a direct effect of FGF23, but the observation did not depend on demographic factors and comorbid conditions, reductions in serum PTH, calcium or phosphate levels or dose of vitamin D sterols.

FInd this article online at Circulation

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