Lowering FGF23 with a calcimimetic associated with reduced risk of CV events and mortalityMoe SM et al. Circulation 2015
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]
BackgroundMineral metabolism is aberrant in early stages of chronic kidney disease (CKD) , 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 , 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 . 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.
- 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.
ConclusionThis 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.
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1. Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011;79:1370-1378.
2. Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305:2432-2439.
3. Fliser D, Kollerits B, Neyer U, et al. Fibroblast Growth Factor 23 (FGF23) Predicts Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol. 2007;18:2600-2608.
4. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393-4408.
5. Gutierrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119:2545-52.
6. Seiler S, Reichart B, Roth D et al. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant. 2010;25:3983-3989.
7. Nakano C, Hamano T, Fujii N, et al. Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone.2012;50:1266-1274.
8. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584-592.
9. Olauson H, Qureshi AR, Miyamoto T, et al. Relation between serum fibroblast growth factor-23 level and mortality in incident dialysis patients: are gender and cardiovascular disease confounding the relationship? Nephrol Dial Transplant. 2010;25:3033-3038.
10. Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant. 2009;24:2792-2796.
11. Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci. 2009;337:116-122.
12. Touchberry CD, Green TM, Tchikrizov V, et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab. 2013;304:E863-873.
13. Koizumi M, Komaba H, Nakanishi S, et al. Cinacalcet treatment and serum FGF23 levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol Dial Transplant. 2012;27:784-790.
14. Wetmore JB, Liu S, Krebill R, et al. Effects of Cinacalcet and Concurrent Low-Dose Vitamin D on FGF23 Levels in ESRD. Clin J Am Soc Nephrol. 2010;5:110-116.