Cardiovascular effects of sevelamer in stage 3 CKD

Abstract

Serum phosphate independently predicts cardiovascular mortality in the general population and CKD, even when levels are in the normal range. Associations between serum phosphate, arterial stiffness, and left ventricular (LV) mass suggest a possible pathophysiological mechanism, potentially mediated by the phosphaturic hormone fibroblast growth factor-23 (FGF-23). To what extent the phosphate binder sevelamer modulates these effects is not well understood. In this single-center, randomized, double-blind, placebo-controlled trial, we enrolled 120 patients with stage 3 nondiabetic CKD. After a 4-week open-label run-in period, during which time all patients received sevelamer carbonate, we randomly assigned 109 patients to sevelamer (n=55) or placebo (n=54) for an additional 36 weeks. We assessed LV mass and systolic and diastolic function with cardiovascular magnetic resonance imaging and echocardiography, and we assessed arterial stiffness by carotid-femoral pulse wave velocity. The mean age was 55 years, and the mean eGFR was 50 ml/min per 1.73 m(2). After 40 weeks, we found no statistically significant differences between sevelamer and placebo with regard to LV mass, systolic and diastolic function, or pulse wave velocity. Only 56% of subjects took ≥ 80% of prescribed therapy; in this compliant subgroup, treatment with sevelamer associated with lower urinary phosphate excretion and serum FGF-23 but not serum phosphate, klotho, vitamin D, or cardiovascular-related outcomes of interest. In conclusion, this study does not provide evidence that sevelamer carbonate improves LV mass, LV function, or arterial stiffness in stage 3 nondiabetic CKD.

Figure 1.

Study consort diagram. Of 1297 patients screened, 120 were recruited into the study. During the 4-week run-in phase 11 patients were withdrawn, leaving 109 to be randomized to treatment (n=55) or placebo (n=54). During the blinded treatment phase an additional five patients were withdrawn from the treatment group and seven from the placebo group. In total, 97 patients completed follow-up to 40 weeks. GI, gastrointestinal.

Figure 2.

After 40 weeks of treatment there was no significant difference in the change in LV mass between sevelamer and placebo groups. Data were analyzed with repeated-measures ANOVA (P=0.58).

Figure 3.

Compliance with study medication was assessed through pill counts of returned medication. Compliance was low with only 56% of patients taking ≥80% of prescribed medication despite regular monitoring under controlled conditions.