Abstract
Background: Phosphate binders lower serum phosphate levels for people with chronic kidney disease (CKD). This is an updated review, previously published in 2011 and 2018. New studies have been published and an update of the current evidence is needed.
Objectives: To assess the benefits and harms of phosphate binders for people with CKD and whether phosphate binders have different effects compared with each other.
Search methods: We searched the Cochrane Kidney and Transplant Register of Studies to 16 December 2024 by contacting the Information Specialist, using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, the International Clinical Trials Registry Platform Search Portal, and ClinicalTrials.gov.
Selection criteria: We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD (any glomerular filtration rate; GFR) comparing a phosphate binder to placebo, usual care, or a different phosphate binder with follow-up of at least eight weeks. The key outcomes were death (all causes), cardiovascular death, hypercalcaemia, nausea, constipation, serum phosphate, and vascular calcification.
Data collection and analysis: Two authors independently selected studies for inclusion and extracted study data. We adjudicated the risk of bias using the Cochrane RoB 1 tool, and we used GRADE to assess the evidence certainty. We estimated treatment effects using random-effects meta-analysis. We expressed the results as risk ratios (RR) for dichotomous outcomes, and mean differences (MD) or standardised MD (SMD) for continuous outcomes, together with 95% confidence intervals (CI).
Main results: This review includes 134 studies involving 20,913 adults. Thirty new studies were added to this update. We assessed the risk of bias as high or unclear for many methodological domains in the studies, and we judged the certainty of the evidence as low or very low. Most studies comparing phosphate binders with placebo/usual care were in people with CKD, while most head-to-head studies comparing two different phosphate binders involved participants on dialysis. The median study duration was 5.4 months, and the median study age was 58 years. Compared to placebo/usual care, sevelamer may have little or no effect on death from any cause (RR 0.45, 95% CI 0.13 to 1.53; 6 studies, 781 participants; low-certainty evidence), and uncertain effects on hypercalcaemia and nausea, but may increase the risk of constipation (RR 3.27, 95% CI 1.38 to 7.74; 5 studies, 632 participants; low-certainty evidence) in people with CKD. Compared to placebo/usual care, sevelamer may have little or no effect on serum phosphate (MD -0.27 mg/L, 95% CI -0.71 to 0.17; 6 studies, 671 participants; low-certainty evidence) and on coronary artery calcium score (MD -70.19, 95% CI -362.44 to 222.06; 2 studies, 115 participants; low-certainty evidence). The effects of sevelamer on cardiovascular death were not estimable as no events were reported in any of the included studies (3 studies, 222 participants; low-certainty evidence). Compared to placebo/usual care, lanthanum may have little or no effect on death from any cause (RR 0.33, 95% CI 0.10 to 1.05; 7 studies, 694 participants; low-certainty evidence) and uncertain effects on both cardiovascular death (no events were reported in any of the included studies) and hypercalcaemia; however, lanthanum may increase the risk of nausea (RR 2.99, 95% CI 1.42 to 6.31; 5 studies, 484 participants; low-certainty evidence) and constipation (RR 2.98, 95% CI 1.21 to 7.30; 4 studies, 299 participants; low-certainty evidence) in people with CKD. Compared to placebo/usual care, lanthanum may slightly reduce serum phosphate (MD -0.31 mg/dL, 95% CI -0.61 to -0.01; 7 studies, 456 participants; low-certainty evidence) but may have uncertain effects on coronary artery calcification score. Compared to calcium, sevelamer may reduce death from any cause (RR 0.54, 95% CI 0.32 to 0.93; 19 studies, 4403 participants; low-certainty evidence), have uncertain effects on cardiovascular death, may result in less hypercalcaemia (RR 0.30, 95% CI 0.20 to 0.43; 20 studies, 4124 participants; low-certainty evidence), and may have little or no effect on nausea (RR 0.98, 95% CI 0.56 to 1.71; 4 studies, 365 participants; low-certainty evidence) and constipation (RR 1.35, 95% CI 0.71 to 2.57; 6 studies, 2652 participants; low-certainty evidence) in people on dialysis. Compared to calcium, sevelamer may have little or no effect on serum phosphate (MD 0.08 mg/dL, 95% CI -0.09 to 0.24 mg/dL; 26 studies, 4537 participants; low-certainty evidence) and coronary artery calcium score (MD -24.89 score, 95% CI -75.66 to 25.88; 4 studies, 517 participants; low-certainty evidence). Compared to calcium, lanthanum may have little or no effect on death from any cause (RR 1.08, 95% CI 0.88 to 1.33; 9 studies, 2829 participants; low-certainty evidence) and cardiovascular death (RR 1.49, 95% CI 1.01 to 2.21; 5 studies, 2672 participants; low-certainty evidence), may result in less hypercalcaemia (RR 0.16, 95% CI 0.06 to 0.43; 8 studies, 1347 participants; low-certainty evidence), but may have little or no effect on nausea (RR 1.65, 95% CI 0.95 to 2.89; 5 studies, 1191 participants; low-certainty evidence) and constipation (RR 0.79, 95% CI 0.50 to 1.26; 5 studies, 1213 participants; low-certainty evidence) in people on dialysis. Compared to calcium, lanthanum may have no effect on serum phosphate (MD -0.04 mg/dL, 95% CI -0.37 to 0.29; I2 = 74%; 11 studies, 497 participants; low-certainty evidence) and uncertain effects on coronary artery calcium score. The evidence for the effects of head-to-head comparisons on key clinical outcomes was sparse.
Conclusions: Sevelamer may lower death from any cause and incur less hypercalcaemia compared to calcium-based binders in people on dialysis. Lanthanum may also result in less hypercalcaemia compared to calcium. Sevelamer may increase the risk of constipation, while lanthanum may increase both the risk of nausea and constipation, but may slightly reduce serum phosphate in people with CKD compared to placebo/usual care. No clinically important benefits of phosphate binders were identified for cardiovascular death or coronary artery calcium score compared to placebo/usual care. The evidence for the effects of other phosphate binders on key clinical outcomes in head-to-head comparisons was uncertain.