Efficacy and Safety of Phosphate-Lowering Agents for Adult Patients with CKD Requiring Dialysis

Key Points Sevelamer was associated with lower all-cause mortality compared with calcium-based agents. Sucroferric oxyhydroxide and tenapanor were estimated to rank high in lowering all-cause mortality compared with other phosphate-lowering agents. Sucroferric oxyhydroxide and lanthanum were associated with slower progression of coronary artery calcium score compared with calcium-based agents. Background It is necessary to update the evidence of each phosphate-lowering agent on dialysis patients. Methods From the CENTRAL, MEDLINE, Embase, and ClinicalTrial.gov databases, randomized controlled trials using oral phosphate-lowering agents on adult patients requiring maintenance dialysis were extracted. The treatment period was required for 8 or more weeks, and the risk of bias was assessed according to the Cochrane Collaboration method. The outcomes were all-cause mortality, cardiovascular mortality, gastrointestinal events, fracture, coronary artery calcium score (CACS), serum calcium, phosphate, intact parathyroid hormone, and bicarbonate levels. A network meta-analyses using multivariate random-effects models were performed for assessing the comparative effectiveness. The ranking of the phosphate-lowering agents was assessed using a surface under the cumulative ranking curve. Results A total of 70 randomized controlled trials involving 15,551 participants were included. Eleven phosphate-lowering agents including calcium-based agents, sevelamer, bixalomer, lanthanum, sucroferric oxyhydroxide, ferric citrate, tenapanor, magnesium, nicotinamide, aluminum, and sucralfate were assessed. Sevelamer was significantly associated with lower all-cause mortality compared with calcium-based agents (risk ratio [95% confidence interval]: 0.59 [0.37 to 0.94]), and sucroferric oxyhydroxide and tenapanor were estimated to rank high in lowering all-cause mortality on the basis of the surface under the cumulative ranking curve. The risk of gastrointestinal events was the highest with nicotinamide, followed by sucroferric oxyhydroxide. Compared with calcium-based agents, CACS was significantly lower among those on lanthanum and sucroferric oxyhydroxide (standardized mean difference [95% confidence interval]: −0.26 [−0.52 to −0.01] and −0.50 [−0.95 to−0.06], respectively). Serum calcium levels were higher, and serum intact parathyroid hormone levels were lower in patients treated with calcium-based agents. Except for sevelamer, serum bicarbonate levels for all other agents were higher compared with placebo. Conclusions Compared with calcium-based agents, sevelamer was associated with lower all-cause mortality, and sucroferric oxyhydroxide and lanthanum were associated with slower progression of CACS. Potential benefits and harms should be considered when selecting phosphate-lowering agents (International prospective register of systematic reviews: CRD42022328388).