Hyperphosphataemia: which phosphate binder?

Nephrol Dial Transplant (2018) 33: 1091–1093 doi: 10.1093/ndt/gfy091 Advance Access publication 18 April 2018 Hyperphosphataemia: which phosphate binder? Department of Nephrology and Amsterdam Cardiovascular Sciences (ACS), VU University Medical Center, Amsterdam, The Netherlands Correspondence and offprint requests to: Marc G. Vervloet; E-mail: BACKGROUND Based on compelling evidence from epidemiological analysis of numerous large cohorts, and supported by convincing experimental studies that revealed phosphate toxicity, targeting hyperphospataemia in chronic kidney disease (CKD) is widely accepted and integrated into guidelines [1]. The treatment options are dietary intervention, modifying dialysis schemes for those with end-stage renal disease, targeting severe hyperparathyroidism and pharmacotherapy such as phosphate binders. For none of these interventions, despite their potential negative impact on quality of life, side effects and costs, does definite proof of benefit exist. In light of the unresolved battle that is lasting for decades among clinicians, researchers, guideline and policymakers, and pharmaceutical companies on the question of what the best phosphate binder is, it is remarkable that selecting a specific drug for hyperphosphataemia is among the most frequently made therapeutic decisions in the clinical care for patients with advanced CKD. When considering initiating phosphate-lowering treatment, the goals of treatment should be taken into account. Although the incentive to initiate, and the parameter to titrate these drugs is the serum phosphate concentration, the goal should be a substantial reduction of absolute risk for a clinical event. In the setting of a high non-modifiable background risk, as frequently exists in older patients on dialysis with severe comorbid conditions, this assumed risk reduction may be limited or absent, which renders even small increases in the burden of treatment unacceptable. With these considerations in mind the next step would be to identify a specific compound to prescribe. Several aspects could contribute to this decision. EFFICACY IN TERMS OF SERUM PHOSPHATE CONCENTRATION CONTROL All marketed phosphate binders lower serum phosphate concentrations [2]. Therefore, in general, this aspect is not helpful in selecting an initial phosphate binder. However, patient-specific factors appear to influence efficacy and may be explained by differences in gastric pH, competition with other compounds for binding in different segments of the gastrointestinal tract, or differences in disintegration of the pill itself. As these factors are largely unpredictable, this may emerge during follow-up. Attained phosphate control in clinical trials examining a range of binders, a very different scenario from real-world clinical practice, was best for iron-based binders in a network meta-analysis [3]. PILL BURDEN Although efficacy exists for all phosphate binders, differences in pill burden to achieve this can be large, ranging from three to four per day for lanthanumcarbonate and sucroferric oxyhydroxide to over nine per day for sevelamer carbonate and calcium-containing binders [4]. Pill burden may negatively affect adherence to prescription, and thereby negatively impact on effectiveness. SIDE EFFECTS All phosphate binders can have side effects, and most of these are gastrointestinal in nature, mainly consisting of nausea, diarrhoea or constipation. These side effects in general are selflimiting, usually after cessation of the offending compound. It is also important to stress that in the majority of patients these side effects do not occur (or are not recognized to be caused by the phosphate-binding agent). Unfortunately, it is impossible to predict who will and who will not experience a side effect. Therefore, the potential for side effects generally does not influence treatment decision on initial therapy, which is a matter of trial and error, together with clinical awareness and monitoring. A more insidious side effect may be accumulation. This may be of relevance in particular for long-term use of aluminumcontaining binders, contributing to bone disease, and for calcium-containing binders, promoting more rapid progression of arterial wall calcification [5, 6]. EFFICACY IN TERMS OF RISK REDUCTION FOR CLINICAL EVENTS As outlined above, the primary aim of any phosphate-lowering intervention is to improve the risk profile for clinically relevant events, and based on the assumed mechanism of phosphate toxicity, in particular cardiovascular events or (all-cause) mortality. The debate on the usefulness of any phosphate binder or a C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. V 1091 NDT DIGEST Marc G. Vervloet side effects, tolerability and acceptance. Green plus symbols indicate positive evaluation, red minus symbols indicate negative evaluation. The next step is either a class switch to monotherapy 2, or dose titration if the individualized treatment goal (including serum phosphate concentration) is not met. If effectiveness is insufficient than a class switch or combination therapy can follow. *If initial phosphate binder is calcium based, then consider limiting its dose to 1000–1500 mg elemental calcium. specific one is dominated by this aspect. Most studies focused on all-cause mortality as primary outcome, but no study compared a binder versus placebo in the setting of overt hyperphosphataemia. Direct head-to-head studies are scarce and essentially confined to the comparison between sevelamer and calcium-based binders. Systematic reviews and a meta-analysis of these studies concluded that sevelamer is a better option than calcium-containing binder, but also recognized that individual studies on which that conclusion is based have a varying degree of bias, one of which was the high average dose of elemental calcium used in the comparator arm [7]. In the absence of other direct head-to-head studies comparing different treatment options, a network meta-analysis can shed some light on the dilemma of how to weigh this aspect in drug selection. This analysis confirmed the superiority of sevelamer over calciumcontaining binders (with the same caveats as indicated above) in terms of all-cause mortality reduction, and found no differences among the novel non-calcium-containing binders, which included sevelamer [3]. There were insufficient data to make such an analysis or to investigate other clinically relevant endpoints. binders, with the exception of sevelamer and sucroferric oxyhydroxide, can bind vitamin K [8]. COMBINATION THERAPY Using two different phosphate binders in parallel has the rationale that at different segments in the gastrointestinal tract different binders may have different binding capacity. In the Current Management of Secondary Hyperparathyroidism: A Multicenter Observational Study (COSMOS) use of combination therapy was associated with lower serum ph (...truncated)