Hyperphosphataemia: which phosphate binder?

Hyperphosphataemia: which phosphate binder? 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 self-limiting, 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 aluminum-containing 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 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 calcium-containing 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. INTERACTIONS Most phosphate binders can interact with levothyroxine especially if ingested within the same time window. Both calcium-containing binders and sevelamer can limit gastrointestinal uptake of several antimicrobial drugs. Calcium-containing binders can inhibit uptake of oral iron, while sevelamer can lower trough levels of some immune suppressants. Most 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 phosphate concentrations [9]. A possible drawback of combination therapy is that it may increase the likelihood of side effects and drug interaction. COSTS In general, novel non-calcium-based phosphate binders are much more expensive than calcium-based and aluminum-based binders. In most countries, the price differences among these new binders (iron-based, lanthanum and sevelamer) are negligible on a daily basis. Generic formulations are available for sevelamer and will soon be available for lanthanum as well. These will be cheaper than the branded compounds. PATIENT PREFERENCES The lack of proof of benefit of one binder over the other (with the exception of higher doses of calcium-containing binders), and the likelihood of comparable safety and efficacy of some, should lead to high priority being given to patients’ preferences. Importantly these preferences cannot be inferred from, for instance, pill number or even side effects, because patients’ tolerance and acceptance of treatment may depend on completely different subjective aspects. These should be evaluated by just asking. Taking account of this subjective aspect was shown to improve adherence and phosphate control [10]. CONCLUSIONS Several aspects should be taken into account when selecting initial phosphate-binder therapy, titrating its dose and deciding to switch strategy. These aspects can have different weights in different circumstances, like availability, reimbursement and patient characteristics. Taking these factors into account may assist in selecting the right strategy for an individual patient, by shared decision-making. A potential algorithm to do so is shown in Figure 1. FIGURE 1 View largeDownload slide Treatment algorithm for phosphate-binder therapy. First-choice binder (monotherapy 1) is initially evaluated with the patient on 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. FIGURE 1 View largeDownload slide Treatment algorithm for phosphate-binder therapy. First-choice binder (monotherapy 1) is initially evaluated with the patient on 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. CONFLICT OF INTEREST STATEMENT M.G.V. reports lecture fees and scientific support from, and is an advisor for Amgen, VFMCRP, Shire and Medice, all companies involved in marketing or developing phosphate-lowering drugs; scientific support from AbbVie and FMC; and being on the advisory board of Otsuka. He is a member of the ERA-EDTA working group on CKD-MBD, and a member of the KDIGO committee on CKD-MBD. This manuscript is not written on behalf of these committees. REFERENCES 1 Ketteler M , Block GA , Evenepoel P et al. Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD). Guideline Update: what’s changed and why it matters . Kidney Int 2017 ; 92 : 26 – 36 Google Scholar CrossRef Search ADS PubMed 2 Tonelli M , Pannu N , Manns B. Oral phosphate binders in patients with kidney failure . N Engl J Med 2010 ; 362 : 1312 – 1324 Google Scholar CrossRef Search ADS PubMed 3 Palmer SC , Gardner S , Tonelli M et al. Phosphate-binding agents in adults with CKD: a network meta-analysis of randomized trials . Am J Kidney Dis 2016 ; 68 : 691 – 702 Google Scholar CrossRef Search ADS PubMed 4 Floege J. Phosphate binders in chronic kidney disease: a systematic review of recent data . J Nephrol 2016 ; 29 : 329 – 340 Google Scholar CrossRef Search ADS PubMed 5 Russo D , Miranda I , Ruocco C et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer . Kidney Int 2007 ; 72 : 1255 – 1261 Google Scholar CrossRef Search ADS PubMed 6 Chertow GM , Burke SK , Raggi P. Treat to goal working G. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients . Kidney Int 2002 ; 62 : 245 – 252 Google Scholar CrossRef Search ADS PubMed 7 Patel L , Bernard LM , Elder GJ. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: a meta-analysis of randomized controlled trials . Clin J Am Soc Nephrol 2015 ; 11 : 232 – 244 Google Scholar CrossRef Search ADS PubMed 8 Neradova A , Schumacher SP , Hubeek I et al. Phosphate binders affect vitamin K concentration by undesired binding, an in vitro study . BMC Nephrol 2017 ; 18 : 149 Google Scholar CrossRef Search ADS PubMed 9 Cannata-Andia JB , Fernandez-Martin JL , Locatelli F et al. Use of phosphate-binding agents is associated with a lower risk of mortality . Kidney Int 2013 ; 84 : 998 – 1008 Google Scholar CrossRef Search ADS PubMed 10 Arenas Jimenez MD , Parra Moncasi E , Alvarez-Ude Cotera F. A strategy based on patient preference improves the adherence and outcomes of phosphate binders in hemodialysis . Clin Nephrol 2017 ; 88 : 1 – 11 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Hyperphosphataemia: which phosphate binder?

Nephrology Dialysis Transplantation , Volume Advance Article (7) – Apr 18, 2018

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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1460-2385
D.O.I.
10.1093/ndt/gfy091
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Abstract

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 self-limiting, 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 aluminum-containing 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 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 calcium-containing 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. INTERACTIONS Most phosphate binders can interact with levothyroxine especially if ingested within the same time window. Both calcium-containing binders and sevelamer can limit gastrointestinal uptake of several antimicrobial drugs. Calcium-containing binders can inhibit uptake of oral iron, while sevelamer can lower trough levels of some immune suppressants. Most 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 phosphate concentrations [9]. A possible drawback of combination therapy is that it may increase the likelihood of side effects and drug interaction. COSTS In general, novel non-calcium-based phosphate binders are much more expensive than calcium-based and aluminum-based binders. In most countries, the price differences among these new binders (iron-based, lanthanum and sevelamer) are negligible on a daily basis. Generic formulations are available for sevelamer and will soon be available for lanthanum as well. These will be cheaper than the branded compounds. PATIENT PREFERENCES The lack of proof of benefit of one binder over the other (with the exception of higher doses of calcium-containing binders), and the likelihood of comparable safety and efficacy of some, should lead to high priority being given to patients’ preferences. Importantly these preferences cannot be inferred from, for instance, pill number or even side effects, because patients’ tolerance and acceptance of treatment may depend on completely different subjective aspects. These should be evaluated by just asking. Taking account of this subjective aspect was shown to improve adherence and phosphate control [10]. CONCLUSIONS Several aspects should be taken into account when selecting initial phosphate-binder therapy, titrating its dose and deciding to switch strategy. These aspects can have different weights in different circumstances, like availability, reimbursement and patient characteristics. Taking these factors into account may assist in selecting the right strategy for an individual patient, by shared decision-making. A potential algorithm to do so is shown in Figure 1. FIGURE 1 View largeDownload slide Treatment algorithm for phosphate-binder therapy. First-choice binder (monotherapy 1) is initially evaluated with the patient on 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. FIGURE 1 View largeDownload slide Treatment algorithm for phosphate-binder therapy. First-choice binder (monotherapy 1) is initially evaluated with the patient on 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. CONFLICT OF INTEREST STATEMENT M.G.V. reports lecture fees and scientific support from, and is an advisor for Amgen, VFMCRP, Shire and Medice, all companies involved in marketing or developing phosphate-lowering drugs; scientific support from AbbVie and FMC; and being on the advisory board of Otsuka. He is a member of the ERA-EDTA working group on CKD-MBD, and a member of the KDIGO committee on CKD-MBD. This manuscript is not written on behalf of these committees. REFERENCES 1 Ketteler M , Block GA , Evenepoel P et al. Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD). Guideline Update: what’s changed and why it matters . Kidney Int 2017 ; 92 : 26 – 36 Google Scholar CrossRef Search ADS PubMed 2 Tonelli M , Pannu N , Manns B. Oral phosphate binders in patients with kidney failure . N Engl J Med 2010 ; 362 : 1312 – 1324 Google Scholar CrossRef Search ADS PubMed 3 Palmer SC , Gardner S , Tonelli M et al. Phosphate-binding agents in adults with CKD: a network meta-analysis of randomized trials . Am J Kidney Dis 2016 ; 68 : 691 – 702 Google Scholar CrossRef Search ADS PubMed 4 Floege J. Phosphate binders in chronic kidney disease: a systematic review of recent data . J Nephrol 2016 ; 29 : 329 – 340 Google Scholar CrossRef Search ADS PubMed 5 Russo D , Miranda I , Ruocco C et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer . Kidney Int 2007 ; 72 : 1255 – 1261 Google Scholar CrossRef Search ADS PubMed 6 Chertow GM , Burke SK , Raggi P. Treat to goal working G. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients . Kidney Int 2002 ; 62 : 245 – 252 Google Scholar CrossRef Search ADS PubMed 7 Patel L , Bernard LM , Elder GJ. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: a meta-analysis of randomized controlled trials . Clin J Am Soc Nephrol 2015 ; 11 : 232 – 244 Google Scholar CrossRef Search ADS PubMed 8 Neradova A , Schumacher SP , Hubeek I et al. Phosphate binders affect vitamin K concentration by undesired binding, an in vitro study . BMC Nephrol 2017 ; 18 : 149 Google Scholar CrossRef Search ADS PubMed 9 Cannata-Andia JB , Fernandez-Martin JL , Locatelli F et al. Use of phosphate-binding agents is associated with a lower risk of mortality . Kidney Int 2013 ; 84 : 998 – 1008 Google Scholar CrossRef Search ADS PubMed 10 Arenas Jimenez MD , Parra Moncasi E , Alvarez-Ude Cotera F. A strategy based on patient preference improves the adherence and outcomes of phosphate binders in hemodialysis . Clin Nephrol 2017 ; 88 : 1 – 11 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: Apr 18, 2018

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