A Brief Overview of Phosphorus Binders: Importance, Types, Risks, and Costs by
Mackenzie Morgan
A paper submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Master of Public Health in the Department of
Nutrition
Chapel Hill, NC
December 4th, 2019
Approved by:
Introduction
Phosphorus is an essential mineral in the human body (2). The majority of the body’s phosphorus, approximately 85%, is stored in the bones, while the rest is mainly stored in cells, where it’s used for energy production and DNA synthesis (3). Under normal conditions, the body mainly excretes phosphorus in the urine. In individuals with chronic kidney disease (CKD), where kidney function is diminished and eventually absent, it becomes harder for the body to excrete phosphorus. For individuals on dialysis, phosphorus intake through the diet is generally more than phosphorus removal through the dialysate, increasing the risk of hyperphosphatemia (4). In general, only approximately 800 mg of phosphorus is removed per treatment, regardless of pre-dialysis serum levels (19). Hyperphosphatemia is an independent risk factor for
cardiovascular disease (CVD) and mortality (1). Therefore, serum phosphorus control is
extremely important in the dialysis population. Phosphorus also plays an important part on bone mineral metabolism with calcium and PTH.
Phosphorus binders are often prescribed to dialysis patients to help control serum phosphorus levels. Binders work to decrease phosphorus absorption by binding the phosphorus in the gut, allowing it to be excreted in the stool (5). However, not all binders are created equally, and there has been growing concern that calcium-based binders are increasing the risk for
cardiovascular disease by disrupting bone mineral metabolism. In this paper, I discuss what I have learned regarding the influences on serum phosphorus, the different types of phosphorus binders, why binders are crucial in phosphorus control, and the risks and benefits associated with binders. Additionally, I will take a deeper dive into the binder Velphoro and close with how to practically integrate this knowledge and apply it to the real world.
Factors That Influence Serum Phosphorus Levels
In patients on dialysis, serum phosphorus levels are regulated through multiple channels. Two main ways serum phosphorus is regulated are through dietary modifications and adherence to phosphorus binder medications (25). Factors that have a lesser but still notable roll in
phosphorus regulation are adherence to dialysis prescription, vitamin D intake, and
of phosphorus per session (2400-3000 mg per week, compared to an average recommended intake of 5600-7000 mg per week) (25).
There are multiple reasons why someone might continue to have high serum phosphorus despite being on a phosphorus binder and trying to comply with the renal diet. First, dialysis, while it only removes a fraction of phosphorus intake, is important in maintaining phosphorus. If a patient is non-compliant with the dialysis prescription by missing or having shortened
treatments, phosphorus that would have been removed instead remains in the body (25). Second, despite an individual’s good intentions in limiting phosphorus intake, protein intake is extremely important in dialysis, and phosphorus and protein are often found in the same foods (25). This can make it difficult to maintain protein status while limiting phosphorus intake. Additionally, when an individual limits phosphorus intake, the body has a natural mechanism that then increases the absorption of whatever phosphorus is present in the GI tract to prevent
hypophosphatemia (25). Third, inorganic phosphorus additives are becoming more prevalent in fast and processed foods and are close to 100% bioavailable compared to organic phosphorus naturally found in foods (25). These foods are readily available and often the easiest choice for individuals with less time, money, or access to invest in cooking at home. Lastly, there are patients who are prescribed calcitriol for low serum calcium levels, which in addition to increasing calcium absorption also increase phosphorus absorption (2).
Of course, despite being prescribed a phosphorus binder and educated on the renal diet, there is also the issue of compliance. There are many reasons a patient might be
non-compliant. The pill burden of the phosphorous binders might be too much for the patient, the size of the phosphorus binder pill might be too large to swallow, the current phosphorus binder might have unwanted GI issues, the patient might find the renal diet to be too restrictive, an
individual’s cultural foods are high in phosphorus and/or potassium and therefore the patient is struggling with limiting these foods, and the patient simply might not be ready to make changes. These are just some of the reasons given by patients at Fresenius Kidney Care Rocky Mountain in Denver, Colorado.
Types and Efficacy of Binders
include calcium acetate (Eliphos, Phoslo) and calcium carbonate (Tums) (7). Non-calcium-based binders include sevelamer carbonate (Renvela), sevelamer hydrochloride (Renagel), lanthanum carbonate (Fosrenol), and magnesium salts (16), as well as the more recently FDA approved Iron-based binders like sucroferric oxyhydroxide (Velphoro) and ferric citrate (Auryxia) (17) (18). Some binders have contraindications, so each person’s needs should be taken into account when prescribing. According to the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI), a globally accepted group that publishes clinical guidelines in nephrology, all binders have been shown to effectively lower serum phosphorus levels (22,23), but studies have shown some binders are more effective than others at lowering serum
phosphorus, after titrated to the appropriate dose (27). For example, one pill of calcium acetate (667 mg) binds less than approximately 106 mg phosphorus, whereas 1 tablet of Velphoro binds 130 mg phosphorus (32,33). The efficacy of Velphoro compared to other phosphorus binders in controlling laboratory values will be discussed more in detail later in this paper. In addition to the variability in efficacy, there is growing that the use of calcium- versus non-calcium-based binders in managing serum phosphorus levels has the potential to increase risk for cardiovascular disease, vascular calcification, and all-cause mortality.
Calcium Based Binders and Cardiovascular Disease
There has been growing concern that calcium-based binders might be linked to an increased risk for cardiovascular disease due to vascular calcification. Cardiovascular mortality accounts for 50% of deaths in patients on dialysis (27). Calcium has multiple functions in the body, including maintaining bone health, muscle contraction, and blood clotting. However, like many other vitamins and minerals, there is a limit set on the amount of calcium recommended for daily consumption (11). The main storage site of calcium in the body is bone, but in CKD, when the kidneys’ function is diminished or non-existent, excess dietary and supplemental calcium that has been absorbed into the body has lost its main method of excretion, allowing calcium to then build up in the body and deposit in soft tissues, causing calcification. One of the areas excess calcium can deposit is in the vasculature of the heart, which is associated with increased risk for cardiovascular disease.
507 mg – 2,028 mg of additional calcium per day on top of dietary intake (7,19). The absorption rate for dietary calcium is 20-30% when doses are kept below 500 mg calcium at any given time, however, absorption rates for calcium supplements differ and are not well studied (20, 21). To put this in perspective, the Recommended Dietary Allowance (RDA) for women aged 19 to 50 years old and men aged 19 to 70 years old is 1,000 mg per day (8,20). This increases to 1,200 mg per day in women 50+ years old and men 70+ years old (8,11,20). The Upper Level (UL) for both women and men aged 19-50 years old is 2500 mg per day and for those aged 51+ years old is 2,000 mg per day (11). Given the quantity of calcium-based binders required to successfully manage hyperphosphatemia and under the assumption that most of the elemental calcium in the calcium-based binders is absorbed, some individuals on dialysis are exceeding the UL for calcium in phosphorus binders alone.
The literature also suggests that there is a paradox between dietary calcium, supplemental calcium, and CVD risk. A 2016 study published in The Journal of the American Heart
Association states that high supplemental calcium intake with low dietary calcium intake might be at increased risk of incident coronary artery calcium (CAC) (9). CAC is an established value for assessing CVD risk (53). Conversely, those with low supplemental calcium intake but high dietary calcium intake had decreased risk of incident CAC, showing a protective effect of dietary calcium (9). However, individuals with impaired kidney function were excluded from this
study(9). In another systematic review of eight studies looking at circulating calcium
difference in risk in their studied population (54,55). More research is needed, especially in the CKD population, in order to make stronger recommendations regarding binder type and dosage.
While it would seem there is good evidence for health practitioners to switch patients from calcium-based binders to non-calcium-based binders, there is another economic challenge that arises, which is that calcium-based binders are generally cheaper than non-calcium-based binders. Calcium based binders are estimated to be four to 70 times lower in yearly costs than non-calcium-based binders (12). Depending on the type of insurance, calcium-based binders might be the only option covered. In Denver, for example, patients with health insurance through Denver Health are only covered for calcium-based-binders with few exceptions to the rule. Denver Health is also the only insurance option for undocumented individuals in Denver (13). While obtaining accurate estimates of the number of undocumented immigrants is not easy, the most recent data from 2017 estimated 180,000 undocumented immigrants in the state of
Colorado (14), with an estimated half of those individuals living in Denver Metro Area (15). Unless a provider is able to submit a prior authorization for a patient due to tolerance issues or consistent hypercalcemia, calcium-based-binders are currently the only option for these individuals.
Velphoro
Velphoro (sucroferric oxyhydroxide) is a phosphorus binder manufactured by Fresenius Medical Care. It was approved by the FDA in 2013 for use in CKD patients on dialysis (17). It binds the most phosphorus in the stomach, but continues to work throughout the GI tract. It does not interfere with fat soluble vitamins, unlike sevelamer carbonate (34,35). Each tablet contains 500 mg iron, however the chemical makeup of the iron in Velphoro means it does not get
Velphoro has been shown to be an effective phosphorus binder, and potentially more effective than other binders (30). A 2018 study concluded a significant reduction in serum phosphorus in patients switched to Velphoro over a 16 week period (46). An early 2019 study showed significant reduction in serum phosphorus and PTH (p<0.05), and non significant
reduction in serum calcium (p=0.21) (45). Two separate 2019 studies found significant reduction in serum phosphorus after 1 year of being switched to Velphoro (p<0.05) (44,47). Pill burden was also significantly reduced and serum albumin was significantly increased (p<0.05) (44). These studies back up the claims by Velphoro regarding significantly improved phosphorus control based on a 2014 study (48,49).
Velphoro seems to positively impacts serum phosphorus, calcium, and PTH in a building block manner. As mentioned earlier in this paper, 1 tablet of Velphoro can bind up to 130 mg of phosphorus, compared to calcium acetates ability to bind approximately 106 mg of phosphorus (32,33). This indicates that Velphoro is a stronger binder of phosphorus, pill for pill. Because Velphoro is a stronger binder of phosphorus, it, in theory, requires fewer pills per day to achieve the same serum phosphorus control as other binders. Velphoro reports that patients on their medication take 52% fewer pills per day (31). I found this statistic to be true in the Rocky Mountain Clinic during my time as an intern. Since Velphoro has a lower pill burden that most other binders, patient adherence to binder regimen is better. The Canadian Agency for Drugs and Technologies in Health (CADTH) released a common drug review in 2018 with patient input on Velphoro. Some of the comments given by real patients prescribed Velphoro were very similar to ones I was told by patients at the Rocky Mountain clinic. Patients reported better appetite, enjoying meals, and less anxiety because their labs were in better control (37).
As discussed earlier, Velphoro is generally a more expensive medication than other binders, both calcium and non-calcium based. The cost of a 90 tablet supply of Velphoro (a 1 month supply if patient is taking 3 tablets per day, 1 with each meal) ranges from approximately $1,200-$1,400 (40,41). The cost of a 270 tablet supply of calcium acetate (a 1 month supply if a patient is taking 9 tablets per day, 3 with each meal) ranges from approximately $50-$75 (42). Both of these refer to the cost of the drug without insurance. Depending on the insurance, some or all of the cost of the drug are covered. While the patients might not take the brunt of the financial cost, some insurance companies require prior authorizations to approve Velphoro for a patient because the drug comes at a much larger cost for the insurance company compared to other binders (43). From my experience, patients that required a prior authorization had to prove that other binders were ineffective for them. This process could take weeks to months. If you’re just starting dialysis and don’t have insurance, you will automatically qualify for Medicare, however, Medicare coverage begins no earlier than the first day of the fourth month of treatment, leaving the first three months without guaranteed coverage of medications (56).
Summary
Phosphorus control is crucial for CKD patients on hemodialysis in regards to cardiovascular disease. Since the majority of dialysis patients are unable to control serum phosphorus through diet alone, phosphorus binders are prescribed. Increased serum phosphorus levels in dialysis patients disrupts bone mineral metabolism, leading to increased calcium in the blood that can deposit on the blood vessels and contribute CVD and death. There is currently concern that calcium based phosphorus binders might actually be contributing to cardiovascular disease due to the additional calcium being absorbed into the body from the binder, potentially depositing around the body and increasing risk for death from CVD (6,9,10). This has led KDIGO to recommend (recommendation was not given a grade) limiting the dose of calcium-based binders in their updated 2017 guidelines (50). The relationship behind calcium calcium-based phosphorus binders and increased risk for CVD is not fully understood, and some studies have also shown no increased risk between calcium-based and non-calcium-based binders (26).
binders are considered to be more effective than others. Patients switched to Velphoro from another phosphorus binder have shown to have statistically improved serum phosphorus control and reduced pill burden in multiple studies (44,45,46,47,48). It has been reasoned that serum calcium and PTH should also be improved on Velphoro due to improved serum phosphorus control, real life results have been less consistent in showing this (45).
In the future, we need more studies looking at the relationship between calcium-based binders, CVD, and mortality to provide stronger evidence to be used in guidelines. Additionally, since Velphoro is a relatively new drug compared to other phosphorus binders, we need studies with longer follow ups to determine efficacy of the drug over longer times. The longest study cited in this paper was 1 year of follow up, yet the average life expectancy on dialysis is 5-10 years (51).
If a patient wants to switch to Velphoro and is financially able to do so, it has been shown to be a safe, very effective phosphorus binder that allows for better binder compliance and
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