Study Questions Phosphate Binders’ Cardiovascular Benefits for Patients with Mild Kidney Disease

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Elevated phosphate levels in the blood—even when levels are in the high normal range—carry increased heart-related risks, but taking a phosphate binder did not improve cardiovascular measures in patients with mild kidney disease in a recent study published in the Journal of the American Society of Nephrology.
“It would appear that for now it would be better to lower the amount of phosphate in the diet rather than rely on pharmacological interventions,” said senior author Charles Ferro, MBChB, MD, of the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, in England.
Because adherence to the study medication was low, though, additional studies are warranted to test the true potential of phosphate binders for protecting the heart health of patients with mild kidney disease.
Chronic kidney disease (CKD) is the most common condition associated with deranged phosphate homeostasis. Ferro and his colleague Colin Chue, MBChB, led a research team that conducted a double-blind, randomized, placebo-controlled trial of 120 patients with stage 3 CKD to test the effects of the phosphate binder sevelamer carbonate, which is approved only for patients with kidney failure. Sevelamer carbonate holds promise for improving cardiovascular health because high blood levels of phosphate promote calcification and stiffening of blood vessels and can cause structural changes in the heart, such as increased wall thickness.
After a 4-week open label run-in period, during which all patients received sevelamer carbonate, 109 patients were randomly assigned to sevelamer or placebo for an additional 36 weeks. The investigators assessed left ventricular mass and systolic and diastolic function with cardiovascular magnetic resonance imaging and echocardiography, and they assessed arterial stiffness by carotid–femoral pulse wave velocity.
“We hoped that by asking a very motivated group of patients with early stage chronic kidney disease to take phosphate binders with every meal, we would be able to reduce the amount of phosphate absorbed from the diet,” Ferro said. However, at the end of the study, the investigators found no differences in any of the measures of cardiovascular structure and function between the groups.
Yet despite repeated reminders and suggested methods to maximize compliance, adherence to treatment was low, with only 56 percent of patients taking more than 80 percent of the study medication. Also, several patients withdrew from the study because of difficulty with the frequency (two tablets taken three times daily) and tolerability of the study agents. When the subgroup of patients with more than 80 percent compliance was analyzed separately, the group taking sevelamer excreted significantly smaller amounts of phosphate in their urine compared with those taking placebo. The sevelamer group also had reduced levels of the hormone fibroblast growth factor 23, which is critical for maintaining phosphate balance but is also toxic to the cardiovascular system. No changes were noted in any of the measures of cardiovascular structure nor in serum levels of phosphate, klotho, and vitamin D, though.
“Although only 56 percent of patients took 80 percent or more of the prescribed medications in this controlled study, which is a legitimate limitation to the results, this level of adherence is very commonly seen in clinical practice, which makes the findings of this study translatable to the real clinical setting,” said Jeannie Kim Lee, PharmD, BCPS, CGP, of the University of Arizona College of Pharmacy. Lee, who was not involved with the study, has conducted extensive research addressing patients’ medication adherence.

More research needed
In an accompanying editorial, Rajiv Agarwal, MD, of the Indiana University School of Medicine, noted that the study “should not serve as a death knell to investigations on phosphorus in progressive CKD, but should instead serve as a crèche for future investigations on the value of phosphorus reduction in preventing cardiovascular disease and CKD progression.”
He noted that it is unlikely that sevelamer is ineffective because the drug is approved with adequate trial data to support its use in people with hyperphosphatemia.
He added that while the drug in the doses used in this trial was not effective in reducing an already normal level of phosphorus concentration, perhaps the participants increased their dietary phosphorus intake, which would prevent an overall decline in serum phosphorus.
Until more information is available about the potential heart-related benefits of phosphate binders for individuals with mild CKD, these patients should focus on dietary changes to reduce their phosphate levels. Foods with large amounts of added phosphate are processed meat, ham, sausages, canned fish, baked goods, cola drinks, and other soft drinks.
“Fast food and ready-to-eat processed foods are the main contributors to today’s rising dietary consumption of phosphate,” Ferro noted. He suggested that a comprehensive public education effort that explains the harmful effects of high phosphate intake and provides clear labeling of the phosphate content of food could help limit the damage done by this cardiovascular risk factor.