COMMENTARY

Effects of Phosphate Binders and Transport Inhibitors on FGF-23 Levels in Patients With CKD

Nisha Bansal, MD, MAS

Disclosures

June 28, 2019

Nicotinamide and Lanthanum Carbonate and Changes in Serum Phosphate and Fibroblast Growth Factor-23 in Patients With CKD: The COMBINE Trial

Alterations in mineral metabolism frequently occur in patients with chronic kidney disease (CKD) and are potentially important risk factors for cardiovascular disease. Specifically, higher levels of serum phosphorus are associated with arterial calcification, increased left ventricular mass, and cardiovascular events.[1,2,3]

Higher serum phosphorus levels and lower glomerular filtration rate (GFR) stimulate upregulation of fibroblast growth factor (FGF)-23, which then stimulates urinary phosphorus excretion. Although elevations in FGF-23 are compensatory adaptations, chronic exposure to high FGF-23 also has significant cardiovascular effects.[4,5] Therefore, lowering serum phosphorus and FGF-23 levels may be important therapeutic targets to reduce cardiovascular disease in patients with CKD.

Intestinal phosphate binders acutely lower phosphorus, but may then promote relative intestinal hyperabsorption. Preclinical data have shown that the combination of intestinal phosphate binders with inhibitors of active intestinal phosphate transport may enhance the phosphorus-lowering.[6,7] With that in mind, the COMBINE trial[8] was designed to test the efficacy and safety of nicotinamide (an inhibitor of active intestinal phosphate transport) and lanthanum carbonate (an intestinal phosphate binder), in isolation and in combination, in patients with CKD.

The Findings

Inclusion criteria for this randomized, double-blind, placebo-controlled were estimated GFR (eGFR) between 20 and 45 mL/min/1.73 m2, serum phosphate concentration ≥ 2.8 mg/dL, and platelet count ≥ 125,000 cells/mm3. Eligible participants underwent a 2-week run-in phase in which they took placebo for both nicotinamide and lanthanum carbonate. Participants who achieved 80% compliance were randomly assigned to one of four treatment groups: nicotinamide plus lanthanum carbonate, nicotinamide plus placebo, lanthanum carbonate plus placebo, or double placebo.

There were a total of 205 participants from seven centers across the United States, with a mean eGFR of 32 mL/min/1.73 m2.[8] Over the 12-month follow-up period, there were no significant differences in the rates of change in serum phosphate or FGF-23 in any of the three active treatment groups compared with the double placebo group.

During the study, 42% of participants in the nicotinamide plus lanthanum carbonate group discontinued one or both drugs, compared with 14% in the double placebo group. Gastrointestinal symptoms and pill burden were the most common reasons for discontinuation; the drugs were titrated to a dosage of nicotinamide 750 mg twice daily and lanthanum 1000 mg three times daily. Rates of serious adverse events, such as hospitalizations and death, were low in all treatment groups.[8]

Takeaways

This trial demonstrates that although nicotinamide and lanthanum carbonate are safe, these medications do not lead to declines in serum phosphorus or FGF-23 levels. Furthermore, the drugs do not seem to be well tolerated, given the high discontinuation rates (even though study participants were preselected for high compliance).

Did the high discontinuation rates affected the study results? In a post hoc analysis, the investigators found a possible decline in FGF-23 levels in adherent participants treated with nicotinamide plus lanthanum carbonate; however, this finding is exploratory and should be interpreted with caution. Another possible explanation for the null findings is the inclusion of patients with CKD with relatively normal phosphate concentrations.

COMBINE is one of the few robust clinical trials of treatment of mineral metabolism in patients with moderate to advanced CKD. It studied medications that target two pathways involved with phosphate homeostasis. The low adherence seen with these medications highlight the importance of focusing on patient tolerability in drug development.

Although some patients can be treated with a single phosphate binder, many require a combination of different phosphate binders. Therefore, discovery of combinations of phosphate-lowering medications that are effective is important.

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