For patients with iron-deficiency anemia who are intolerant of or unresponsive to oral iron, intravenous formulations can rapidly correct iron deficiency, but certain formulations are known to induce fibroblast growth factor 23–mediated hypophosphatemia. In a report from two randomized trials comparing ferric derisomaltose and ferric carboxymaltose (FCM), researchers found that ferric derisomaltose (also known as iron isomaltoside 1000) led to a lower incidence of hypophosphatemia. Led by Myles Wolf, MD, of the Duke University School of Medicine in North Carolina, the study authors noted that further research is needed to determine the clinical importance of this difference in a larger real-world population.
The investigators performed two identical open-label randomized trials across 30 sites in the U.S., results of which were published in JAMA.
Both trials enrolled adults with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance of or unresponsiveness to oral iron for 1 month or more. Individuals with reduced kidney function were excluded from the trials.
Participants were randomized to either intravenous ferric derisomaltose 1,000 mg, infused over 20 minutes on day 0, or FCM 750 mg infused on days 0 and 7. The number of patients randomized to either group in trials A and B was as follows:
- trial A: ferric derisomaltose 1,000 mg (n=62) and FCM 750 mg (n=61)
- trial B: ferric derisomaltose 1,000 mg (n=61) and FCM 750 mg (n=61)
At baseline, the mean ages of patients treated with ferric derisomaltose and FCM were 43 years and 44.7 years, respectively.
The primary endpoint of these two open-label trials was incidence of hypophosphatemia (defined as a serum phosphate level <2.0 mg/dL) from baseline to day 35. Secondary efficacy endpoints included:
- changes in hemoglobin per gram of iron infused
- changes in ferritin and transferrin saturation
Secondary safety endpoints included adverse drug reactions, persistent hypophosphatemia prevalence at day 35, changes in biomarkers of mineral and bone homeostasis (e.g., serum phosphate, urinary fractional excretion of phosphate, and intact fibroblast growth factor 23). Investigators measured serum phosphate and the biomarkers of mineral and bone homeostasis on days 0, 1, 7, 8, 14, 21, and 35.
In trial A, the hypophosphatemia incidence at any time from baseline to day 35 was significantly lower within the group of patients treated with ferric derisomaltose compared with those treated with FCM: 8% versus 75% (adjusted rate difference = –67%; 95% CI 77% to –52%; p<0.001). The same relationship was observed in trial B: Hypophosphatemia occurred in 8.1% of patients who received ferric derisomaltose, compared with 74% in the FMC group (adjusted rate difference = –66%; 95% CI –77% to 50%; p<0.001).
In post hoc analyses, the prevalence of hypophosphatemia in both trials was significantly lower in the ferric derisomaltose arm than the FCM arm by day 7. Severe hypophosphatemia, defined by serum phosphate level ≤1.0 mg/dL, was observed in 11% of patients treated with FCM, but was not observed in patients treated with ferric derisomaltose (p<0.001).
Overall, the investigators observed more frequent adverse drug reactions with FCM than with ferric derisomaltose in both trials (45% vs. 11% in trial A and 49% vs. 23% in trial B). Only 1 patient (1%) experienced a serious or severe hypersensitivity reaction in the ferric derisomaltose group, whereas 2 patients (2%) in the FCM arm experienced dyspnea and swelling.
Throughout the study period, urinary phosphate excretion was higher in the FCM arm, with peak levels observed at day 14. Compared with treatment with ferric derisomaltose, treatment with FCM also was associated with larger magnitude reductions in serum phosphate but increases in total and bone-specific alkaline phosphatase levels.
Within 24 hours of the first dose of FCM on day 0, the mean level of biologically active intact fibroblast growth factor 23 rose from 46.2 pg/mL to 151.2 pg/mL; on day 8, after the second FCM dose, levels reached a peak of 343.6 pg/mL. Following this peak, intact fibroblast growth factor 23 decreased through day 35 in patients treated with FCM but remained higher than in patients treated with ferric derisomaltose at all assessment visits.
To explain how FCM led to such a substantially higher incidence of hypophosphatemia compared with the other intravenous iron formulation, the authors noted that the increases in fibroblast growth factor 23 lead to suppression of the active form of vitamin D. In turn, this can decrease serum calcium. Secondary hyperparathyroidism in response to decreased calcium further exacerbates hypophosphatemia by promoting renal phosphate losses. “The findings of these two trials suggest that [FCM] activated this entire pathophysiological cascade by acutely increasing intact fibroblast growth factor 23 within 1 day,” the authors wrote.
However, they noted that the mechanism behind FCM’s ability to elevate intact fibroblast growth factor 23 is unknown.
According to the authors, the differences in dosing between the FCM and ferric derisomaltose formulations could have affected the findings. Other limitations of the study include its short assessment window and the lack of assessment of clinical outcomes.
Study authors report relationships with Pharmacosmos, which sponsored these trials.
Wolf M, Rubin J, Achebe M, et al. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials. JAMA. 2020;323:432-443.