Simplified iron supplementation regimen

2 small studies evaluated the efficiency of differing ways to supplement oral iron in iron-deficient women (See doi.org/10.1016/ S2352-3026(17)30194-1).

Details:

--all women were age 18-40 with documented serum ferritin levels <25 mcg/L

--Study 1:

    ​--40 women, median age 22,  given iron repletion with 60 mg iron at 0800h daily for 14 days vs 60 mg iron every other day for 28 days

    --baseline mean hemoglobin 13, ferritin 13.8, Fe/TIBC= 18/82 (in mM), transferrin saturation 22%, serum hepcidin 0.8 nM, 

--Study 2:

    --20 women, median age 27, were given 120 mg iron at 0800 h vs 60 mg at 0800h plus 60 mg at 1700 h for 3 consecutive days. then, after 14 day washout, these groups were switched

    --baseline mean hemoglobin 13, ferritin 20, Fe/TIBC= 17/80 (in mM), transferrin saturation 21%, serum hepcidin 0.8 nM, 

--co-primary outcomes in both studies: iron bioavailability (total and fractional iron absorption, assessed by isotopic label abundance in erythrocytes 14 days after administration), and serum hepcidin levels 

Results:

--study 1:

    --cumulative fractional iron absorption was 16.3% in the consecutive-day group vs 21.8% in the alternate-day group (p=0.0013)

    --cumulative total iron absorption was 131.0 mg vs 175.3 mg (p=0.0010)

    --serum hepcidin levels were higher in the consecutive-day vs alternate-day group (p=0.0031)

--study 2:

    --cumulative fractional iron absorption was 11.8% in the once daily group vs 13.1% in the twice daily group (p=NS)

    --cumulative total iron absorption was 44.3 mg in the once daily group vs 49.4 mg in the twice daily group (p=NS)​

    ​--serum hepcidin levels were higher in the twice daily vs once daily group (p=0.013)

--no grade 3 or 4 adverse events were reported; but for grade 1-2 adverse events, nausea and abdominal pain were 33% higher with consecutive-day dosing than alternate-day dosing

Commentary:

--as a point of reference: FeSO₄ 325mg delivers 65mg elemental iron; ferrous gluconate 325mg has 38 mg elemental iron, though it is more efficiently absorbed (the organic anion gluconate is better absorbed than the inorganic sulfate; also the lower elemental iron dose is associated with fewer GI adverse effects)

--hepcidin is the central regulatory molecule in iron metabolism; it is low in iron-deficiency, oral doses of supplemental iron acutely raise its level, and it down-regulates duodenal iron absorption and macrophage iron release. A 2011 study (Pasricha S, Haematologica. 2011 Aug; 96(8): 1099; doi: 10.3324/haematol.2010.037960 ) found that to diagnose iron deficiency, hepcidin <8 ng/mL to be more sensitive (79% vs 42%) and almost as specific (86% vs 98%) as the ratio of soluble transferrin receptor/log ferritin. 

--the above study basically found a few things in women with iron-deficiency but not anemia:

    ​--alternate-day oral iron supplementation with 60 mg elemental iron (ie, one tablet of FeSO_4,about 2 of ferrous gluconate) was associated with a 34% higher iron absorption than with  consecutive-day supplementation

    ​--this data should translate into an estimated hemoglobin difference of about 7 g/L after taking 30 doses of iron (their calculation. seems high to me.....)

    --there was no benefit to splitting the dose of iron into 1/2-dose in am and 1/2-dose in pm (ie, give just one dose in the am, easier for patients anyway)

--prior studies suggest that iron supplementation may be better when consumed without food (5-28% vs 2-13%); and there is a diurnal variation in hepcidin and iron aborption: better absorption in the am

--study limitations: small numbers of women, only a few were mildly anemic, and the first study was not masked (which might affect subjective tolerability of the iron)

--other studies, for example, have found that in 90 hospitalized patients more than 80yo with actual iron-deficiency anemia, there was no difference in hemoglobin or ferritin concentrations with 15, 50, or 150 mg Fe daily for 2 months, though more adverse effects of the higher doses. in this study, the 15 and 50 mg supplements were of liquid ferrous gluconate, and the 150 mg dose was ferrous calcium citrate tablets, and the hemoglobin levels increased from 10 g/L to 11.5 g/L

so, this study reinforces the benefits of less aggressive iron supplementation. older studies from decades ago had suggested not just better med adherence but better absorption of iron in patients given one tablet a day vs the older standby of three a day (as in, FeSO₄ 325mg tid). This study suggests more efficacy with even lower iron doses and given every other day!!although the study of hospitalized elderly patients does support​ lower dose iron supplementation in anemic patients, ​it would be great to repeat the current study in iron-deficient patients, with long enough followup to document actual changes in hemoglobin concentrations in different groups of patients (different ages, comorbidities, sex, race/ethnicity, etc). 

probably the most effective therapy, from this study and some others, is to use ferrous gluconate at a dose of 2 tablets every other day, but one tablet every other day in the elderly