IDA is a public health problem affecting 32.8% of premenopausal and 40.1% of pregnant women, 41.7% of growing children , between 13 and 90% of patients with various medical diseases [11,12,13,14,15,16,17,18], and 30% of elderly people ; furthermore, approximately two-thirds of patients undergoing major surgery develop postoperative anemia [20,21,22].
The real limit of oral iron supplements is their absorption. In fact, it happens like through a funnel. The heme-iron is absorbed by a heme transporter , ferric iron is absorbed by the DMT1 (divalent metal transport 1) transporter [24,25,26,27,28], lactoferrin binds iron through a lactoferrin-binding protein/receptor [29,30,31], and ferritin iron can be taken up via an endocytic process in Caco-2 cells (which have some enterocyte-like characteristics) and probably also in vivo [32,33,34]. All these iron carriers can be heavily upregulated, as DMT1, up to 4–12-fold during iron deficiency anemia and erythropoietin increase [35, 36]. However, these receptors, also when upregulated, allow a limited iron absorption. The iron efflux from enterocytes is regulated by ferroportin that likely allows a maximum increase in iron absorption of 3–4 folds, as seen in thalassemic patients [37, 38]. Moreover, in iron-deficient patients, the administration of oral iron sulfate causes an increase of serum hepcidin, a hormone blocking ferroportin and protecting against iron overload, that falls to basal levels 48 h after treatment, thus imposing an every-other-day administration schedule for an optimal iron absorption .
A typical Western diet provides about 15 mg of iron per day and only 10% of it is absorbed . Recovery from blood loss causes an increase in iron absorption in the duodenum up to 20-fold. Patients with severe IDA or with normal iron stores receiving erythropoietin can absorb up to 20 to 40 mg/day of iron and the amount decreases when Hb levels increase [40, 41].
Oral iron is a cheap and effective way of correcting the martial deficiencies in patients without comorbidities, when iron loss exceeds the iron amount absorbed through food in the small intestine.
The cheapest commercially available oral iron formulation in Italy is iron sulfate. It is absorbed via a DMT1 transporter localized in the duodenal enterocyte brush border. Each tablet contains 325 mg of iron salts, containing 65 mg of elemental iron [35, 42]. However, gastrointestinal side effects are common [9, 43, 44]. It is estimated that 30% or more of patients taking iron-containing oral preparations develop gastrointestinal symptoms like nausea, constipation, diarrhea, dark stools, epigastric pain, and vomiting [45,46,47]. Gastrointestinal symptoms are proportional to the amount of elemental iron ingested .
Sucrosomial® iron is a new oral iron formulation, in which ferric pyrophosphate is protected by a phospholipid bilayer membrane composed mainly by sunflower lecithin, enveloped in a sucrester matrix stabilized by other ingredients as tricalcium phosphate and starch, forming the “sucrosome,” absorbed as a vesicle-like structure, through intestinal M cells, through a paracellular or intracellular way, bypassing the conventional iron DMT-1 absorption pathway [7, 49, 50]. Each tablet contains 30 mg of pyrophosphate iron.
The use of intravenous (i.v.) iron is indicated in patients intolerant to oral iron or when there is a problem of iron absorption (as in celiac disease, inflammatory bowel disease, gastric bypass, chronic inflammatory disease, cancer chemotherapy) or when intestinal blood losses exceed the ability of the normal duodenum to absorb ingested iron (as in obstetrics or surgical blood loss or in Osler-Weber-Rendu syndrome), because it bypasses mechanisms of duodenal absorption and increases Hb levels more quickly than oral iron [51,52,53,54,55].
In the current study, it is noteworthy that the number of days required to achieve a 1-g increase in hemoglobin levels after enrollment and the time to reach target hemoglobin level of 12 g/dl is practically identical in the two treatment groups. It seems that for the SI group, the iron given in the Sucrosomial formulation bypassed all the usual absorption mechanisms present in the brush border membrane of enterocytes, behaving, therefore, almost like the SFGC delivered parenterally.
This result is in open contrast to what would be expected by administering any other oral iron formulation. For example, we can consider the case of oral iron sulfate. The median amount of iron needed to achieve an increase of 1 g/dl of hemoglobin based on the aforementioned formula would be 225 mg. Considering that each iron sulfate tablet contains 65 mg of elemental iron, of which a maximum of 25 mg is absorbed, and that the optimal administration schedule is 1 tablet every other day, 18 days of treatment would be needed theoretically to achieve the desired goal vs 9 days in the SI group and 7 days in the SFGC group. Furthermore, to achieve the target Hb level of 12 g/dl in 72 days of treatment with iron sulfate should be needed vs 28 days in the SI group and 24 days in the SFGC group.
Some doubts can arise from the high amount of elemental iron received in the SI group in a month; in fact, it could potentially cause hemosiderosis. However, if we consider that the quantity of elemental iron necessary to reach the median level of 12 g/dl of hemoglobin, reached in 1 month in the SI group, is a median of 900 mg, that the median continuous loss of hemoglobin in each patient was 2 g/dl per month, corresponding to a median of 450 mg of elemental iron, and that 1000 mg of iron is needed to replenish martial stocks, the total median iron needed is 2350 mg. Moreover, in feces, humans loss about 13% of lipid and sugar ingested , corresponding to 18 tablets of Sideral loss in stools each month, for a total of 540 mg of elemental iron; thus, the total median requirement for each patient in the SI group monthly is about 2800 mg. This might explain why at a median time of 12 months from enrollment the median value of ferritin at end of treatment was 260 ng/ml (R: 150–320) in the SI group, without any evidence of hemosiderosis.
Results in patients taking proton pump inhibitors (PPIs) were superimposable, without statistically significant differences, to those not taking PPIs in each treatment group. This is in contrast with the evidence that proton pump inhibitors affect iron absorption, at least for the SI group [57,58,59,60,61].
Gastrointestinal side effects, mainly of low level, were reported in 27% of patients from the SI group, in accordance with data already reported in the literature . It is not surprising that the totality of patients with side effects are 80 years old or older. In fact, 40% of elderly patients show gastrointestinal side effects [48, 62] and probably the high number of octogenarians with gastrointestinal side effects is only due to the low number of patients in our study. On the other hand, it is noteworthy that in patients taking Sucrosomial iron with food, gastrointestinal side effects are reduced to almost one-third (only 10%), a markedly lower percentage in comparison to previous studies.
Equally important is the fact that the administration of Sucrosomial iron with food does not impair its absorption, as shown by the same effectiveness of intravenous iron. In fact, usually, when oral iron formulation is given with food, its absorption is impaired by calcium, polyphenols, phytates, eggs, or soy contained in aliments .
ID, in which IDA is included , causes physical productivity reduction and cognitive and physical disability with an economic loss quantified, in 2002, as an absolute dollar value of $4.2 billion annually (corresponding to € 3.8 billion), with reference only to physical productivity losses in South Asia . Economic loss secondary to ID has been estimated, in 2019, as CHF 78 million (€ 73.12 million) for direct medical costs and between CHF 26 million (€ 24.37 million) and CHF 33 million (€ 31 million) in a Swiss female population [65, 66].
The economic evaluation of SI treatment–related costs in the current study showed a possible cost saving, translated into a 60% abatement of overall monthly expenditures per patient compared to the SFGC group. Indeed, although the treatment cycle with Sucrosomial iron had higher purchase costs compared to i.v. iron, it greatly reduced other direct clinical expenditures (cost minimization) for the hospital and the public healthcare system as well as indirect costs. The information acquired by comparing the costs of the two different therapies confirms what our group has already observed in the context of myelodysplastic syndromes. In that case too, the high number of hospital admissions resulted in an increase in indirect costs and losses deriving from patients’ absences from work .
Moreover, a warning issued by the EMA and by the Italian Drugs Agency (AIFA) advises against the use of i.v. iron outside hospital with an intensive care unit, given the potentially fatal side effects linked to i.v. hypersensitization . This imposes SFGC administration only in hospital, considerably worsening quality of life of patients receiving SFGC and explaining the higher value of perceived quality of life in the SI group.