Abstract
Background
Anemia affects one-fourth of the world's population and is caused mostly by iron deficiency. Iron supplementation is the most essential strategy for preventing iron deficiency anemia. Conventional oral iron salts have many drawbacks such as poor absorption & bioavailability, and poor tolerability resulting in poor clinical outcomes.
Objective
To compare the effectiveness and safety of ferrous ascorbate, ferrous fumarate, ferrous bis-glycinate, and Sucrosomial iron in the management of iron deficiency anemia.
Method
The study is a retrospective observational clinical study comprising 260 subjects with hemoglobin between 7–10 g/dl. The patients were divided into four groups I, II, III, and IV, and received ferrous fumarate, ferrous ascorbate, ferrous bis-glycinate, and Sucrosomial iron respectively. Hematological profile and iron store indices were measured at baseline and month 3. One-way ANOVA followed by Tukey multiple comparison test was used to assess statistical significance (P < 0.05) using GraphPad Prism V.9.3.1 software.
Results
The observational study showed that hemoglobin levels were significantly increased in the ferrous ascorbate group (11.86 ± 0.09; P < 0.0001), ferrous fumarate group (11.72 ± 0.08; P < 0.0001), ferrous bis-glycinate group (11.69 ± 0.11; P = 0.0003) and Sucrosomial iron group (12.20 ± 0.1; P < 0.0001) compared to the baseline. The Sucrosomial iron-supplemented group showed significantly higher improvement in hemoglobin levels and serum ferritin levels compared to conventional oral iron salts (P < 0.05) with a better safety profile.
Conclusion
The Sucrosomial iron showed significantly higher improvement in hemoglobin levels and higher improvement in iron store indices parameters along with a good tolerability profile compared to other conventional oral iron salts.
Graphical abstract
Keywords: Ferrous ascorbate, Ferrous bis-glycinate, Ferrous fumarate, Sucrosomial iron, Iron deficiency anemia
Introduction
Anemia affects over 25% of the world's population, or over 1.6 billion people, and is a serious public health concern [1]. Anemia is defined as having hemoglobin (Hb) levels that are two standard deviations below the age-specific mean for the patient. A hemoglobin content of less than 11 g/dL is considered anemia, according to the WHO [2]. Anemia may be caused by a combination of factors including heredity, chronic infections, and nutritional deficiencies such as hemoglobinopathies, iron shortage, inadequate folate, and vitamin B12 deficiency. Iron deficiency is a leading cause of iron deficiency anemia and has a substantial effect on a baby's brain development. Iron is essential for neuronal myelination, metabolism, neurotransmission, and neurogenesis in addition to its effects on behavior, memory, learning, and sensory systems [3–6]. Forty to sixty percent of maternal fatalities from heart failure, bleeding, infection, and pre-eclampsia are caused by it, either directly or indirectly [7]. Additionally, it raises the odds of perinatal death and morbidity brought on by preterm births, intrauterine growth restriction, insufficient iron reserves, iron deficiency anemia, and newborns' cognitive and emotional impairments [8–10]. Anemia is more common in underdeveloped nations where it continues to be a major cause of maternal death. Its frequency, etiology, and severity vary among groups [11]. Iron deficiency, folic acid insufficiency, vitamin B12 deficiency, other nutritional deficiencies, and hemoglobinopathies—of which iron deficiency anemia is the most frequent—are major causes of anemia in pregnancy [12, 13]. When treating iron deficiency anemia, conventional oral iron salts like ferrous fumarate, ferrous sulfate, and ferrous gluconate are used. However, these salts have several drawbacks, such as low bioavailability (10% to 15%), which is even lower for ferric iron salts or ferric iron complexes (polysaccharides, amino acids, ovo-albumin, etc.). In addition, typical oral iron salts have a poor tolerability profile (gastrointestinal side effects were noted by 50% of patients), which results in low compliance and subpar clinical outcomes [14]. The use of conventional iron salts has been linked to several adverse effects, including dyspepsia, vomiting, nausea, diarrhea, and stomach discomfort [15]. Furthermore, food consumption, simultaneous chronic inflammatory illnesses (increased hepcidin restricting further iron absorption), and the concurrent use of proton pump inhibitors or antacids may decrease the absorption of iron from normal oral iron salts and decrease its utilization [14]. Furthermore, several meal components, including phytates, polyphenols, calcium, and tannins, which oxidize ferrous iron to ferric iron, decrease absorption from these preparations [15]. This might make the therapy less successful or postpone the achievement of the intended hematological state. Additionally, 50% of the patients taking oral iron supplements reported experiencing gastrointestinal side effects, which may point to a lack of adherence to oral iron therapy [14]. Due to the limitations of traditional iron salts, novel oral iron preparations such as Sucrosomial iron have emerged. Sucrosomial iron is a novel oral iron supplement that has ferric pyrophosphate as the core ingredient surrounded by the phospholipid bilayer membrane and Sucrester layer which provides gastro-resistant properties and reduces the gastrointestinal side effects. Moreover, the Sucrosomial iron gets absorbed in the peyers’ patches of the small intestine through M-cells, transcellular and paracellular routes. Hence, it bypasses the normal absorption pathway of DMT-1 channels irrespective of hepcidin levels. Earlier studies have reported the uptake of radiolabelled Sucrosomial iron through M-cells of the Peyer's patches in the intestine in ex-vivo studies using immunofluorescence analysis and microscopic examination of excised rat intestinal tissues. This uptake was followed by uptake in CD68 + macrophages, which also serve as a temporary storage site for Sucrosomial iron [16]. In an in vitro investigation, Sucrosomial iron was found to be more readily absorbed than conventional oral iron salts such as ferrous sulfate, ferrous bis-glycinate, ferrous ascorbate, and ferrous edetate in the presence of M cells (RajiB cells). Sucrosomial iron is absorbed through the intestinal epithelium via a DMT-1 independent process that is unaffected by the divalent iron chelator bathophenanthroline disulfonic acid, according to ex-vivo permeation tests using an excised rat intestine model.14 This finding supports the recognized mechanism for Sucrosomial iron absorption through M-cells and avoiding the DMT-1-dependent route. The bioavailability of iron (Fe+3) with Sucrosomial iron was found to be much higher than that with ferric pyrophosphate after 5 h of administration. Moreover, Sucrosomial iron supplementation compared to treatment with ferric pyrophosphate, several organs from a sacrificed rat, including the liver, spleen, and bone marrow, revealed substantially increased Fe+3 concentration. The Pharmacokinetic profiles revealed a significantly higher area under the curve (AUC) and maximal plasma concentration of iron (Cmax) for Sucrosomial iron than those for ferric pyrophosphate. These data suggest that Sucrosomial iron has higher bioavailability, and the excess iron amount required apart from the hematopoiesis and metabolic processes, is mainly stored in the hepatocytes [16–18]. Sucrosomial iron showed higher accumulation of serum ferritin levels within enterocytes compared to ferrous sulfate and ferric pyrophosphate (threefold higher) and phospholipid containing ferric pyrophosphate or micronized, dispersible ferric pyrophosphate (3.5-fold higher) in an experimental model using CACO-2 cell culture [14]. The previous pre-clinical study showed significant improvement in hematological profile along with improvement in iron store indices (serum iron, total iron binding capacity, transferrin saturation, and serum ferritin) with the use of Sucrosomial iron compared to conventional oral iron formulations [19]. Anecdotal comparative evidence with conventional oral iron salts is available for Sucrosomial iron for the management of iron deficiency anemia. However, up to the best of our knowledge, no clinical trials were conducted in India to assess the comparative hematinic potential and tolerability profile of Sucrosomial iron to that of conventional oral iron supplements such as ferrous ascorbate, ferrous fumarate, and ferrous bis-glycinate. Therefore, the present study aimed to evaluate the effectiveness and safety profile of different oral iron salts for the management of iron deficiency anemia in anemic patients.
Material and methods
Participants
The present study was a retrospective observational clinical study comprising 260 patients, suffering from iron deficiency anemia attending the tertiary care centers in Ahmedabad, India during the period June 2021 to December 2022. After obtaining ethical clearance from the independent ethics committee, subjects of age ≥ 18 years with hemoglobin between 7–10 g/dL were included in the study. The observational study plan 2021-IDA-001 was approved by the ACEAS independent ethics committee, Ahmedabad.
Study treatment
The patients were stratified into four groups of 65 patients each. Subjects in group I received ferrous ascorbate [elemental iron 100 mg + folic acid 1.5 mg], group II received ferrous fumarate [elemental iron 50 mg + folic acid 1.5 mg], group III received ferrous bis-glycinate [elemental iron 30 mg + elemental zinc 11 mg + folic acid 0.5 mg + vitamin B12 7.5 mcg], and group IV received Sucrosomial iron [elemental iron 30 mg) + L-methylfolate 500 mcg + vitamin B12 1 mcg + L-lysine 40 mg] as per the routine clinical practice. All patients received oral iron supplements once daily after breakfast and were followed for three months.
Assessment
A complete blood count profile and iron store indices (a subset of patients) were assessed at the baseline and the end of 3 months. Adverse effects associated with iron supplements were reported at the end of the study period such as gastric irritation, bloating, constipation, nausea & vomiting, diarrhea, abdominal pain, and blackish discoloration of stools. Subjects who had anemia other than IDA, gastric ulcer or erosions, hematological malignancy, and hypersensitivity to iron preparations or were affected by a major hemoglobinopathy e.g., B thalassemia major sickle cell disease were excluded from the data analysis. Subjects with a history of blood/product transfusion received in the last 6 months and having a history of allergy/ contraindications to any of the ingredient(s) of the supplement were excluded from the data analysis. The primary outcome measures were the improvement in hematological profile and iron store indices (Serum iron & ferritin levels, Total iron binding capacity, and Transferrin saturation percentage) measured as per routine clinical practice. The hematological parameters such as hemoglobin (g/dl), hematocrit (%), red blood cells (RBCs), mean corpuscle volume (MCV), mean cell hematocrit (MCH), mean corpuscle hemoglobin concentration (MCHC), packed cell volume (PCV), platelets count, total leukocytes count and red cell distribution width (RDW) were measured after treatment of specific days using an automatic blood analyzer (Horiba ABX, MICROS 60) [20, 21]. Using a semi-auto analyzer from Beckman Coulter, the AU480, immunoassay experiments were performed to measure the levels of serum iron (SI) concentration, total iron binding capacity (TIBC), serum ferritin (SF), and transferrin saturation (TSAT%). Transferrin saturation (TSAT) % was calculated from the ratio of the SI concentration to the TIBC as follows [22]:
The Secondary outcome measure was the safety and tolerability profile of the different iron salts. The Naranjo scale questionnaire was used to assess the probability of adverse drug reactions caused by drugs or other factors in all groups. The adverse drug reactions probability was assigned as definite, probable, possible, or doubtful as per the Naranjo scale questionnaire [23].
Statistical analysis
Data were compiled and tabulated as the averages of the 65 determinants with Standard Error of Mean (SEM) and subjected to one-way ANOVA analysis before being subjected to the Tukey multiple comparison test. To assess significance, nonparametric statistical techniques were applied, and P > 0.05 was chosen as the probability threshold at which the null hypothesis had to be rejected (GraphPad Prism V.9.3.1).
Results
Demographic data of participants
There was a total of 260 patients (207 females and 53 males) with a mean age of 36.93 ± 13.42 years. Patients’ demographic details, anthropometric measures, grading of anemia, comorbid conditions, and dietary pattern details are mentioned in Table 1.
Table 1.
Patients’ Socio-demographic details
| Patients age group | ||||||
| Age group (Years) | Overall Patients (N = 260) | Percentage (%) of patients | Ferrous ascorbate (n = 65) | Ferrous fumarate (n = 65) | Ferrous bisglycinate (n = 65) | Sucrosomial iron (n = 65) |
| 18–24 | 56 | 26.92% | 16 (24.6%) | 10 (15.4%) | 15 (23.1%) | 15 (23.1%) |
| 25–34 | 70 | 39.61% | 14 (21.5%) | 18 (27.7%) | 22 (33.8%) | 16 (24.6%) |
| 35–44 | 55 | 25% | 12 (18.5%) | 17 (26.2%) | 13 (20%) | 13 (20%) |
| 45–54 | 72 | 4.61% | 13 (20%) | 10 (15.4%) | 7 (10.8%) | 13 (20%) |
| ≥ 55 | 7 | 3.84% | 10 (15.4%) | 10 (15.4%) | 8 (12.3%) | 8 (12.3%) |
| Patients’ Anthropometric Measures | ||||||
| BMI (Kg/m2) | Frequency (n) | Percentage (%) of patients | Ferrous ascorbate (n = 65) | Ferrous fumarate (n = 65) | Ferrous bisglycinate (n = 65) | Sucrosomial iron (n = 65) |
| Underweight (< 18.5 kg/m2) | 30 | 11.53% | 5 (8%) | 5 (8%) | 9 (14%) | 11 (17%) |
| Normal (18.5–22.99 kg/m2) | 146 | 56.15% | 40 (62%) | 43 (66%) | 31 (48%) | 38 (58%) |
| Overweight (23–24.99 kg/m2) | 51 | 19.62% | 8 (12%) | 12 (18%) | 15 (23%) | 13 (20%) |
| Obese (≥ 25 kg/m2) | 33 | 12.69% | 12 (18%) | 5 (8%) | 10 (15%) | 4 (6%) |
| Grading of anemia* | ||||||
| Severity of anemia | Frequency (n) | Percentage (%) of patients | Ferrous ascorbate (n = 65) | Ferrous fumarate (n = 65) | Ferrous bisglycinate (n = 65) | Sucrosomial iron (n = 65) |
| Mild | 124 | 48% | 32 (49%) | 33 (51%) | 30 (46%) | 29 (45%) |
| Moderate | 136 | 52% | 33 (51%) | 32 (49%) | 35 (54%) | 36 (55%) |
| Severe | - | - | - | - | - | - |
| Comorbid conditions with anemia | ||||||
| Disease conditions | Frequency (n) | Percentage (%) | Ferrous ascorbate (n = 65) | Ferrous fumarate (n = 65) | Ferrous bisglycinate (n = 65) | Sucrosomial iron (n = 65) |
| Hypertension | 22 | 8.46% | 5 (7.69%) | 7 (10.77%) | 4 (6.15%) | 6 (9.23%) |
| Diabetes Mellitus | 16 | 6.15% | 5 (7.69%) | 4 (6.15%) | 4 (6.15%) | 3 (4.62%) |
| Joint pain & Arthritis | 13 | 5% | 6 (9.23%) | 2 (3.07%) | 1 (1.54%) | 4 (6.15%) |
| Hypothyroidism | 8 | 3.08% | 1 (1.54%) | 2 (3.07%) | 2 (3.07%) | 3 (4.62%) |
| Gastro-esophageal reflux disease | 8 | 3.08% | 2 (3.07%) | 1 (1.54%) | 3 (4.62%) | 2 (3.07%) |
| Respiratory illness | 4 | 1.54% | 2 (3.07%) | 1 (1.54%) | - | 1 (1.54%) |
| Chronic liver disease | 3 | 1.15% | - | 1 (1.54%) | 1 (1.54%) | 1 (1.54%) |
| Malignancy | 1 | 0.38% | - | - | 1 (1.54%) | - |
| Dietary Pattern Details | ||||||
| Nature of Diet | Frequency (n) | Percentage (%) | Ferrous ascorbate (n = 65) | Ferrous fumarate (n = 65) | Ferrous bisglycinate (n = 65) | Sucrosomial iron (n = 65) |
| Vegetarian | 205 | 78.85% | 46 (70.77%) | 55 (84.62%) | 47 (72.31%) | 57 (87.69%) |
| Non-vegetarian | 48 | 18.46% | 15 (23.08%) | 16 (24.62%) | 7 (10.77%) | 10 (15.38%) |
| Eggetarian | 7 | 2.69% | 2 (3.08%) | 2 (3.08%) | 1 (1.54%) | 2 (3.08%) |
*Grading of anemia (Mild: Hemoglobin 10.0 g/dL to 11 g/dL; Moderate: Hemoglobin 8.0 to 9.9 g/dL; Severe: Hemoglobin 6.5 to 7.9 g/dL)
Effectiveness of iron supplements on primary evaluation parameters
All four groups were comparable in age, hematological profile, and iron store indices at the baseline without any significant difference. A complete blood count (CBC) profile assessment revealed significant improvement in hematological parameters in patients receiving oral iron supplements groups on day 90 as shown in Table 2.
Table 2.
Complete blood count profile on baseline and day 90
| Treatment | Visit | Red blood cells (RBC) (cu. mm) | Packed cell volume (PCV) | Mean corpuscular volume (MCV) (fl) | Mean corpuscular hemoglobin (MCH) (pg) | Mean corpuscular hemoglobin concentration (MCHC) (g/dl) | Red cells dis (RDW) (fL) | Total leukocyte count | Platelets/mm3 | Hemoglobin (g/dl) |
|---|---|---|---|---|---|---|---|---|---|---|
| Ferrous ascorbate | Day 0 | 3.91 × 106 ± 0.07 | 34.84 ± 0.60 | 83.33 ± 1.20 | 26.62 ± 0.46 | 30.61 ± 0.21 | 16.25 ± 0.21 | 9.142 ± 0.68 | 243.8 × 103 ± 12.62 | 9.88 ± 0.08 |
| Day 90 | 4.79 × 106 ± 0.04* | 39.31 ± 0.40* | 91.26 ± 1.0^ | 27.95 ± 0.48 | 32.14 ± 0.22* | 14.58 ± 0.16 | 8.36 ± 0.39 | 290.67 × 103 ± 9.16 | 11.86 ± 0.09* | |
| Ferrous fumarate | Day 0 | 3.80 × 106 ± 0.060 | 34.80 ± 0.60 | 83.81 ± 1.15 | 27.19 ± 0.39 | 31.01 ± 0.19 | 16.26 ± 0.21 | 8.37 ± 0.55 | 219.29 × 103 ± 11.15 | 9.87 ± 0.10 |
| Day 90 | 4.37 × 106 ± 0.06* | 38.39 ± 0.61$ | 90.52 ± 1.2^ | 28.33 ± 0.41 | 32.53 ± 0.20* | 14.88 ± 0.19 | 7.79 ± 0.49 | 248.87 × 103 ± 11.33 | 11.72 ± 0.08* | |
| Ferrous bisglycinate | Day 0 | 3.78 × 106 ± 0.05 | 33.99 ± 0.64 | 83.48 ± 0.79 | 28.39 ± 0.37 | 31.25 ± 0.19 | 16.13 ± 0.18 | 7.63 ± 0.40 | 205.85 × 103 ± 9.64 | 9.99 ± 0.09 |
| Day 90 | 4.36 × 106 ± 0.06 | 37.46 ± 0.69 | 90.16 ± 0.8 | 29.61 ± 0.39 | 32.73 ± 0.19 | 14.67 ± 0.14 | 7.25 ± 0.38 | 226.04 × 103 ± 10.22 | 11.69 ± 0.11* | |
| Sucrosomial iron | Day 0 | 3.84 × 106 ± 0.05 | 32.47 ± 0.66 | 82.37 ± 0.89 | 27.39 ± 0.46 | 30.87 ± 0.20 | 16.52 ± 0.19 | 9.27 ± 0.41 | 245.95 × 103 ± 12.57 | 9.96 ± 0.08 |
| Day 90 | 4.59 × 106 ± 0.04* | 40.09 ± 0.60*@ | 88.74 ± 0.9& | 28.62 ± 0.48* | 32.32 ± 0.20* | 14.80 ± 0.16 | 8.92 ± 0.35 | 266.6 × 103 ± 11.02 | 12.20 ± 0.10*# |
The data are expressed as mean ± SD and analyzed by a Two-way ANOVA test
*P < 0.0001 as compared to the baseline of the same group; #P < 0.05 as compared to the ferrous ascorbate, ferrous fumarate, and ferrous bis-glycinate at day 90; $P < 0.05 as compared to the baseline of the same group; @P < 0.05 as compared to the ferrous bis-glycinate at day 90; ^P < 0.05 as compared to the baseline of the same group; &P < 0.05 as compared to the baseline of the same group
RBC Red blood cells, PCV Packed cell volume, MCV Mean corpuscular volume, MCH Mean corpuscular hemoglobin, MCHC Mean corpuscular hemoglobin concentration, RDW Red cell distribution width, TLC Total leukocyte count, PLT Platelets, Hb Hemoglobin
Mean hemoglobin levels at baseline in group I, II, III, and IV were 9.88 ± 0.08, 9.87 ± 0.10, 9.99 ± 0.09, and 9.96 ± 0.08 g/dl respectively. A complete blood count profile assessed at the end of 3 months revealed significant improvement in hematological parameters in patients receiving different oral iron supplements. Hemoglobin levels were significantly increased in the ferrous ascorbate group (11.86 ± 0.09; P < 0.0001), ferrous fumarate group (11.72 ± 0.08; P < 0.0001), ferrous bis-glycinate group (11.69 ± 0.11; P = 0.0003) and Sucrosomial iron (12.20 ± 0.1; P < 0.0001) compared to the baseline (Fig. 1). The Sucrosomial iron receiving group showed higher improvement in hemoglobin levels compared to conventional oral iron salts such as the ferrous ascorbate group, ferrous fumarate group, and ferrous bis-glycinate group (P < 0.05).
Fig. 1.
Hemoglobin levels on baseline and day 90. The data are expressed as mean ± SD and analyzed by a Two-way ANOVA test. *P < 0.0001 as compared to the baseline of the same group; #P < 0.05 as compared to the ferrous ascorbate, ferrous fumarate, and ferrous bis-glycinate at day 90
Serum ferritin levels were significantly increased on day 90 in the ferrous ascorbate group (37.86 ± 6.90; P = 0.0016) and Sucrosomial iron group (38.46 ± 6.56; P < 0.0001); but not in the ferrous fumarate group (33.91 ± 5.96) and ferrous bis-glycinate group (35.41 ± 9.20) compared to the baseline as shown in Fig. 2. The Sucrosomial iron receiving group showed higher improvement in serum ferritin levels compared to conventional oral iron salts such as the ferrous ascorbate group (P = 0.0057), ferrous fumarate group (P = 0.0003), and ferrous bis-glycinate group (P < 0.0001).
Fig. 2.
Serum ferritin levels on baseline and day 90. The data are expressed as mean ± SD and analyzed by a Two-way ANOVA test. *P < 0.0001 as compared to the baseline of the same group; &P = 0.0016 as compared to the baseline of the same group; #P < 0.0001 as compared to the ferrous bis-glycinate at day 90; $P = 0.0003 as compared to the ferrous fumarate at day 90; @P = 0.0057 as compared to the ferrous ascorbate at day 90
Serum iron levels were significantly increased on day 90 in the ferrous ascorbate group (49.86 ± 13.36; P < 0.0001), ferrous fumarate group (42.55 ± 13.73; P = 0.0015), and Sucrosomial iron group (60.93 ± 16.27; P < 0.0001); but not in the ferrous bis-glycinate group (42.55 ± 13.73) compared to the baseline as shown in Fig. 3. The Sucrosomial iron receiving group showed higher improvement in serum iron levels compared to conventional oral iron salts such as the ferrous ascorbate group (P = 0.0057), ferrous fumarate group (P = 0.0003), and ferrous bis-glycinate group (P < 0.0001).
Fig. 3.
Serum iron levels on baseline and day 90. The data are expressed as mean ± SD and analyzed by a Two-way ANOVA test. *P < 0.0001 as compared to the baseline of the same group; #P = 0.0015 as compared to the baseline of the same group; $P = 0.0057 as compared to the ferrous ascorbate at day 90; @P = 0.0003 as compared to the ferrous fumarate at day 90; &P < 0.0001 as compared to the ferrous bis-glycinate at day 90
Total iron binding capacity (TIBC) was significantly decreased on day 90 in the ferrous ascorbate group (275.72 ± 28.58; P < 0.0001), ferrous fumarate group (282.41 ± 27.62; < 0.0001), ferrous bis-glycinate group (275.14 ± 25.13; P < 0.0001) and Sucrosomial iron group (254.39 ± 28.68; P < 0.0001) compared to the baseline as shown in Fig. 4. The Sucrosomial iron receiving group showed a higher reduction in TIBC compared to conventional oral iron salts such as the ferrous ascorbate group (P = 0.0013), ferrous fumarate group (P < 0.0001), and ferrous bis-glycinate group (P = 0.0053).
Fig. 4.
TIBC levels on baseline and day 90. The data are expressed as mean ± SD and analyzed by a Two-way ANOVA test. *P < 0.0001 as compared to the baseline of the same group; #P = 0.0013 as compared to the ferrous ascorbate at day 90; $P < 0.0001 as compared to the ferrous fumarate at day 90; &P = 0.0053 as compared to the ferrous bis-glycinate at day 90
Transferrin saturation (TSAT) (%) was significantly increased on day 90 in the ferrous ascorbate group (36.79 ± 6.74; P < 0.0001), ferrous fumarate group (37.00 ± 6.27; < 0.0001), ferrous bis-glycinate group (36.55 ± 6.42; P < 0.0001) and Sucrosomial iron group (42.71 ± 7.88; P < 0.0001) compared to the baseline as shown in Fig. 5. The Sucrosomial iron receiving group showed higher improvement in TSAT (%) compared to conventional oral iron salts such as the ferrous ascorbate group (P = 0.0026), ferrous fumarate group (P < 0.0111), and ferrous bis-glycinate group (P = 0.0042).
Fig. 5.
Transferrin saturation (TSAT) (%) on baseline and day 90. The data are expressed as mean ± SD and analyzed by a Two-way ANOVA test. * P < 0.0001 as compared to the baseline of the same group; # P = 0.0026 as compared to the ferrous ascorbate at day 90; $ P < 0.0111 as compared to the ferrous fumarate at day 90; & P = 0.0042 as compared to the ferrous bis-glycinate at day 90
Effectiveness of iron supplements on secondary evaluation parameters
The most common adverse effects that occurred with all iron supplements were gastric irritation, bloating, nausea & and vomiting, and abdominal pain. A total of 52 patients reported gastrointestinal side effects as shown in Table 3. Out of a total of 94 adverse drug reactions reported, 88 reactions (93.62%) showed a possible association and 6 adverse drug reactions had a probable association (6.38%) with the drug as assessed by the Naranjo scale. A total of 11 patients (16.92% patients) reported 18 gastrointestinal side effects in the ferrous ascorbate group, 20 patients (30.77% patients) reported 36 gastrointestinal side effects in the ferrous fumarate group, 15 patients (23.07% patients) reported 27 gastrointestinal side effects in the ferrous bis-glycinate group, and 6 patients (9.23% patients) reported 9 gastrointestinal side effects in Sucrosomial iron group as shown in Table 4. Sucrosomial iron-receiving patients reported the least gastrointestinal side effects than other oral iron supplements.
Table 3.
Adverse events were reported in different iron-supplemented groups at Day 90 (± 1 week)
| Parameters | Ferrous ascorbate | Ferrous fumarate | Ferrous bis-glycinate |
Sucrosomial iron |
|---|---|---|---|---|
| Gastric irritation | 6 | 9 | 7 | 4 |
| Bloating | 2 | 4 | 4 | 1 |
| Constipation | 0 | 0 | 0 | 0 |
| Nausea & Vomiting | 3 | 5 | 3 | 1 |
| Diarrhea | 0 | 0 | 0 | 0 |
| Abdominal pain | 0 | 2 | 1 | 0 |
| Blackish discoloration of stools | 0 | 0 | 0 | 0 |
| Total no. of patients reporting adverse events | 11 | 20 | 15 | 6 |
Table 4.
Distribution of cases according to the number of side effects
| Treatment | Patient with 1 Side effect | Patient with 2 Side effects | Patient with 3 Side effects | Patient with 4 Side effects | Total number of patients with Side effects | Total no. of Side effects |
|---|---|---|---|---|---|---|
| Ferrous ascorbate | 6 | 3 | 2 | 0 | 11 (16.92%) | 18 |
| Ferrous fumarate | 9 | 5 | 4 | 2 | 20 (30.77%) | 39 |
| Ferrous bisglycinate | 7 | 4 | 3 | 1 | 15 (23.07%) | 28 |
| Sucrosomial iron | 4 | 1 | 1 | 0 | 6 (9.23%) | 9 |
Discussion
Iron deficiency is the most prevalent dietary deficiency in the world. Iron deficiency is associated with reduced size and number of red blood cells. Iron depletion, which causes no physiological defects, and iron deficiency anemia, which compromises the operation of several organ systems, are two different types of iron deficiency. Ceruloplasmin, Divalent metal transporter 1 (DMT-1), hepcidin, and hephaestin are proteins that are crucial for both iron absorption from the gut and iron efflux from enterocytes [14, 20]. The current study assessed the comparative hematinic potential of Sucrosomial iron to that of conventional oral iron salts in routine clinical practice. The findings of the present retrospective observational clinical study for the management of iron deficiency anemia validate the findings observed in the previous pre-clinical studies. The present study showed significant improvement in hemoglobin levels in all iron-supplemented groups, interestingly, the Sucrosomial iron receiving group showed significantly higher improvement in hemoglobin levels compared to all other conventional oral iron salts such as the ferrous ascorbate group, ferrous fumarate group, and ferrous bis-glycinate group (P < 0.05). All oral iron supplements showed significant improvement in other hematological parameters such as PCV, MCV, MCHC, and RBC count without any significant group difference. However, the Sucrosomial iron group showed marginally higher improvement in all assessed hematological parameters compared to other conventional oral iron salts. Additionally, the Sucrosomial iron group showed significantly higher improvement in iron store indices such as serum ferritin levels, TIBC, and TSAT (%) compared to conventional oral iron salts. The Sucrosomial iron supplement has comparatively less elemental iron (30 mg) content than other oral iron supplements. Therefore, these higher improvements in hematological parameters in the Sucrosomial group may be due to its higher absorption and bioavailability through transcellular, paracellular, and M-cells in the small intestine as reported in in-vivo studies [14, 16]. In addition, the utilization of iron from Sucrosomial iron is independent of hepcidin, a key controlling factor responsible for iron absorption and utilization [16]. A study conducted by Bumrungpert A et al. (2022) found a significantly higher increase in serum iron levels with ferrous bis-glycinate (equivalent to elemental iron 24 mg) in supplement form with folinic acid and multivitamins compared to ferrous fumarate (equivalent to elemental iron 66 mg) during the bioavailability assessment (p < 0.001). the ferrous bis-glycinate also showed numerically higher improvement in Hb, erythrocytes, reticulocytes, MCV, MCH, MCHC, %TSAT, and ferritin levels at 3 and 6 months than ferrous fumarate. Additionally, the ferrous bis-glycinate was found to have lesser side effects such as nausea, abdominal pain, bloating, constipation, or metallic taste than the ferrous fumarate group (p < 0.001). Similarly, in the present study, ferrous bis-glycinate was associated with lesser side effects than the ferrous fumarate group; however, the improvement in hematological parameters was similar in both groups in the present study. Studies have also reported therapeutic equivalence between 30 mg of ferrous bis-glycinate and 120 mg of ferrous sulfate in preventing IDA [24]. A study conducted by Patil SS et al. (2014) found a significant increase in hemoglobin levels in women of reproductive age group with carbonyl iron, ferrous bis-glycinate, and ferrous fumarate without any significant group difference among the groups. However, contrary to the previous study, ferrous fumarate increased serum ferritin levels more than carbonyl iron and ferrous bis-glycinate. In agreement with the previous study, the ferrous fumarate supplementation was associated with a higher incidence of side effects (epigastric pain, nausea & vomiting) [25]. Contrary to the previous studies, the study conducted by Panicker NK et al. (2016) found that ferrous fumarate, ferrous calcium citrate, ferrous sulfate, and ferric ammonium citrate significantly improved the mean hemoglobin and anemia indices without any significant group difference. All iron supplements showed similar gastrointestinal side effects profiles without any significant difference [26]. Similarly, the study conducted by Chavan S et al. (2021) found equal therapeutic efficacy in terms of improving hemoglobin levels with ferrous sulfate, ferrous ascorbate, and iron hydroxide poly-maltose complex in pregnant women with moderate IDA in India [27]. These results suggest that almost all conventional oral iron salts have equal therapeutic efficacy and side effect profiles. However, in disagreement with these results, a study conducted by Gupta N et al. (2020) found a significantly higher increase in hemoglobin levels and serum ferritin levels in gynecological and post-natal patients in India with ferrous ascorbate (elemental iron 100 mg/day) compared to ferrous sulfate (elemental iron 100 mg/day), ferrous fumarate (elemental iron 98.6 mg/day), colloidal iron (elemental iron 50 mg/ml), and ferric ammonium citrate (elemental iron 15 mg/ml) [28]. In agreement with these results, the ferrous ascorbate group was found to have numerically higher improvement in hematological parameters than the ferrous bis-glycinate and ferrous fumarate group but not compared to the Sucrosomial iron group. In agreement with our study results, a recent clinical trial conducted by Helal KF et al. (2023) reported a significantly higher improvement in complete blood count (CBC) findings, ferritin, iron, and TIBC with Sucrosomial iron therapy (elemental iron 30 mg) compared to the ferrous bis-glycinate therapy (elemental iron 27 mg) in anemic pregnant women. Additionally, side effects such as epigastric discomfort, nausea and vomiting, constipation, and metallic taste were reported with the ferrous bis-glycinate therapy but not with the Sucrosomial iron therapy [29]. Moreover, a study conducted by Parisi F et al. (2017) in 80 healthy pregnant women found that the Sucrosomial iron (elemental iron 14 mg and 28 mg) receiving group reported significantly higher improvement in hemoglobin and ferritin levels compared with the ferrous sulfate group (elemental iron 30 mg) [30]. In agreement with these results, the present retrospective observational clinical study revealed Sucrosomial iron to be more effective in terms of improving hemoglobin levels and iron store indices than ferrous ascorbate, ferrous fumarate, and ferrous bis-glycinate. A study conducted by Elli A, et al. (2018) found significant improvement in hemoglobin levels with Sucrosomial iron (elemental iron 30 mg) and ferrous sulfate (elemental iron 105 mg) supplementation for 3 months in celiac patients with iron deficiency anemia. Importantly, the Sucrosomial iron group reported lower severity of gastrointestinal side effects such as abdominal pain and bloating, constipation than the ferrous sulfate group and also showed higher improvement in quality of life [31]. A clinical study conducted by Singhal SR et al. (2015) found that ferrous fumarate was associated with maximum gastrointestinal side effects followed by ferrous sulfate, ferrous bis-glycinate, ferrous ascorbate, and sodium feredetate [32]. In agreement with these results, in the present study, Sucrosomial iron was found to be associated with the least gastrointestinal side effects followed by ferrous ascorbate, ferrous bis-glycinate, and ferrous fumarate. This favorable tolerability profile of Sucrosomial iron may be due to the presence of a gastro-resistant Sucrester layer surrounding the ferric pyrophosphate (iron) core. These phospholipid bilayers surrounded by the Sucrester layer not only protect the gastrointestinal lining from the harmful effects of labile iron but also enhance its intestinal absorption, thus reducing dosage and side effects [14]. The present retrospective observational clinical study revealed Sucrosomial iron as the most efficacious oral iron supplement in improving hematological profile and iron indices parameters with excellent tolerability profile than other oral iron salts in patients with iron deficiency anemia [33]. In addition to iron, hematopoiesis requires a sufficient amount of folic acid and vitamin B12 for RBCs production. Folic acid and vitamin B12 are also reported to improve iron deficiency anemia than iron supplementation alone [34, 35]. Therefore, the improved benefits reported in the Sucrosomial iron group might be due to the beneficial effect of other nutrients such as L-methyl folate (Bioactive form of folic acid), and vitamin B12 present in the formulation. The present study has certain limitations, such as the retrospective design of the study, smaller sample size, and treatment for a short period. Therefore, the present study results cannot be generalized to the entire population. Hence, further randomized, blind clinical studies with larger sample sizes and for a longer duration period are warranted. Additionally, the observational study primarily focused on the hematological parameters but did not evaluate the effect on red blood cell morphology which needs to be addressed by conducting further clinical studies.
Conclusion
The present retrospective observational clinical study showed the significant potential of Sucrosomial iron for improving hematological parameters and iron store indices parameters along with a good tolerability profile compared to other conventional oral iron salts. Sucrosomial iron with folic acid and vitamin B12 as a multivitamin supplement possesses good hematinic potential with comparatively better effectiveness and tolerability with a lower elemental iron dosage. Further randomized clinical studies in a large number of patients are warranted to assess the hematinic potential in patients with iron deficiency anemia.
Acknowledgements
Nil.
Authors’ contributions
MS-Design of study, Concept, Implementation of the study protocol, Manuscript preparation and Submission of the article, Manuscript review.
PT- Design of study, Concept, Implementation of the study protocol, Manuscript preparation and Submission of the article, Manuscript review.
Funding
Nil.
Data availability
Data will be available on request based on requirements.
Declarations
Ethics approval and consent to participate
The observational study plan 2021-IDA-001 was approved by the ACEAS independent ethics committee, Ahmedabad. Consent for participation was taken.
Consent for publication
Consent for publication was taken.
Competing interests
There is no conflict of interest among the authors.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
Data will be available on request based on requirements.