Which iron supplement is better tolerated by patients, ferrous sulfate or ferric citrate?

Which Iron Supplement is Better Tolerated?

Ferric maltol demonstrates the best tolerability profile with GI side effects comparable to placebo, while ferrous sulfate—though the most cost-effective first-line option—causes significantly more gastrointestinal side effects than placebo or IV iron. 1

Tolerability Hierarchy Based on Evidence

Best Tolerated: Ferric Maltol

• GI side effects and treatment cessation rates were comparable to placebo in patients with inactive IBD and moderate iron deficiency anemia 1
• In 12-week trials, ferric maltol normalized hemoglobin in 63-66% of cases with excellent tolerability 1
• The primary limitation is cost (£47.60 vs £1.00 for 28-day supply of ferrous sulfate), making it considerably more expensive than traditional iron salts 1

Standard First-Line: Ferrous Sulfate

• Ferrous sulfate significantly increases risk of GI side effects with an odds ratio of 2.32 versus placebo [95% CI 1.74-3.08, p<0.0001] and OR of 3.05 versus IV iron [95% CI 2.07-4.48, p<0.0001] 2
• Despite higher side effect rates, ferrous sulfate remains the gold standard due to cost-effectiveness and efficacy 1, 3
• The American College of Gastroenterology notes that no single formulation has proven advantages over others in terms of tolerability 4

Alternative Ferrous Salts

When comparing different oral iron formulations in a systematic review of 10,695 patients:

• Ferrous sulfate with mucoproteose had the lowest incidence of adverse effects (4.1% overall AEs, 3.7% GAEs) 5
• Ferrous fumarate had the highest incidence (47.0% overall AEs, 43.4% GAEs; OR: 19.87 compared to reference) 5
• Standard ferrous sulfate without mucoproteose: 32.3% overall AEs, 30.2% GAEs (OR: 11.21) 5
• Ferrous gluconate: 30.9% overall AEs, 29.9% GAEs (OR: 11.06) 5
• Iron protein succinylate: 7.3% overall AEs, 7.0% GAEs (OR: 1.96) 5

Comparing Ferrous vs Ferric Formulations

A head-to-head comparison found ferrous formulations more effective but with slightly higher GI side effects than ferric formulations 6:

• Blood test values improved significantly after switching from ferric to ferrous iron (p<0.01) 6
• However, ferric products generally have lower absorption rates 7
• One study found ferrous fumarate with ascorbic acid significantly more effective than ferric polysaccharide complex, with only slightly higher GI side effects 7

Critical Dosing Strategy to Improve Tolerability

Once-daily dosing of 50-100 mg elemental iron is recommended rather than multiple daily doses 1, 4:

• Short-term studies show that 60 mg elemental iron stimulates hepcidin levels, reducing subsequent iron absorption by 35-45% 1
• Overall absorption from 60 mg once daily was similar to 60 mg twice daily 1
• Alternate-day dosing leads to significantly increased fractional iron absorption compared to daily dosing in iron-depleted individuals 1, 4

Strategies to Minimize Side Effects

Timing and Co-Administration

• Taking iron with 250-500 mg vitamin C enhances absorption by forming a chelate with iron 4, 8
• Iron should be taken on an empty stomach to maximize absorption, though this increases GI side effects 4
• If GI side effects are intolerable, taking iron with food improves tolerability but decreases absorption 8

What to Avoid

• Avoid tea or coffee within an hour of iron intake (coffee decreases absorption by 54%) 8
• Avoid calcium-containing foods or medications with iron 4
• Modified-release preparations are indicated as "less suitable for prescribing" by the British National Formulary 1

Clinical Algorithm for Iron Selection

Start with ferrous sulfate 200 mg once daily (65 mg elemental iron) on an empty stomach 1, 4:

1. If intolerable GI side effects develop:

   • Try taking with food (accept reduced absorption for improved adherence) 8
   • Consider alternate-day dosing 1, 4
   • Switch to ferrous sulfate with mucoproteose (if available) 5

2. If still not tolerated:

   • Consider ferric maltol for patients with previous intolerance to traditional iron salts 1
   • Consider IV iron for patients intolerant or refractory to oral iron 4, 3

3. Monitor response:

   • Expect hemoglobin rise of at least 10 g/L after 2 weeks (sensitivity 90.1%, specificity 79.3% for adequate response) 1
   • Absence of this response strongly predicts treatment failure 1

Important Caveats

Meta-regression did not find a relationship between iron dose and GI side effects, suggesting that side effects are inherent to the formulation rather than dose-dependent 2. This finding supports once-daily dosing strategies that maximize absorption while minimizing exposure frequency 1.

The marked heterogeneity in tolerability data (particularly in pregnant women, I² = 66.1%) suggests individual patient factors play a significant role 2, but the overall trend consistently favors ferric maltol for tolerability and ferrous sulfate for cost-effectiveness 1, 5.