What clinical trials support the efficacy of ferrous sulfate versus heme iron in improving hemoglobin and ferritin levels?
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Executive summary
Recent randomized trials and a 2024–25 systematic review show limited, mixed evidence that heme iron polypeptide (HIP) is superior to ferrous sulfate for raising hemoglobin and ferritin: a large Gambian RCT (n=208) found no benefit on the co‑primary endpoints hemoglobin and ferritin after 12 weeks but reported superiority of HIP on five secondary iron‑status measures [1] [2]. A 2024 meta‑analysis concluded heme may have greater impact than non‑heme iron but rated overall certainty of evidence as very low and highlighted ongoing trials including the Gambian HIP vs ferrous salts study [3] [4].
1. The biggest direct head‑to‑head trial: Gambian infants
A double‑blind, randomized, supervised supplementation trial in rural Gambia randomized 208 anemic infants (6–12 months) to 84 days of 10 mg elemental iron daily as HIP versus the same dose as ferrous sulfate; the trial’s primary outcomes were end‑of‑intervention hemoglobin and serum ferritin [2]. Study reports state HIP did not improve those primary endpoints compared with ferrous sulfate, although investigators found HIP superior on five secondary iron‑status measures and framed those secondary results as potentially relevant to rapidly developing organs [1] [2].
2. Systematic review and the state of the evidence
A December 2024 systematic review and meta‑analysis of randomized trials concluded bioavailability and observational data suggest heme iron may more strongly affect iron status indicators than non‑heme iron, but the authors judged the certainty of clinical evidence as very low and identified only a small number of RCTs — including one ongoing HIP vs ferrous salts trial in Gambian infants — underscoring the need for higher‑quality trials [3] [4].
3. Other randomized comparisons: ferrous salts vs alternative formulations
Multiple randomized trials compare ferrous sulfate with other non‑heme formulations (e.g., ferric polysaccharide, iron polysaccharide complex). For example, an 80‑patient pediatric RCT found ferrous sulfate produced greater hemoglobin increases over 12 weeks than ferric polysaccharide preparations; a separate JAMA trial (Powers et al.) compared low‑dose ferrous sulfate to iron polysaccharide complex in young children [5] [6] [7]. These trials show ferrous salts often perform as well or better than some non‑heme alternatives in hemoglobin response.
4. Trials in adults and special populations show mixed results
Smaller RCTs and trials in dialysis or peritoneal dialysis patients report variable findings: some showed similar hemoglobin responses between HIP and ferrous salts while others reported higher ferritin with ferrous sulfate or no advantage to HIP — and cost and tolerability differences were noted [8] [9] [10]. The HEMATOCRIT protocol and other PD studies highlight ongoing interest but also underline heterogeneity in doses, populations and endpoints [9].
5. Key limitations and why conclusions remain uncertain
Available randomized evidence is constrained by small sample sizes, heterogeneous populations (infants, dialysis patients, pregnant women), variable elemental iron doses between arms, and reliance on secondary endpoints or surrogate markers [10] [4] [8]. The systematic review explicitly states the evidence certainty is very low and calls for higher‑quality RCTs [4]. The Gambian RCT, while larger and directly comparative, found no difference for primary hemoglobin/ferritin endpoints — weakening a simple claim that HIP is superior [1] [2].
6. Practical implications for clinicians and policymakers
Current trials do not support a clear, generalizable superiority of HIP over ferrous sulfate for raising hemoglobin and ferritin across populations. Ferrous sulfate continues to show consistent efficacy against several non‑heme preparations in randomized studies and remains a standard treatment, while HIP may offer benefits on secondary iron metrics or tolerability in some settings but at higher cost; decisions should weigh local anemia etiology, inflammation/hepcidin prevalence, cost and supply [5] [8] [2].
7. How future trials should be designed
The literature and review authors call for larger, well‑powered RCTs with standardized elemental iron dosing, prespecified primary hematologic endpoints (hemoglobin, ferritin), longer follow up, and stratification by inflammation/hepcidin status — the Gambian trial is a step in that direction but secondary‑endpoint findings require confirmation [11] [4] [2].
Limitations of this briefing: I used only the provided sources; available sources do not mention long‑term clinical outcomes (neurodevelopment, functional status) from HIP versus ferrous sulfate and do not settle cost‑effectiveness across settings (not found in current reporting).