# Erythropoietic response to oral iron with sodium-glucose co-transporter 2 inhibitors

Pedro Marques¹,²,³ Ⓓ Paula Matias¹ · Christoforos K. Travlos⁴ · António Angélico-Gonçalves²,⁵ · Hugo Diniz⁶ ·

Francisco Vasques-Nóvoa¹,² · Milton Packer⁷,⁸ · Fernando Friões¹,⁹ · Michael A. Tsoukas¹⁰ · Thomas A. Mavrakanas⁴ ·

Abhinav Sharma³ · João Pedro Ferreira²,¹¹

Received: 24 February 2025 / Accepted: 17 May 2025

© The Author(s) 2025

## Abstract

**Background** Anemia and iron deficiency are common in heart failure (HF) and chronic kidney disease (CKD). These conditions are associated with upregulation of hepcidin, which impairs the enteric absorption of iron, limiting the use of oral iron formulations in these populations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are associated with enhanced erythropoiesis and have been shown to augment the erythropoietic response to intravenous iron. The effect of baseline SGLT2i therapy in the erythropoietic response following oral iron supplementation is currently not known.

**Objectives** To compare the erythropoietic response to oral iron supplementation in patients with HF or CKD, using and not using SGLT2i as background therapy.

**Methods** This is a retrospective analysis of ambulatory patients with HF or CKD followed in cardio-kidney-metabolic clinics from a quaternary care hospital in Canada and a tertiary care hospital from Portugal. An age- and sex-matched population of patients using (n=76) and not using (n=76) a SGLT2i was compared for changes in hemoglobin and hematocrit following oral iron supplementation. Secondary outcomes included changes in iron biomarkers, natriuretic peptides and kidney function.

**Results** Overall, the mean age was 75±9 years, 49% were men, 119 (78%) had CKD, 107 (70%) HF, and 113 (74%) had anemia. After adjustment for baseline differences, SGLT2i users experienced a greater increase in hemoglobin and hematocrit compared to SGLT2i non-users: hemoglobin +0.80 g/dL (95% confidence interval [CI] 0.39–1.21 g/dL, *p* < 0.001); hematocrit +3.0% (95% CI 1.0–4.0%, *p* < 0.001). No significant differences on iron biomarkers or any of the secondary outcomes were found between the groups.

Pedro Marques and Paula Matias equally contributed to this work.

Abhinav Sharma and João Pedro Ferreira equally contributed as senior authors to this work.

☑ Pedro Marques
pedromsmarq@gmail.com

☑ João Pedro Ferreira
jpferreira@med.up.pt

¹ Internal Medicine Department, Unidade Local de Saúde de São João, Porto, Portugal

² Department of Surgery and Physiology, Cardiovascular Research and Development Center (UnIC@RISE), Faculty of Medicine of the University of Porto, Porto, Portugal

³ Division of Cardiology, McGill University Health Centre, Montreal, QC, Canada

⁴ Division of Nephrology, McGill University Health Centre, Montreal, QC, Canada

⁵ Cardiology Department, Unidade Local de Saúde de Gaia e Espinho, Vila Nova Gaia, Portugal

⁶ Nephrology Department, Unidade Local de Saúde de São João, Porto, Portugal

⁷ Baylor University Medical Center, Dallas, TX, USA

⁸ Imperial College, London, UK

⁹ Department of Medicine, Faculty of Medicine of the University of Porto, Porto, Portugal

¹⁰ Division of Endocrinology, McGill University Health Centre, Montreal, QC, Canada

¹¹ Inserm, Centre d'Investigations Cliniques, - Plurithématique 14-33, Inserm U1116, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Université de Lorraine, CHRU Nancy, Nancy, France
**Conclusions** Oral iron supplementation in patients with background therapy including a SGLT2i (vs. SGLT2i non-users) was associated with a greater increase in hemoglobin and hematocrit. These results suggest that patients with HF or CKD patients treated with SGLT2i might have an enhanced erythropoietic response to oral iron supplementation.

**Graphical Abstract**

<figure><img src="image_1.png" /></figure>

**Central illustration** - Potential mechanisms underlying the enhanced erythropoietic effect of oral iron supplementation in patients with heart failure and chronic kidney disease chronically treated with sodium-glucose co-transporter 2 inhibitors. Heart failure and chronic kidney disease are characterized by an inflammatory state resulting in the upregulation of hepcidin, limiting iron gut absorption (A). Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been shown to upregulate erythropoietin, transferrin receptor 1 protein and potentially erythroferrone, while inhibiting pro-inflammatory biomarkers (IL-6, ferritin and hepcidin). Together, these actions result in an increased erythropoietic response following SGLT2i initiation (B). In patients chronically treated with SGLT2i (vs SGLT2i non-users), initiation of oral iron supplementation resulted in an increased erythropoietic response without impacting the levels of serum iron biomarkers. These effects are potentially related to an enhanced oral iron absorption and iron utilization in SGLT2i-treated patients (C). CKD, chronic kidney disease; Fe, iron biomarkers; Hb, hemoglobin; Htc, hematocrit; HF, heart failure; SGLT2i, sodium-glucose co-transporter 2 inhibitor; TfR1, transferrin receptor 1 protein

**Keywords** Anemia · Iron deficiency · Heart failure · Chronic kidney disease · Oral iron · SGLT2i

**Abbreviations**

<table><tr><td>CKD</td><td>Chronic kidney disease</td></tr><tr><td>CKM</td><td>Cardio-kidney-metabolic</td></tr><tr><td>eGFR</td><td>Estimated glomerular filtration rate</td></tr><tr><td>HF</td><td>Heart failure</td></tr><tr><td>HFrEF</td><td>Heart failure with reduced ejection fraction</td></tr><tr><td>IRONOUT-HF</td><td>Iron-repletion effects On Oxygen UpTake in Heart Failure</td></tr><tr><td>SGLT2i</td><td>Sodium-glucose co-transporter 2 inhibitor</td></tr><tr><td>TfR1</td><td>Transferrin receptor protein 1</td></tr><tr><td>TSAT</td><td>Transferrin saturation</td></tr></table>

**Background**

Anemia and iron deficiency are common in heart failure (HF) or chronic kidney disease (CKD) as these conditions are characterized by a chronic inflammatory state that upregulates ferritin and hepcidin resulting in a functional, rather than absolute, iron-deficiency state [1–3]. Upregulation of hepcidin, in particular, impairs the enteric absorption of iron, limiting the effectiveness of oral iron formulations in these patient populations [4].

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve the prognosis of patients with HF and CKD [5–7]. SGLT2i increases erythrocytosis through multiple mechanisms including the downregulation of inflammatory mediators and the activation of hypoxia-inducible factor 2 alpha signaling pathways, increasing erythropoietin
[8–11]. Post hoc analyses from major placebo-controlled trials have consistently shown that SGLT2i treatment increases erythropoietin and soluble transferrin receptor levels, while reducing hepcidin and ferritin [12–14]. Together, these changes result in enhanced erythropoiesis and increased iron absorption and mobilization.

While the concomitant use of SGLT2i in patients with HF with reduced ejection fraction (HFrEF) treated with intravenous iron has been shown to enhance the erythrocytosis effect of these drugs comparing to SGLT2i non-users, it is unclear whether a similar response is observed in patients treated with oral iron [15].

To clarify this, we aim to compare the erythropoietic response to oral iron supplementation in a group of patients with HF or CKD, using and not using SGLT2i as background therapy. We hypothesize that SGLT2i use (vs no use) will provide a greater increase in hemoglobin and hematocrit following treatment with oral iron.

## Methods

We performed a retrospective analysis of ambulatory patients with HF or CKD with iron deficiency supplemented with oral iron. We focused on a population with chronic HF or CKD as these conditions are associated with a systemic pro-inflammatory environment known to impact oral iron absorption [3]. For that, we chart-reviewed patients previously evaluated in cardio-kidney-metabolic (CKM) clinics from the McGill University Health Centre (MUHC), a quaternary care hospital in Montreal, Canada, and *Unidade Local de Saúde de São João* (ULS-SJ), a tertiary care hospital in Porto, Portugal. From the MUHC, we retrospectively analyzed (from October 2023 to October 2024) data from the DECIDE-CV clinic, a synchronous care CKM clinic for patients with type 2 diabetes [16], the G4 registry, a prospective cohort study of patients with stage 4 CKD, and patients evaluated in cardiovascular and renal clinics. From the ULS-SJ, we retrospectively analyzed patients evaluated in the HF and CKD outpatient clinics from October 2023 to October 2024. Ethical approval was granted by the local etics boards (MUHC: study number 2022-8183; 2022-7791).

From the aforementioned registries and clinics, we identified patients treated with oral iron and, using local prescription records, confirmed the date of initiation of oral iron and SGLT2i. Only those with prescription records covering at least 3 months of oral iron treatment were included. Patients were then divided into two different groups according to the presence or absence of background treatment with a SGLT2i at the moment of oral iron initiation. To be included in the SGLT2i group, the patient had to be prescribed any of the SGLT2i within the 3 months preceding the baseline laboratory data collection. Patients were required to have taken

SGLT2i for at least 90 days before the start of oral iron supplementation to account for the known erythropoietic effect that follows the initiation of these medications [17]. Those who initiated treatment with an SGLT2 inhibitor during oral iron supplementation were excluded. Other exclusion criteria included: (1) concomitant use of intravenous iron, erythropoietin-stimulating agents, red blood cell units or other blood products in the analyzed timeframe; (2) relevant intercurrent illnesses known to be associated with an inflammatory response, such as infections, acute kidney injury or acute decompensated HF, during the analyzed timeframe; (3) patients with confirmed or suspected active bleeding; (4) patients with end-stage renal disease or receiving renal replacement therapy; (5) history of any type of active cancer, and (6) history of solid or non-solid organ transplantation.

Based on a sample size calculation (see below), retrospective chart review was conducted until an age- and sex-matched sample of 76 patients per group was reached.

Previous medical history and concomitant medications were collected from the selected population. The first available laboratory data, including complete blood count (hemoglobin, hematocrit) and iron biomarkers (total iron, ferritin and transferrin saturation [TSAT]), dating up to 6 months before and 3–6 months after oral iron initiation, was used for the analysis.

The 3-month period post-oral iron initiation was defined based on data from randomized clinical trials that analyzed the hemoglobin response following oral iron initiation in patients with CKD [18]. The investigator responsible for laboratory data collection was blinded for the treatment allocation group.

## Outcomes

The primary outcome was the magnitude of change in hemoglobin (before vs. after oral iron administration) between SGLT2i users and non-users. Secondary outcomes included changes in hematocrit, iron biomarkers (total iron, ferritin and TSAT), natriuretic peptides, inflammatory biomarkers and kidney function (creatinine and estimated glomerular filtration rate [eGFR] using the CKD-EPI 2021 equation [19]).

## Sample size calculation

A random sample of 152 patients (76 patients per group) was estimated to attain an 80% probability of detecting, as significant at the 5% level, an increase in hemoglobin of 0.5 g/dL on average in patients treated with oral iron alone vs a 1.0 g/dL average hemoglobin increase in patients treated with oral iron plus a SGLT2i, with a standard deviation of change of 1.1 g/dL.
## Statistical analysis

Categorical variables were described as frequencies (proportions) and continuous variables as mean ± standard deviation or median (interquartile range [IQR]), depending on their distributions. Changes in the primary and secondary outcomes were compared between SGLT2i users and non-users by linear regression with SGLT2i use as independent variable adjusted on all the significant inter-group differences (a history of heart failure and atrial fibrillation, a baseline treatment with an angiotensin receptor/neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, anti-platelet or oral anticoagulant agents at baseline, type of oral iron formulation used and baseline eGFR, i.e., *P* < 0.05 in Table 1) plus the baseline value of the variable being studied. Variable transformations (e.g., log transformation) were applied as needed to meet the model's requirements. Both B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NTproBNP) levels were described, given different natriuretic peptides were available in the two centers analyzed. Total iron load was calculated by multiplying the daily elemental iron dose available in the different oral iron formulations by the number of days spanning from the oral iron initiation date to the post-oral iron laboratory results. In addition, a non-pre-specified, exploratory subgroup analysis among relevant comorbidities was performed to assess the effects of SLGT2i use (vs SGLT2i non-users) following oral iron initiation on hemoglobin change. A *p* value < 0.05 was used for statistical significance, except for the interaction test where the considered *p* value was < 0.10. All statistical analyses were performed with Stata® (StataCorp. 2021: Release 17.0.).

## Results

From 2892 patients with HF and/or CKD identified from chart review, 240 were prescribed oral iron (Fig. 1). From those, 152 patients were included in our analysis (76 SGLT2i non-users and 76 SGLT2i users). Main exclusion criteria were intercurrent illnesses during the analyzed timeframe (*n* = 32) and prescription records covering less than 3 months of oral iron therapy (*n* = 21).

The median time of the laboratory results before oral iron initiation was 16 (IQR 6–38) days and did not differ between SGLT2i non-users and SGLT2i users: 20 (IQR 6–37) days vs 14 (IQR 6–43) days, *p* = 0.80. Likewise, median time from oral iron initiation to follow-up laboratory results did not differ between groups: 112 (IQR 97–150) days in SGLT2i non-users vs 116 (IQR 99–146) days in SGLT2i users, *p* = 0.61. Patients allocated to the SGLT2i group were treated with a SGLT2i for a median time of 460 (IQR 268–601) days.

SGLT2i users and non-users were treated with different oral iron formulations, with those not receiving a SGLT2i at the time of oral iron initiation being treated more frequently with iron fumarate than those with a background treatment including a SGLT2i (Table 1). Nevertheless, the elemental oral iron dose and total iron load were similar in both groups: median elemental oral iron dose 99 (IQR 60–100) mg/day in SGLT2i non-users vs 66 (IQR 66–100) mg/day in SGLT2i users (*p* = 0.99), total iron load in SGLT2i non-users 9491 (IQR 6099–14256) mg vs 9015 (IQR 6504–11400) mg in SGLT2i users (*p* = 0.61).

## Baseline characteristics

Table 1 summarizes patient characteristics, overall and by baseline treatment without (*n* = 76) and with a SGLT2i (*n* = 76). Overall, the mean age was 75 ± 9 years, 49% were men, 119 (78%) had a history of CKD with median baseline eGFR of 38 (27–56) mL/min/1.73 m², 107 (70%) had HF with a median left ventricular ejection fraction of 42 (IQR 30–60)% and 74% (*n* = 113) had anemia before oral iron initiation. Baseline hemoglobin was 11.5 ± 1.8 g/dL with a hematocrit of 35.5 ± 5.6%, a ferritin of 48 (IQR 24–102) µg/L, a TSAT of 15 ± 7% and a total iron of 50 ± 21 µg/dL.

SGLT2i users and non-users were balanced for most baseline characteristics except for a past medical history of heart failure and atrial fibrillation, and use of beta-blockers, angiotensin receptor/neprilysin inhibitor (ARNi), mineralocorticoid receptor antagonists (MRA), anti-platelets and oral anticoagulants. In addition, patients treated with a SGLT2i had a higher baseline hemoglobin and hematocrit compared with SGLT2i non-users (11.9 ± 1.8 g/dL vs 11.0 ± 1.6 g/dL, *p* < 0.01 and 37.2 ± 0.1%, vs 33.8 ± 0.1%, respectively) as well as a higher eGFR (44 [32–61] mL/min/1.73 m² vs 33 [23–47] mL/min/1.73 m², *p* < 0.01).

## Effect of oral iron on the outcomes stratified by SGLT2i use

Table 2 and Fig. 2 show the results for the prespecified outcomes. Overall, hemoglobin increased by + 0.99 g/dL (95% confidence interval [CI], 0.79–1.19 g/dL) while hematocrit increased by 3.0% (95% CI 2.0 to 3.0%) after oral iron supplementation. In SGLT2i users, oral iron supplementation led to an increase of + 1.39 g/dL (95% CI 1.06 to 1.71 g/dL) in hemoglobin and + 4.0% (95% CI 3.0 to 5.0%) in hematocrit. In SGLT2i non-users, oral iron supplementation was accompanied by an increase of + 0.59 g/dL (95% CI 0.38 to 0.79 g/dL) in hemoglobin and + 2.0% (95% CI 1.0 to 2.0%) in hematocrit.

After adjustment, SGLT2i users had a greater hemoglobin increase of + 0.80 g/dL (95% CI 0.39–1.21 g/dL, *p* < 0.001) compared to SGLT2i non-users. Similarly, SGLT2i users

<figure><img src="image_2.png" /></figure>
<table><caption>**Table 1** Baseline characteristics, overall and by SGLT2i use</caption><thead><tr><th>Characteristic</th><th>Overall (N=152)</th><th>No SGLT2i (N=76)</th><th>SGLT2i (N=76)</th><th>p value</th></tr></thead><tbody><tr><td>Age (years)</td><td>75 (9)</td><td>76 (9)</td><td>74 (10)</td><td>0.29</td></tr><tr><td>Sex (male)</td><td>75 (49)</td><td>33 (43%)</td><td>42 (55%)</td><td>0.14</td></tr><tr><td>BMI (Kg/m²)</td><td>28.7 (5.9)</td><td>28.2 (5.9)</td><td>29.2 (5.9)</td><td>0.27</td></tr><tr><td>Past medical history</td><td></td><td></td><td></td><td></td></tr><tr><td>Hypertension</td><td>147 (97%)</td><td>75 (99%)</td><td>72 (95%)</td><td>0.17</td></tr><tr><td>Dyslipidemia</td><td>138 (91%)</td><td>69 (91%)</td><td>69 (91%)</td><td>1.00</td></tr><tr><td>Diabetes</td><td>98 (65%)</td><td>46 (61%)</td><td>52 (68%)</td><td>0.31</td></tr><tr><td>Atrial fibrillation</td><td>56 (37%)</td><td>17 (22%)</td><td>39 (51%)</td><td><strong>&lt;0.01</strong></td></tr><tr><td>Coronary artery disease</td><td>61 (40%)</td><td>30 (39%)</td><td>31 (41%)</td><td>0.87</td></tr><tr><td>Peripheral artery disease</td><td>22 (15%)</td><td>10 (13%)</td><td>12 (16%)</td><td>0.64</td></tr><tr><td>Stroke</td><td>30 (20%)</td><td>14 (18%)</td><td>16 (21%)</td><td>0.68</td></tr><tr><td>Venous thromboembolism</td><td>10 (7%)</td><td>2 (3%)</td><td>8 (11%)</td><td>0.05</td></tr><tr><td>COPD</td><td>22 (15%)</td><td>9 (12%)</td><td>13 (17%)</td><td>0.36</td></tr><tr><td>Obstructive sleep apnea</td><td>32 (21%)</td><td>11 (14%)</td><td>21 (28%)</td><td>0.05</td></tr><tr><td>Chronic kidney disease</td><td>119 (78%)</td><td>62 (82%)</td><td>57 (75%)</td><td>0.33</td></tr><tr><td>Heart failure</td><td>107 (70%)</td><td>40 (53%)</td><td>67 (88%)</td><td><strong>&lt;0.01</strong></td></tr><tr><td>Etiology</td><td></td><td></td><td></td><td>0.14</td></tr><tr><td>Ischemic</td><td>49 (46%)</td><td>22 (55%)</td><td>27 (40%)</td><td></td></tr><tr><td>Non-ischemic</td><td>58 (54%)</td><td>18 (45%)</td><td>40 (60%)</td><td></td></tr><tr><td>LVEF</td><td>42 (30–60)</td><td>43 (35–60)</td><td>42 (30–60)</td><td>0.58</td></tr><tr><td>HFH last year</td><td>42 (40%)</td><td>16 (40%)</td><td>26 (39%)</td><td>0.95</td></tr><tr><td>Anemia</td><td>113 (74%)</td><td>60 (79%)</td><td>53 (70%)</td><td>0.19</td></tr><tr><td>History of major bleeding</td><td>12 (8%)</td><td>8 (11%)</td><td>4 (5%)</td><td>0.23</td></tr><tr><td>Treatment</td><td></td><td></td><td></td><td></td></tr><tr><td>ACEi/ARB</td><td>94 (62%)</td><td>51 (67%)</td><td>43 (57%)</td><td>0.18</td></tr><tr><td>ARNI</td><td>28 (18%)</td><td>9 (12%)</td><td>19 (25%)</td><td><strong>0.04</strong></td></tr><tr><td>Beta-blocker</td><td>104 (68%)</td><td>44 (58%)</td><td>60 (79%)</td><td><strong>&lt;0.01</strong></td></tr><tr><td>MRA</td><td>44 (29%)</td><td>15 (20%)</td><td>29 (38%)</td><td><strong>0.01</strong></td></tr><tr><td>Loop diuretic</td><td>80 (53%)</td><td>34 (45%)</td><td>46 (61%)</td><td>0.05</td></tr><tr><td>Metolazone</td><td>10 (7%)</td><td>3 (4%)</td><td>7 (9.2%)</td><td>0.19</td></tr><tr><td>Anti-platelet</td><td>61 (40%)</td><td>37 (49%)</td><td>24 (32%)</td><td><strong>0.03</strong></td></tr><tr><td>Oral anticoagulant</td><td>62 (41%)</td><td>15 (20%)</td><td>47 (62%)</td><td><strong>&lt;0.01</strong></td></tr><tr><td>Proton pump inhibitor</td><td>94 (62%)</td><td>50 (66%)</td><td>44 (58%)</td><td>0.32</td></tr><tr><td>Cardiac device</td><td>31 (20%)</td><td>12 (16%)</td><td>19 (25%)</td><td>0.16</td></tr><tr><td>Baseline laboratory values</td><td></td><td></td><td></td><td></td></tr><tr><td>Oral iron to baseline labs time (days)</td><td>16 (6–38)</td><td>20 (6–37)</td><td>14 (6–43)</td><td>0.80</td></tr><tr><td>Hemoglobin (g/dL)</td><td>11.5 (1.8)</td><td>11.0 (1.6)</td><td>11.9 (1.8)</td><td><strong>&lt;0.01</strong></td></tr><tr><td>Hematocrit (%)</td><td>35.5 (5.6)</td><td>33.8 (0.1)</td><td>37.2 (0.1)</td><td><strong>&lt;0.01</strong></td></tr><tr><td>MCV (fL)</td><td>88.8 (6.8)</td><td>89.3 (6.4)</td><td>88.4 (7.2)</td><td>0.44</td></tr><tr><td>MCH (pg)</td><td>28.3 (4.4)</td><td>28.9 (4.2)</td><td>27.8 (4.6)</td><td>0.11</td></tr><tr><td>RDW (%)</td><td>15.5 (2.4)</td><td>15.1 (2.6)</td><td>15.8 (2.2)</td><td>0.21</td></tr><tr><td>HbA1c (%)</td><td>6.7 (1.1)</td><td>6.7 (1.1)</td><td>6.7 (1.1)</td><td>0.95</td></tr><tr><td>Serum creatinine (mg/dL)</td><td>1.5 (1.2–2.0)</td><td>1.7 (1.2–2.4)</td><td>1.4 (1.1–1.7)</td><td><strong>0.01</strong></td></tr><tr><td>eGFR (mL/min/1.73 m²)</td><td>38 (27–56)</td><td>33 (23–47)</td><td>44 (32–61)</td><td><strong>&lt;0.01</strong></td></tr><tr><td>Na⁺ (mmol/L)</td><td>139 (3)</td><td>139 (3)</td><td>140 (3)</td><td>0.05</td></tr><tr><td>K⁺ (mmol/L)</td><td>4.5 (0.5)</td><td>4.5 (0.5)</td><td>4.5 (0.5)</td><td>0.73</td></tr><tr><td>NTproBNP (pg/mL)</td><td>1450 (467–3008)</td><td>1466 (577–4026)</td><td>1450 (467–3008)</td><td>0.89</td></tr><tr><td>BNP (pg/mL)</td><td>175 (73–348)</td><td>164 (77–272)</td><td>180 (73–380)</td><td>0.83</td></tr><tr><td>C-reactive protein (mg/dL)</td><td>3.2 (1.7–7.8)</td><td>2.6 (1.5–6.3)</td><td>3.7 (1.9–10.0)</td><td>0.22</td></tr><tr><td>Ferritin (µg/L)</td><td>48 (24–102)</td><td>60 (28–126)</td><td>41 (19–82)</td><td>0.08</td></tr></tbody></table>
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Characteristic</th><th>Overall (N=152)</th><th>No SGLT2i (N=76)</th><th>SGLT2i (N=76)</th><th>p value</th></tr></thead><tbody><tr><td>TSAT (%)</td><td>15 (7)</td><td>15 (1)</td><td>14 (1)</td><td>0.50</td></tr><tr><td>Iron (µg/dL)</td><td>50 (21)</td><td>51 (18)</td><td>50 (24)</td><td>0.64</td></tr><tr><td>Oral iron</td><td></td><td></td><td></td><td></td></tr><tr><td>Oral iron formulation</td><td></td><td></td><td></td><td><strong>&lt;0.01</strong></td></tr><tr><td>Sulfate</td><td>79 (52%)</td><td>34 (45%)</td><td>45 (59%)</td><td></td></tr><tr><td>Fumarate</td><td>33 (22%)</td><td>26 (34%)</td><td>7 (9%)</td><td></td></tr><tr><td>Oxide polymaltose</td><td>20 (13%)</td><td>7 (9%)</td><td>13 (17%)</td><td></td></tr><tr><td>Ferric protein succinylate</td><td>10 (7%)</td><td>3 (4%)</td><td>7 (9%)</td><td></td></tr><tr><td>Polysaccharide</td><td>9 (6%)</td><td>5 (7%)</td><td>4 (5%)</td><td></td></tr><tr><td>Gluconate</td><td>1 (1%)</td><td>1 (1%)</td><td>0 (0%)</td><td></td></tr><tr><td>Elemental iron (mg/day)</td><td>66 (60–100)</td><td>99 (60–100)</td><td>66 (66–100)</td><td>0.99</td></tr><tr><td>Total iron load (mg)</td><td>9254 (6324–12,623)</td><td>9491 (6099–14256)</td><td>9015 (6504–11400)</td><td>0.61</td></tr><tr><td>Post-iron laboratory data</td><td></td><td></td><td></td><td></td></tr><tr><td>Oral iron to follow-up labs time (days)</td><td>114 (98–148)</td><td>112 (97–150)</td><td>116 (99–146)</td><td>0.61</td></tr><tr><td>Hemoglobin (g/dL)</td><td>12.4 (1.8)</td><td>11.6 (1.5)</td><td>13.3 (1.8)</td><td>*</td></tr><tr><td>Hematocrit (%)</td><td>38.2 (5.5)</td><td>35.4 (4.6)</td><td>40.9 (5.0)</td><td>*</td></tr><tr><td>MCV (fL)</td><td>90.8 (5.8)</td><td>90.6 (5.9)</td><td>91.0 (5.8)</td><td>*</td></tr><tr><td>MCH (pg)</td><td>29.8 (2.4)</td><td>29.8 (2.4)</td><td>29.8 (2.4)</td><td>*</td></tr><tr><td>RDW (%)</td><td>14.8 (2.0)</td><td>14.6 (2.0)</td><td>15.1 (2.0)</td><td>*</td></tr><tr><td>Ferritin (µg/L)</td><td>69 (39–132)</td><td>87 (49–178)</td><td>64 (37–113)</td><td>*</td></tr><tr><td>TSAT (%)</td><td>20 (8)</td><td>20 (7)</td><td>19 (8)</td><td>*</td></tr><tr><td>Iron (µg/dL)</td><td>67 (23)</td><td>68 (20)</td><td>66 (26)</td><td>*</td></tr><tr><td>eGFR (mL/min/1.73 m²)</td><td>39 (26–59)</td><td>32 (22–58)</td><td>45 (32–59)</td><td>*</td></tr><tr><td>Na⁺ (mmol/L)</td><td>139 (3)</td><td>139 (3)</td><td>140 (2.9)</td><td>*</td></tr><tr><td>K⁺ (mmol/L)</td><td>4.6 (0.5)</td><td>4.6 (0.5)</td><td>4.5 (0.6)</td><td>*</td></tr><tr><td>NTproBNP (pg/mL)</td><td>1063 (423–2354)</td><td>1063 (415–2446)</td><td>1057 (451–2262)</td><td>*</td></tr><tr><td>BNP (pg/mL)</td><td>135 (64–261)</td><td>93 (63–152)</td><td>175 (64–305)</td><td>*</td></tr></tbody></table>

Results are presented as mean (stand deviation, SD), median (interquartile range), or absolute number (%), as appropriate. Missing values: Iron pre-iron, 24 (16%); Ferritin pre-iron, 17 (11%); TSAT pre-iron, 28 (18%); HbA1c, 6 (4%); BNP, 103 (68%); NTproBNP, 113 (74%); C-reactive protein, 82 (54%). All other values have 0 missing values

Bold denotes *p*-value < 0.05

*See Table 2 for adjusted differences

ACEi/ARB angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; AFib atrial fibrillation; ARNi angiotensin receptor neprilysin inhibitor; BNP B-type natriuretic peptide; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; eGFR estimated glomerular filtration rate; Hb hemoglobin; HF heart failure; HFH heart failure hospitalization; Htc hematocrit; K⁺ potassium; LVEF left ventricular ejection fraction; MCH mean corpuscular hemoglobin; MCV mean corpuscular volume; MRA mineralocorticoid receptor antagonist; Na⁺ sodium; NTproBNP N-terminal B-type natriuretic peptide; RDW red cell distribution width; SGLT2i, sodium-glucose co-transporter 2 inhibitor, TSAT transferrin saturation

experienced a greater adjusted increase in hematocrit of +3.0% (95% CI 1.0–4.0%, *p* < 0.001) compared to SGLT2i non-users. There were no statistically significant differences in ferritin, TSAT and total iron changes between SGLT2i users and non-users after oral iron administration, and there were no significant changes between groups in eGFR, electrolytes or natriuretic peptide levels.

The magnitude of change in hemoglobin between SGLT2i users (vs. non-users) after oral iron administration was consistent across the subgroups of patients with heart failure (interaction *P* = 0.37), kidney impairment (interaction

*P* = 0.64), and anemia (interaction *P* = 0.86) (Supplementary Table 1).

Discussion

In our study, among patients with HF and/or CKD treated with oral iron, those with a background treatment including a SGLT2i experienced a greater increase in hemoglobin and hematocrit, without impacting the levels of iron biomarkers.
<figure><img src="image_3.png" /><figcaption>**Fig. 1** Study flowchart. CKD chronic kidney disease; ESA erythropoietin-stimulating agent; HF heart failure; IV intravenous; SGLT2i sodium-glucose co-transporter 2 inhibitor</figcaption></figure>

The link between SGLT2i and erythropoietic response has been extensively studied [13, 17, 20]. However, to the best of our knowledge, this is the first study to report an enhanced erythrocytosis effect following oral iron supplementation in HF and/or CKD patients concomitantly treated with a SGLT2i and comparing the results with patients not treated with SGLT2i.

As previously shown in patients with HFrEF with iron deficiency treated with intravenous iron, the incremental effects of SGLT2i on hemoglobin and hematocrit were not accompanied by significant changes in serum iron biomarkers (total iron, ferritin and TSAT) [15]. Although the

underlying mechanisms are not completely understood, this effect may be attributed to an increased gut iron absorption, enhanced iron transport to cells and greater iron availability for erythropoiesis in patients receiving SGLT2i, resulting in unchanged serum iron and TSAT. Ferritin, on the other hand, is an acute phase protein with a high dispersion of values particularly in the setting of inflammation, where its levels do not reliably reflect iron stores; therefore, this study might have been underpowered for detecting changes in ferritin levels [21]. Of note, the effect on erythrocytosis following oral iron supplementation in SGLT2i users is particularly remarkable considering that these patients had
<table><caption>**Table 2** Changes in laboratory values from pre- to post-oral iron administration, overall and by SGLT2i use</caption><thead><tr><th>Variable change</th><th>Overall</th><th>No SGLT2i</th><th>SGLT2i</th><th>Adj. difference*</th></tr></thead><tbody><tr><td>Hb, g/dL</td><td>0.99 (0.79 to 1.19)</td><td>0.59 (0.38 to 0.79)</td><td>1.39 (1.06 to 1.71)</td><td>0.80 (0.39 to 1.21)<br><b>p</b> &lt; 0.001</td></tr><tr><td>Htc, %</td><td>3.0 (2.0 to 3.0)</td><td>2.0 (1.0 to 2.0)</td><td>4.0 (3.0 to 5.0)</td><td>3.0 (1.0 to 4.0)<br><b>p</b> &lt; 0.001</td></tr><tr><td>MCV, fL</td><td>2.0 (1.3 to 2.8)</td><td>1.3 (0.5 to 2.2)</td><td>2.8 (1.5 to 4.0)</td><td>1.0 (–0.5 to 2.5)<br><b>p</b> = 0.18</td></tr><tr><td>MCH, pg</td><td>1.50 (0.83 to 2.17)</td><td>0.91 (0.02 to 1.80)</td><td>2.09 (1.07 to 3.10)</td><td>0.16 (–0.68 to 1.00)<br><b>p</b> = 0.71</td></tr><tr><td>RDW, %</td><td>–0.60 (–1.00 to –0.30)</td><td>–0.6 (–1.09 to –0.03)</td><td>–0.71 (–1.2 to –0.21)</td><td>0.36 (–0.32 to 1.04)<br><b>p</b> = 0.30</td></tr><tr><td>Ferritin, log</td><td>0.38 (0.27 to 0.49)</td><td>0.40 (0.25 to 0.54)</td><td>0.37 (0.20 to 0.53)</td><td>–0.12 (–0.34 to 0.09)<br><b>p</b> = 0.25</td></tr><tr><td>TSAT, %</td><td>4.0 (3.0 to 6.0)</td><td>5.0 (3.0 to 7.0)</td><td>4.0 (2.0 to 7.0)</td><td>1.0 (–3.0 to 4.0)<br><b>p</b> = 0.73</td></tr><tr><td>Iron, µg/dL</td><td>15.3 (10.6 to 20.0)</td><td>14.9 (8.6 to 21.3)</td><td>15.6 (8.6 to 22.6)</td><td>3.4 (–6.1 to 13.0)<br><b>p</b> = 0.48</td></tr><tr><td>eGFR, mL/min/1.73 m<sup>2</sup></td><td>–0.1 (–1.7 to 1.6)</td><td>0.5 (–1.8 to 2.8)</td><td>–0.6 (–2.9 to 1.7)</td><td>0.3 (–3.5 to 4.0)<br><b>p</b> = 0.90</td></tr><tr><td>Na<sup>+</sup>, mmol/L</td><td>0.1 (–0.5 to 0.5)</td><td>0.1 (–0.8 to 0.9)</td><td>–0.1 (–0.6 to 0.5)</td><td>0.7 (–0.4 to 1.7)<br><b>p</b> = 0.23</td></tr><tr><td>K<sup>+</sup>, mmol/L</td><td>0.08 (–0.01 to 0.17)</td><td>0.09 (–0.03 to 0.21)</td><td>0.07 (–0.04 to 0.19)</td><td>–0.04 (–0.20 to 0.13)<br><b>p</b> = 0.67</td></tr><tr><td>BNP, log</td><td>–0.38 (–0.62 to –0.14)</td><td>–0.61 (–0.95 to –0.27)</td><td>–0.26 (–0.59 to 0.07)</td><td>0.33 (–0.39 to 1.06)<br><b>p</b> = 0.35</td></tr><tr><td>NTproBNP, log</td><td>–0.20 (–0.36 to –0.03)</td><td>–0.61 (–1.24 to 0.02)</td><td>–0.11 (–0.26 to 0.05)</td><td>0.31 (–0.21 to 0.83)<br><b>p</b> = 0.22</td></tr><tr><td>C-reactive protein, mg/dL</td><td>–0.40 (–2.18 to 1.38)</td><td>0.25 (–2.54 to 3.04)</td><td>–0.90 (–3.43 to 1.63)</td><td>–0.04 (–3.44 to 3.52)<br><b>p</b> = 0.98</td></tr></tbody></table>

Skewed variables were log transformed to meet the model's assumptions. Values are presented as beta coefficient (95% confidence interval)

ARNI angiotensin receptor neprilysin inhibitor; BNP B-type natriuretic peptide; eGFR estimated glomerular filtration rate; Hb hemoglobin; Htc hematocrit; MCH mean corpuscular hemoglobin; MCV mean corpuscular volume; MRA mineralocorticoid receptor antagonist; N-terminal B-type natriuretic peptide; RDW red cell distribution width; SGLT2i, sodium-glucose co-transporter 2 inhibitor; TSAT transferrin saturation

*Difference between SGLT2i users and non-users derived from a linear regression model adjusted on the baseline value of the variable of interest plus an history of heart failure and atrial fibrillation, a baseline treatment with an ARNI, beta-blocker, MRA, anti-platelet or oral anticoagulant at baseline, type of oral iron formulation and baseline eGFR, i.e., variables with a *P* value < 0.05 in Table 1

a significantly higher baseline hemoglobin and hematocrit levels.

The erythropoietic response observed with SGLT2i treatment is thought to be the result of a complex interplay between inflammatory and erythropoietic pathways [20, 22–24]. Data from placebo-controlled trials showed that SGLT2i upregulates erythropoietin, transferrin receptor protein 1 (TfR1) and potentially erythroferrone while down-regulating ferritin, hepcidin and IL-6 [8, 13, 17, 20, 25, 26]. These effects may explain why patients treated with SGLT2i show enhanced erythropoiesis and increased iron utilization related to the mobilization of body iron stores and potentially enhanced dietary iron absorption [11, 13, 24]. Our data suggest that SGLT2i may overcome the limited oral iron absorption imposed by hepcidin in patients with HF and/or CKD. Following enhanced iron absorption, the upregulation of erythropoietin and TfR1 in SGLT2i chronically

treated patients, results in increased erythropoiesis, regardless of baseline hemoglobin and hematocrit levels (Central illustration).

The absence of significant changes in natriuretic peptide levels during follow-up, along with the exclusion of patients who experienced worsening heart failure events, which included those requiring intensification of oral loop diuretics or administration of intravenous diuretics, further supports that the observed changes in hemoglobin were not related to guideline-directed medical therapy uptitration or decongestive interventions.

Patients with HF and CKD typically respond poorly to oral iron supplementation. Compared to placebo-treated iron-deficient HFrEF patients, only 25% of patients receiving oral iron (300 mg of iron polysaccharide) for 4 months showed biochemical correction of iron deficiency in the iron-repletion effects ON Oxygen UpTake in Heart Failure
<figure><img src="image_4.png" /><figcaption>**Fig. 2** Change in hemoglobin, hematocrit and iron biomarkers post-oral iron administration according to sodium-glucose co-transporter 2 inhibitor use at baseline. Boxplot of the pre-to-post-oral iron change in hemoglobin (A), hematocrit (B), ferritin (C) and TSAT (D) by SGLT2i treatment status. Adjusted difference (CI) and *p* value derived from a linear regression model adjusted on the baseline value</figcaption></figure>

of the variable of interest plus a previous history of heart failure and atrial fibrillation, a baseline treatment with an ARNI, beta-blocker, MRA, anti-platelet or oral anticoagulant at baseline, type of oral iron formulation and baseline eGFR. CI confidence interval; Hb hemoglobin; Htc hematocrit; SGLT2i sodium-glucose co-transporter 2 inhibitor; TSAT transferrin saturation

(IRONOUT-HF) trial [27, 28]. Similarly, in patients with non-end stage CKD, randomization to oral vs intravenous iron for 8 weeks resulted in significant differences in pre-to-post-treatment change in hemoglobin, serum ferritin and TSAT. Those treated with oral iron showed a mean increase in hemoglobin of 0.49 g/dL (comparable to the 0.59 g/dL change observed in SGLT2i non-users in our study), while those treated with intravenous iron experienced a 0.94 g/dL increase [29].

Our results are clinically relevant as they suggest that HF and CKD patients treated with a SGLT2i may be responsive to oral iron therapy. Future trials should explore the potential treatment effects on cardiovascular outcomes of oral iron supplementation in SGLT2i-treated HF and CKD patients.

Our study has limitations. The observational nature of our study provides weaker evidence than a randomized trial; still, the response to oral iron with SGLT2i was similar to

what we had expected prior to the analysis, is biologically plausible, and corrections for potential confounders were performed. Data on reticulocyte count, erythroferrone, IL-6, hepcidin levels or other relevant biomarkers were not available to allow for additional mechanistic insights. Finally, the sample size, although powered to ascertain differences in hemoglobin, was underpowered for the assessment of changes in iron biomarkers, natriuretic peptides and patients' subgroups.

## Conclusions

In a group of patients with HF and/or CKD with iron deficiency treated with oral iron supplementation, those using SGLT2i experienced a greater increase in hemoglobin and hematocrit than those not using SGLT2i. Our results suggest
that SGLT2i may enhance oral iron absorption and potentiate the erythropoietic response to oral iron supplementation.

**Supplementary Information** The online version contains supplementary material available at https://doi.org/10.1007/s00392-025-02685-6.

**Funding** Open access funding provided by FCTIFCCN (b-on). Non applicable.

## Declarations

**Conflict of interest** PM received salary support from an educational grant by Janssen. MP reports consulting fees from 89Bio, Abbvie, Altimmune, Amgen, Ardelyx, AstraZeneca, Boehringer-Ingelheim, Cadriarius, Casana, CSL Behring, Cytokinetics, Lilly, Moderna, Novartis, Reata, Regeneron, Relypsa and Salamandra. MAT reports personal fees from Boehringer-Ingelheim, AstraZeneca, Janssen, Novo-Nordisk and Eli Lilly, outside the submitted work. TAM received speaker honoraria from Daiichi Sankyo, BMS Canada, Janssen, Astra Zeneca, and Pfizer and has served on advisory boards for Böhringer Ingelheim, Bayer, GSK, and Servier outside the submitted work. He has also received an unrestricted research grant from Astra Zeneca and operational grants from the Kidney Foundation of Canada, the Heart & Stroke foundation of Canada and the Canadian Institute of Health Research. He is receiving salary support from the Fonds de Recherche Quebec Santé (Junior 1 Clinician Scholar Award # 298742) and is supported by a KRESCENT New Investigator Award. AS has received support from the Fonds de Recherche Santé Quebec (FRSQ) Junior 1 clinician scholars' program, Canadian Institute of Health Research (Grant #175095), Roche Diagnostics, Boehringer-Ingelheim, Novartis, Janssen, Novo-Nordisk, Servier, AstraZeneca, and Takeda. JPF has received research support from Boehringer-Ingelheim, AstraZeneca and Novartis, through his institution, the University of Porto. The reminder authors report not having relevant conflicts of interest regarding the content of this manuscript.

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## References

1. Khan MS, Samman Tahhan A, Vaduganathan M et al (2020) Trends in prevalence of comorbidities in heart failure clinical trials. Eur J Heart Fail 22:1032–1042

2. Anand I, McMurray JJ, Whitmore J et al (2004) Anemia and its relationship to clinical outcome in heart failure. Circulation 110:149–154

3. Silverberg DS, Wexler D, Iaina A, Schwartz D (2006) The interaction between heart failure and other heart diseases, renal failure, and anemia. Semin Nephrol 26:296–306

4. Bregman DB, Morris D, Koch TA, He A, Goodnough LT (2013) Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. Am J Hematol 88:97–101

5. Zelniker TA, Wiviott SD, Raz I et al (2019) SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393:31–39

6. Vaduganathan M, Docherty KF, Claggett BL et al (2022) SGLT2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet 400:757–767

7. Neuen BL, Young T, Heerspink HJ et al (2019) SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 7:845–854

8. Zannad F, Ferreira JP, Butler J et al (2022) Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme. Eur Heart J 43:4991–5002

9. Inzucchi SE, Zinman B, Fitchett D et al (2018) How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41:356–363

10. Packer M (2024) Mechanistic and clinical comparison of the erythropoietic effects of SGLT2 inhibitors and prolyl hydroxylase inhibitors in patients with chronic kidney disease and renal anemia. Am J Nephrol 55:255–259

11. Packer M (2023) Potential interactions when prescribing SGLT2 inhibitors and intravenous iron in combination in heart failure. Heart Fail 11:106–114

12. Ghanim H, Abuaysheh S, Hejna J et al (2020) Dapagliflozin suppresses hepcidin and increases erythropoiesis. J Clin Endocrinol Metab 105:e1056–e1063

13. Docherty KF, Welsh P, Verma S et al (2022) Iron deficiency in heart failure and effect of dapagliflozin: findings from DAPA-HF. Circulation 146:980–994

14. Fuchs Andersen C, Omar M, Glenthøj A et al (2023) Effects of empagliflozin on erythropoiesis in heart failure: data from the Empire HF trial. Eur J Heart Fail 25:226–234

15. Marques P, Matias P, Packer M et al (2023) Erythropoietic response after intravenous iron in patients with heart failure and reduced ejection fraction with and without background treatment with sodium-glucose cotransporter 2 inhibitors. Eur J Heart Fail 25:2191–2198

16. Marques P, Mavrakanas TA, Guida J et al (2024) Utilizing synchronous care to improve cardiovascular and renal health among patients with type 2 diabetes: proof-of-concept results from the DECIDE-CV clinical programme. Diabetes Obes Metab. https://doi.org/10.1111/dom.15691

17. Ferreira JP, Anker SD, Butler J et al (2022) Impact of anaemia and the effect of empagliflozin in heart failure with reduced ejection fraction: findings from EMPEROR-reduced. Eur J Heart Fail 24:708–715. https://doi.org/10.1002/ejhf.2409

18. Macdougall IC, Bock AH, Carrera F et al (2014) FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia. Nephrol Dial Transplant 29:2075–2084

19. Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612

20. Sano M, Goto S (2019) Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation 139:1985–1987

21. Vasques-Nóvoa F, Pimentel MJ, Marques P et al (2024) Ferritin, inflammation, and iron deficiency in acute heart failure: evidence from the EDIFICA cohort. Clin Res Cardiol 1–8

22. Packer M (2023) Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium-glucose cotransporter 2 inhibitors. Eur Heart J 44:5027–5035

<figure><img src="image_5.png" /></figure>
23. Herrington WG, Savarese G, Haynes R et al (2021) Cardiac, renal, and metabolic effects of sodium-glucose co-transporter 2 inhibitors: a position paper from the European society of cardiology ad-hoc task force on sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail 23:1260-1275

24. Packer M (2022) How can sodium-glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron-deficient? Implications for understanding iron homeostasis in heart failure. Eur J Heart Fail 24:2287-2296

25. Packer M, Ferreira JP, Butler J et al (2024) Reaffirmation of mechanistic proteomic signatures accompanying SGLT2 inhibition in patients with heart failure: a validation cohort of the EMPEROR program. J Am Coll Cardiol 84:1979-1994

26. Benedikt M, Mangge H, Aziz F et al (2023) Impact of the SGLT2-inhibitor empagliflozin on inflammatory biomarkers after acute myocardial infarction-a post-hoc analysis of the Emmy trial. Cardiovasc Diabetol 22:166

27. Lewis GD, Malhotra R, Hernandez AF et al (2017) Effect of oral iron repletion on exercise capacity in patients with heart failure

with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA 317:1958-1966

28. Ambrosy AP, Lewis GD, Malhotra R et al (2019) Identifying responders to oral iron supplementation in heart failure with a reduced ejection fraction: a post-hoc analysis of the IRONOUT-HF trial. J Cardiovasc Med 20:223-225

29. Kalra PA, Bhandari S, Saxena S et al (2016) A randomized trial of iron isomaltoside 1000 versus oral iron in non-dialysis-dependent chronic kidney disease patients with anaemia. Nephrol Dial Transplant 31:646-655

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