Intravenous Iron Increases Hemoglobin in Heart Failure Treated with SGLT2 Inhibition

Kieran F. Docherty, PhD

Credit: University of Glasgow

A posthoc exploratory analysis of the IRONMAN trial identified an increasing trend in hemoglobin levels with intravenous ferric derisomaltose treatment among iron-deficient patients with heart failure on a sodium-glucose cotransporter-2 (SGLT2) inhibitor at baseline.¹

The IRONMAN trial randomized patients with heart failure with reduced ejection fraction (HFreF), a left ventricular ejection fraction (LVEF) ≤45%, and iron deficiency (transferrin saturation [TSAT] <20% or ferritin <100 µg/L) to open-label intravenous ferric derisomaltose or usual care. Site investigators reported the use of SGLT2 inhibitors at baseline.

“To our knowledge, these are the first randomized trial data providing insights into the treatment of iron deficiency with intravenous iron in patients with HFrEF taking an SGLT2 inhibitor, although any conclusions are limited by the small number of patients taking an SGLT2 inhibitor at baseline,” wrote the investigative team, led by Kieran F. Docherty, PhD, BHF Cardiovascular Research Center, school of cardiovascular and metabolic health, University of Glasgow.

Iron deficiency is frequently observed in patients with heart failure and is associated with anemia and poorer prognosis. Correction of iron deficiency in patients with HFrEF with intravenous iron can improve symptoms, increase exercise capacity, and reduce hospitalization risk. Guidelines indicate patients with HFrEF should be routinely tested for iron deficiency and receive intravenous iron when necessary.

Recent literature has suggested the potential correlation between iron administration and SGLT2 inhibitors. Besides reductions in worsening heart failure and CV risk, SGLT2s lead to changes in biomarkers consistent with improvement in iron utilization, including increased serum transferrin receptor and reduced ferritin, transferrin saturation, and hepcidin.

Together, intravenous iron and SGLT2 inhibitors could lead to a rapid increase in hematocrit, possibly reducing the risk of thromboembolic effects. In this analysis, Docherty and colleagues assessed the interactions between intravenous iron and SGLT2 inhibition, examining changes in hemoglobin according to baseline use or not use of SGLT2 inhibition, in a post-hoc exploratory analysis of IRONMAN.

A total of 1137 patients with heart failure were randomized 1:1 to open-label intravenous ferric derisomaltose or usual care. Blood samples for the hemoglobin levels were collected at baseline, 4 weeks, and 4 months. Of the randomized population, 29 (2.6%) received an SGLT2 inhibitor at baseline.

Baseline characteristics showed the mean hemoglobin levels were 11.9 g/dL and 12.0 g/dL in patients taking or not taking an SGLT2 inhibitor. A history of diabetes was more common in patients taking an SGLT2 inhibitor (79% vs. 45%).

Upon analysis, the mean change in hemoglobin levels from baseline at 4 weeks in those taking an SGLT2 inhibitor at baseline was 1.3 g/dL in patients randomized to ferric derisomaltose and 0.1 g/dL in the usual-care group (between-group difference, 1.0 g/dL [95% CI, 0.1 - 1.8]).

Equivalent numbers in those not treated with SGLT2 inhibition were 0.6 g/dL in those randomized to ferric derisomaltose and 0.1 g/dL in the usual care group (between-group difference, 0.4 g/dL [95% CI, 0.3 - 1.6]; interaction P value = .10). Investigators observed similar results at 4 months (interaction P value = .45).

Despite the increase in hemoglobin tending to be larger in patients receiving SGLT2 inhibition at baseline, no patient receiving an SGLT2 inhibitor developed polycythemia during the first 4 months, defined as hemoglobin >16.5 g/dL in men or >16 g/dL in women. For those not receiving SGLT2 inhibition, there was 1 polycythemia case among those randomized to intravenous iron at 4 weeks and 1 case in each randomized group at 4 months.

Docherty and colleagues noted any conclusions from this posthoc analysis of the IRONMAN trial are constrained by the limited number of patients receiving SGLT2 inhibition.

“Further evidence regarding any interaction between SGLT2 inhibitors and intravenous iron should soon be provided by the Ferric Carboxymaltose in Heart Failure with Iron Deficiency (HEART-FID) trial,” investigators wrote.

References

1. _{Docherty KF, McMurray JJV, Kalra PR, et al. Intravenous iron and SGLT2 inhibitors in iron-deficient patients with heart failure and reduced ejection fraction. ESC Heart Fail. Published online March 28, 2024. doi:10.1002/ehf2.14742}
2. _{Graham FJ, Pellicori P, Kalra PR, Ford I, Bruzzese D, Cleland JGF. Intravenous iron in patients with heart failure and iron deficiency: an updated meta-analysis. Eur J Heart Fail. 2023;25(4):528-537. doi:10.1002/ejhf.2810}
3. _{McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. 2021 Oct 14;:]. Eur Heart J. 2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368}