Dr. Kieran F. Docherty

Credit: University of Glasgow

A post-hoc exploratory analysis of the IRONMAN trial found a trend toward increased hemoglobin levels with intravenous ferric derisomaltose treatment in heart failure iron-deficient patients receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors at baseline. was confirmed.¹

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

“To our knowledge, these are the first randomized trial data to provide insight into the treatment of iron deficiency with intravenous iron in HFrEF patients taking SGLT2 inhibitors, but not SGLT2 inhibitors at baseline. “The small number of patients taking the drug limits any conclusions,” wrote the research team, led by Dr Kieran F. Docherty of the BHF Cardiovascular Research Center in the School of Cardiovascular and Metabolic Health at the University of Glasgow.

Iron deficiency is frequently observed in patients with heart failure and is associated with anemia and poor prognosis. Correcting iron deficiency in patients with HFrEF with intravenous iron improves symptoms, improves exercise capacity, and reduces the risk of hospitalization. The guidelines state that people with HFrEF should be regularly tested for iron deficiency and given intravenous iron as needed.

Recent literature suggests a potential correlation between iron administration and SGLT2 inhibitors. In addition to worsening heart failure and reducing CV risk, SGLT2 results in changes in biomarkers consistent with improved iron utilization, including increased serum transferrin receptors, decreased ferritin, transferrin saturation, and hepcidin.

Concomitant use of intravenous iron and SGLT2 inhibitors may rapidly increase hematocrit and reduce the risk of thromboembolic effects. In this analysis, Docherty et al. examined changes in hemoglobin in response to baseline use or nonuse of SGLT2 inhibition and evaluated interactions between intravenous iron and SGLT2 inhibition in a post hoc exploratory analysis of IRONMAN.

A total of 1,137 heart failure patients were randomized 1:1 to open-label intravenous ferric derisomaltose or usual care. Blood samples to measure hemoglobin levels were collected at baseline, 4 weeks, and 4 months. Of the randomized population, 29 (2.6%) received their SGLT2 inhibitor at baseline.

Baseline characteristics showed mean hemoglobin levels of 11.9 g/dL and 12.0 g/dL for patients taking and not taking SGLT2 inhibitors. History of diabetes was more common in patients taking SGLT2 inhibitors (79% vs. 45%).

Analysis showed that the mean change in hemoglobin levels from baseline after 4 weeks in patients taking SGLT2 inhibitors at baseline was 1.3 g/dL in patients randomized to ferric derisomaltose. , 0.1 g/dL in the usual treatment group (group difference, 1.0 g/dL [95% CI, 0.1 – 1.8]).

For patients not treated with SGLT2 inhibition, the equivalent value was 0.6 g/dL for patients randomized to ferric derisomaltose and 0.1 g/dL for the usual care group (the between-group difference was 0.4 g/dL) [95% CI, 0.3 – 1.6]; Alternating current P value = .10). Researchers observed similar results after 4 months (interaction) P value = 0.45).

Polycythemia (hemoglobin >16.5 in men) occurred during the first 4 months in patients receiving SGLT2 inhibitors, although hemoglobin increases tended to be greater in patients receiving SGLT2 inhibition at baseline. g/dL, defined as >16 g/dL in women). Among patients not receiving SGLT2 inhibition, there was one case of polycythemia at 4 weeks among those randomized to receive intravenous iron, and one case in each randomization group at 4 months.

Docherty et al. noted that the conclusions drawn from this post-hoc analysis of the IRONMAN trial are limited by the limited number of patients receiving SGLT2 inhibition.

“Further evidence for the interaction of SGLT2 inhibitors with intravenous iron should soon be provided by the ferric carboxymaltose in Heart Deficiency in Iron Deficiency (HEART-FID) trial,” the researchers 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 failure. Published online March 28, 2024. doi:10.1002/ehf2.14742}
2. _{Graham FJ, Pericoli P, Carla 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. _{McDonough TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure [published correction appears in Eur Heart J. 2021 Oct 14;:]. euro heart j. 2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368}