Combining Iron Supplements With SGLT2 Inhibitor-Stimulated Erythropoiesis in Heart Failure: Should We Be Worried About Thromboembolic Events?

Abstract

Physicians have long believed that anemia might contribute to the progression of heart failure (HF). A decade ago, clinical trials investigated whether erythropoiesis-stimulating agents could increase hemoglobin levels in patients with anemia in the hope that enhancing oxygen delivery would improve outcomes. In the RED-HF (Reduction of Events by Darbepoetin Alfa in Heart Failure) trial,1Swedberg K Young JB Anand IS Cheng S Desai AS Diaz R et al.RED-HF committees, RED-HF investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure.N Engl J Med. 2013; 368: 1210-1219Crossref PubMed Scopus (413) Google Scholar 2278 patients with HF, reduced ejection fraction, hemoglobin 9.0–12.0 g/dL, and transferrin saturation (TSAT) ≥ 15% (median 24%) were randomized to placebo or darbepoetin, a synthetic analogue of erythropoietin. Darbepoietin was given monthly to maintain the hemoglobin levels between 13.0 and 14.5 g/dL; iron supplements (usually oral) were coadministered when the TSAT was < 20% and were prescribed in ≈ 80% of patients. Darbepoetin did not reduce the primary endpoint of all-cause mortality or hospitalizations for HF, but it did increase the risk of thromboembolic events (13.5% vs 10.0%; P = 0.009). Similarly, in the TREAT (TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia) trial,2Pfeffer MA Burdmann EA Chen CY Cooper ME de Zeeuw D Eckardt KU et al.TREAT investigatorsA trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1712) Google Scholar darbepoetin increased the risk of stroke in patients with diabetes, chronic kidney disease or anemia. Why did darbepoetin increase the risk of thromboembolic events? Darbepoetin (with iron supplementation) increased hemoglobin by ≈ 1.5 g/dL to achieve a median of 13.0 g/dL (IQR 12.4–13.4), rising meaningfully during the first 3 months, with a peak after 6 months. Increases in hemoglobin of this magnitude might enhance blood viscosity. Recent experience with prolyl-hydroxylase inhibitors in patients with chronic kidney disease underscores these findings. These drugs potentiate the action of hypoxia-inducible factors (HIF-1α and HIF-2α), which are the primary endogenous stimuli for erythropoietin production. In trials of patients receiving intravenous iron, the prolyl-hydroxylase inhibitor roxudustat yielded a greater increase in hemoglobin but also a higher risk of thromboembolic events3Kurata Y Tanaka T Nangaku M. An evaluation of roxadustat for the treatment of anemia associated with chronic kidney disease.Expert Opin Pharmacother. 2022; 23: 19-28Crossref PubMed Scopus (7) Google Scholar when compared with darbepoietin—a striking finding, given that darbepoetin itself promotes thromboembolic events.1Swedberg K Young JB Anand IS Cheng S Desai AS Diaz R et al.RED-HF committees, RED-HF investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure.N Engl J Med. 2013; 368: 1210-1219Crossref PubMed Scopus (413) Google Scholar,2Pfeffer MA Burdmann EA Chen CY Cooper ME de Zeeuw D Eckardt KU et al.TREAT investigatorsA trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1712) Google Scholar The totality of evidence indicates that the increases in hemoglobin that follow erythropoiesis stimulation combined with iron supplementation appear to augment thromboembolic risk in patients with cardiovascular disease. Currently, most physicians using erythropoiesis-stimulating agents in chronic kidney disease target a hemoglobin level no higher than 10–11 g/dL. Although anemia has negative prognostic implications in patients with HF,4Cleland JG Zhang J Pellicori P Dicken B Dierckx R Shoaib A et al.Prevalence and outcomes of anemia and hematinic deficiencies in patients with chronic heart failure.JAMA Cardiol. 2016; 1: 539-547Crossref PubMed Scopus (93) Google Scholar most of the essential medicines for the treatment of HF lead to a decrease in hemoglobin and increase the proportion of patients with anemia, even though they reduce mortality rates and hospitalizations due to HF.5Komajda M Anker SD Charlesworth A Okonko D Metra M Di Lenarda A et al.The impact of new-onset anaemia on morbidity and mortality in chronic heart failure: results from COMET.Eur Heart J. 2006; 27: 1440-1446Crossref PubMed Scopus (187) Google Scholar,6Marathias KP Lambadiari VA Markakis KP Vlahakos VD Bacharaki D Raptis AE et al.Competing effects of renin angiotensin system blockade and sodium-glucose cotransporter-2 inhibitors on erythropoietin secretion in diabetes.Am J Nephrol. 2020; 51: 349-356Crossref PubMed Scopus (25) Google Scholar Should we, therefore, be concerned about increases in hemoglobin when erythropoiesis stimulation and iron supplementation are combined in the modern era of HF management? Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization due to HF for a broad range of patients, and they may reduce the risk of cardiovascular death in those with reduced ejection fraction.7McMurray JJV Solomon SD Inzucchi SE Køber L Kosiborod MN Martinez FA et al.DAPA-HF trial committees and investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008Crossref PubMed Scopus (3430) Google Scholar,8Anker SD Butler J Filippatos G Ferreira JP Bocchi E Böhm M et al.EMPEROR-Preserved trial investigators. Empagliflozin in heart failure with a preserved ejection fraction.N Engl J Med. 2021; 385: 1451-1461Crossref PubMed Scopus (1520) Google Scholar Initiation of SGLT2 inhibitors is accompanied by an increase in hemoglobin, which averages ≈ 0.7 g/dL, with a mean achieved hemoglobin level of ≈ 14.5 g/dL; the magnitude of the increase is similar in patients with and without anemia.7McMurray JJV Solomon SD Inzucchi SE Køber L Kosiborod MN Martinez FA et al.DAPA-HF trial committees and investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008Crossref PubMed Scopus (3430) Google Scholar, 8Anker SD Butler J Filippatos G Ferreira JP Bocchi E Böhm M et al.EMPEROR-Preserved trial investigators. Empagliflozin in heart failure with a preserved ejection fraction.N Engl J Med. 2021; 385: 1451-1461Crossref PubMed Scopus (1520) Google Scholar, 9Docherty KF Curtain JP Anand IS Bengtsson O Inzucchi SE Køber L et al.DAPA-HF investigators and committees. Effect of dapagliflozin on anaemia in DAPA-HF.Eur J Heart Fail. 2021; 23: 617-628Crossref PubMed Scopus (35) Google Scholar The increase occurs over the first 4 weeks and plateaus after 4–8 months; the early increase in hemoglobin levels is a statistical marker of the action of these medicines to reduce hospitalizations due to HF.10Fitchett D Inzucchi SE Zinman B Wanner C Schumacher M Schmoor C et al.Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial.ESC Heart Fail. 2021; 8: 4517-4527Crossref PubMed Scopus (31) Google Scholar Although there has been much speculation about the action that causes hemoconcentration, SGLT2 inhibitors increase hemoglobin primarily by stimulating the endogenous production of erythropoietin,11Zannad F Ferreira JP Butler J Filippatos G Januzzi JL Sumin M et al.Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights from the EMPEROR program.Eur Heart J. 2022; : ehac495https://doi.org/10.1093/eurheartj/ehac495Crossref PubMed Scopus (34) Google Scholar,12Packer M. Critical examination of mechanisms underlying the reduction in heart failure events with SGLT2 inhibitors: identification of a molecular link between their actions to stimulate erythrocytosis and to alleviate cellular stress.Cardiovasc Res. 2021; 117: 74-84Crossref PubMed Scopus (44) Google Scholar which may reflect enhanced nutrient deprivation and HIF-2α signaling, the latter effect being akin to that of prolyl hydroxylase inhibitors.12Packer M. Critical examination of mechanisms underlying the reduction in heart failure events with SGLT2 inhibitors: identification of a molecular link between their actions to stimulate erythrocytosis and to alleviate cellular stress.Cardiovasc Res. 2021; 117: 74-84Crossref PubMed Scopus (44) Google Scholar However, the use of iron supplementation in trials of SGLT2 inhibitors was very low (< 5%). Intravenous iron improves symptoms and exercise capacity in patients with HF and reduced ejection fraction who fulfill current criteria for iron deficiency; most of them had mild anemia (mean hemoglobin level of ≈ 12.0–12.5 g/dL).13Anker SD Comin Colet J Filippatos G Willenheimer R Dickstein K Drexler H et al.FAIR-HF trial investigatorsFerric carboxymaltose in patients with heart failure and iron deficiency.N Engl J Med. 2009; 361: 2436-2448Crossref PubMed Scopus (1449) Google Scholar,14Ponikowski P van Veldhuisen DJ Comin-Colet J Ertl G Komajda M Mareev V et al.CONFIRM-HF investigatorsBeneficial effects of long-term intravenous iron therapy wih ferric carboxymaltose with in patients with symptomatic heart failure and iron deficiency.Eur Heart J. 2015; 36: 657-668Crossref PubMed Scopus (775) Google Scholar In 2 trials (AFFIRM-AHF [Randomised, Double-Blind Placebo Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient Patients Admitted for Acute Heart Failure] and IRONMAN [Intravenous Iron or Placebo for Anaemia in Intensive Care]),15Ponikowski P Kirwan BA Anker SD McDonagh T Dorobantu M Drozdz J et al.AFFIRM-AHF investigatorsFerric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.Lancet. 2020; 396: 1895-1904Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar,16Kalra PR, Cleland JGF, Petrie MC, Thomson EA, Kalra PA, Squire IB, et al., IRONMAN Study Group. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400:2199–209.Google Scholar intravenous iron supplementation (with ferric carboxymaltose or ferric derisomaltose) reduced the risk of hospitalization for HF with no conclusive effect on mortality rates. Intravenous iron increased hemoglobin by ≈ 0.6–1.0 g/dL, with a mean achieved hemoglobin of ≈12.5–13.0 g/dL; the increase occurred within 4 weeks and plateaued after 4–12 months.13Anker SD Comin Colet J Filippatos G Willenheimer R Dickstein K Drexler H et al.FAIR-HF trial investigatorsFerric carboxymaltose in patients with heart failure and iron deficiency.N Engl J Med. 2009; 361: 2436-2448Crossref PubMed Scopus (1449) Google Scholar, 14Ponikowski P van Veldhuisen DJ Comin-Colet J Ertl G Komajda M Mareev V et al.CONFIRM-HF investigatorsBeneficial effects of long-term intravenous iron therapy wih ferric carboxymaltose with in patients with symptomatic heart failure and iron deficiency.Eur Heart J. 2015; 36: 657-668Crossref PubMed Scopus (775) Google Scholar, 15Ponikowski P Kirwan BA Anker SD McDonagh T Dorobantu M Drozdz J et al.AFFIRM-AHF investigatorsFerric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.Lancet. 2020; 396: 1895-1904Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar, 16Kalra PR, Cleland JGF, Petrie MC, Thomson EA, Kalra PA, Squire IB, et al., IRONMAN Study Group. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400:2199–209.Google Scholar Increases in hemoglobin levels were most apparent in those with anemia at baseline, but iron alone did not always correct the anemia.13Anker SD Comin Colet J Filippatos G Willenheimer R Dickstein K Drexler H et al.FAIR-HF trial investigatorsFerric carboxymaltose in patients with heart failure and iron deficiency.N Engl J Med. 2009; 361: 2436-2448Crossref PubMed Scopus (1449) Google Scholar The use of SGLT2 inhibitors in trials of iron supplementation was low (< 5%).16Kalra PR, Cleland JGF, Petrie MC, Thomson EA, Kalra PA, Squire IB, et al., IRONMAN Study Group. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400:2199–209.Google Scholar In the absence of treatment with an SGLT2 inhibitor, ≈ 50% of patients with HF and reduced ejection fraction appear to be iron deficient and would be considered candidates for intravenous iron.17Masini G Graham FJ Pellicori P Cleland JGF Cuthbert JJ Kazmi S et al.Criteria for iron deficiency in patients with heart failure.J Am Coll Cardiol. 2022; 79: 341-351Crossref PubMed Scopus (42) Google Scholar SGLT2 inhibitors decrease both hepcidin and ferritin,18Docherty KF Welsh P Verma S De Boer RA O'Meara E Bengtsson O et al.DAPA-HF investigators and committees. Iron deficiency in heart failure and effect of dapagliflozin: findings from DAPA-HF.Circulation. 2022; 146: 980-994Crossref PubMed Scopus (25) Google Scholar which may be related to their erythropoietic action or to their ability to minimize systemic inflammation or cellular stress.19Packer M. Potential interactions when prescribing SGLT2 inhibitors and intravenous iron in combination in heart failure.JACC Heart Fail. 2023; 11: 106-114Crossref PubMed Scopus (12) Google Scholar SGLT2 inhibition also produce a slight decrease in TSAT due to an increase in transferrin, with little change in serum iron concentrations.18Docherty KF Welsh P Verma S De Boer RA O'Meara E Bengtsson O et al.DAPA-HF investigators and committees. Iron deficiency in heart failure and effect of dapagliflozin: findings from DAPA-HF.Circulation. 2022; 146: 980-994Crossref PubMed Scopus (25) Google Scholar The decreases in TSAT and ferritin may be interpreted by clinicians as worsening iron deficiency; thus, during SGLT2 inhibition, the proportion of patients deemed to be iron deficient by current criteria increases to nearly 70%.18Docherty KF Welsh P Verma S De Boer RA O'Meara E Bengtsson O et al.DAPA-HF investigators and committees. Iron deficiency in heart failure and effect of dapagliflozin: findings from DAPA-HF.Circulation. 2022; 146: 980-994Crossref PubMed Scopus (25) Google Scholar Thus, most patients treated with an SGLT2 inhibitor might be considered for intravenous iron therapy. What can we expect when SGLT2 inhibitors and intravenous iron are combined? There are 2 possibilities (Fig. 1). On the one hand, the decrease in serum hepcidin during SGLT2 inhibitor use should increase the duodenal absorption of iron and enhance the release of iron from the reticuloendothelial system. Simultaneously, the effect of SGLT2 inhibitors in lowering ferritin can reduce the sequestration of intracellular iron, thus enhancing release of iron into the cytosolic pool. The action by SGLT2 inhibitors to decrease both hepcidin and ferritin would, therefore, lead to an increase in iron availability, thus alleviating intracellular iron deficiency.19Packer M. Potential interactions when prescribing SGLT2 inhibitors and intravenous iron in combination in heart failure.JACC Heart Fail. 2023; 11: 106-114Crossref PubMed Scopus (12) Google Scholar Under these circumstances, iron supplementation would be expected to have little effect on erythropoiesis. On the other hand, if worsening of conventional iron biomarkers during SGLT2 inhibition were to reflect the depletion of cytosolic iron (which would limit erythrocyte production), then iron supplementation would potentiate the increase in hemoglobin produced by these drugs. If the 2 treatments had additive effects, we would expect a hemoglobin level of 12.0 g/dL to rise to ≈ 13.5 g/dL for patients with HF and iron deficiency, and patients without anemia might achieve even higher hemoglobin concentrations. Increases in hemoglobin of this magnitude, driven by darbepoetin in patients with HF or with prolyl hydroxylase inhibitors in chronic kidney disease, increase the risk of thromboembolic events.1Swedberg K Young JB Anand IS Cheng S Desai AS Diaz R et al.RED-HF committees, RED-HF investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure.N Engl J Med. 2013; 368: 1210-1219Crossref PubMed Scopus (413) Google Scholar,2Pfeffer MA Burdmann EA Chen CY Cooper ME de Zeeuw D Eckardt KU et al.TREAT investigatorsA trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1712) Google Scholar Concerns have been raised that the increase in hemoglobin levels produced by SGLT2 inhibitors alone might explain why these drugs do not reduce the risk of stroke.20Imprialos KP Boutari C Stavropoulos K Doumas M Karagiannis AI. Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?.J Neurol Neurosurg Psychiatry. 2017; 88: 249-253Crossref PubMed Scopus (42) Google Scholar If SGLT2 inhibitors cause cytosolic iron depletion (as is commonly believed9Docherty KF Curtain JP Anand IS Bengtsson O Inzucchi SE Køber L et al.DAPA-HF investigators and committees. Effect of dapagliflozin on anaemia in DAPA-HF.Eur J Heart Fail. 2021; 23: 617-628Crossref PubMed Scopus (35) Google Scholar), the concurrent treatment of patients with SGLT2 inhibitors and intravenous iron may amplify the erythrocytic response, leading, potentially, to a greater improvement in symptoms but, possibly, to an increased risk of thromboembolic events. Based on the lessons of RED-HF, we cannot assume that the greater increases in hemoglobin are safe. However, if SGLT2 inhibitors cause cytosolic iron repletion (as has been recently proposed19Packer M. Potential interactions when prescribing SGLT2 inhibitors and intravenous iron in combination in heart failure.JACC Heart Fail. 2023; 11: 106-114Crossref PubMed Scopus (12) Google Scholar), worrisome erythrocytosis will be avoided, and the need for intravenous iron therapy reduced. Therefore, there is an urgent need for additional clinical trial evidence to understand the benefits and risks of prescribing intravenous iron together with SGLT2 inhibitors before the combination is widely deployed. MP reports personal fees for consulting with Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra. JGFC is supported by a British Heart Foundation Centre of Research Excellence (Grant #RE/18/6/34217). JGFC reports grants from British Heart Foundation, personal fees from Abbott and Amgen, grants and personal fees from Bayer and Bristol Myers Squibb, personal fees from Novartis, Medtronic, Servier, Astra-Zeneca, Biopeutics, Torrent, and Idorsia, grants and personal fees from Johnson & Johnson, Pharmacosmos, Viscardia, and Vifor, personal fees and nonfinancial support from Boehringer-Ingelheim, from Myokardia, personal fees from Respicardia, personal fees and nonfinancial support from NI Medical, and grants from Pharma Nord.

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