Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis

J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgaa057. doi: 10.1210/clinem/dgaa057.


Context: Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit, possibly due to its diuretic effects and hemoconcentration.

Objective: Since type 2 diabetes is a proinflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in proinflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis.

Design: Prospective, randomized, and placebo-controlled study.

Setting: Single endocrinology center.

Patients: Fifty-two obese type 2 diabetes patients.

Intervention: Patients were randomized (1:1) to either dapagliflozin (10 mg daily) or placebo for 12 weeks. Blood samples were collected before and after treatments and serum, plasma, and mononuclear cells (MNC) were prepared.

Main outcome measure: Hepcidin and other hematopoietic factors.

Results: Following dapagliflozin treatment, there was a significant fall in HbA1c and a significant increase in hemoglobin concentration and hematocrit. Dapagliflozin treatment significantly reduced circulating hepcidin and ferritin concentrations while causing a significant increase in levels of the hepcidin inhibitor, erythroferrone, and a transient increase in erythropoietin. Additionally, dapagliflozin increased plasma transferrin levels and expression of transferrin receptors 1 and 2 in MNC, while there was no change in the expression of the iron cellular transporter, ferroportin. Dapagliflozin treatment also caused a decrease in hypoxia-induced factor-1α expression in MNC while it increased the expression of its inhibitor, prolyl hydroxylase-2. There were no significant changes in any of these indices in the placebo group.

Conclusions: We conclude that dapagliflozin increases erythropoiesis and hematocrit through mechanisms that involve the suppression of hepcidin and the modulation of other iron regulatory proteins.

Trial registration: ClinicalTrials.gov NCT02433678.

Keywords: dapagliflozin; erythropoiesis; hepcidin; iron.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / therapeutic use
  • Benzhydryl Compounds / therapeutic use*
  • Biomarkers / analysis*
  • Blood Glucose / analysis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Double-Blind Method
  • Erythropoiesis / drug effects*
  • Female
  • Follow-Up Studies
  • Glucosides / therapeutic use*
  • Glycated Hemoglobin / analysis
  • Hepcidins / antagonists & inhibitors
  • Hepcidins / therapeutic use*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Male
  • Middle Aged
  • Obesity / physiopathology*
  • Prognosis
  • Prospective Studies
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use


  • Anti-Infective Agents
  • Benzhydryl Compounds
  • Biomarkers
  • Blood Glucose
  • Glucosides
  • Glycated Hemoglobin A
  • HIF1A protein, human
  • Hepcidins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Sodium-Glucose Transporter 2 Inhibitors
  • hemoglobin A1c protein, human
  • dapagliflozin
  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases

Associated data

  • ClinicalTrials.gov/NCT02433678