Skip to main content

Advertisement

SpringerLink
Log in

Masked anemia and hematocrit elevation under sodium glucose transporter inhibitors: findings from a large real-world study

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Aims

Sodium glucose transporter inhibitors (SGLT2i) therapy is associated with an increase in hematocrit as a class effect. There is a lack of information regarding the clinical magnitude and significance of hematocrit elevation, especially cardiovascular outcomes in patients with polycythemia and possible masking of lower hemoglobin levels as a sign of potential severe disease.

Methods

A retrospective study utilizing large community healthcare provider electronic database. Hematocrit levels and variables with potential effect on hematocrit change were compared before and during SGLT2i treatment in adults with type 2 diabetes mellitus.

Results

Study population included 9646 patients treated with Dapagliflozin or Empagliflozin between 01.2015 and 06.2019. Hematocrit levels were significantly higher after treatment initiation (2.1%), with higher median elevation among male vs female (2.3% vs. 1.8%). Anemia prevalence was significantly lower under treatment (20% vs. 31.6%). In multivariable model, gender, smoking status, SGLT2i type, pretreatment hematocrit, diabetes duration, body mass index and estimated glomerular filtration rate change significantly effected hematocrit change.

Conclusions

In the current study SGLT2i treatment was associated with significant hematocrit elevation, polycythemia and lower anemia prevalence. Further studies are needed to determine the clinical significance and approach to patients with pretreatment or on treatment polycythemia and the approach to patients with lower-normal hemoglobin levels under SGLT2i treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Yau K, Dharia A, Alrowiyti I, Cherney DZI (2022) Prescribing SGLT2 inhibitors in patients with CKD: expanding indications and practical considerations. Kidney Int Rep 7:1463–1476. https://doi.org/10.1016/j.ekir.2022.04.094

    Article  PubMed  PubMed Central  Google Scholar 

  2. Zinman B, Lachin JM, Inzucchi SE (2016) Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes. N Engl J Med 374:1094

    PubMed  Google Scholar 

  3. Neal B, Perkovic V, Mahaffey KW et al (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377:644–657. https://doi.org/10.1056/nejmoa1611925

    Article  CAS  PubMed  Google Scholar 

  4. Wiviott SD, Raz I, Bonaca MP et al (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380:347–357. https://doi.org/10.1056/nejmoa1812389

    Article  CAS  PubMed  Google Scholar 

  5. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al (2020) Dapagliflozin in patients with chronic kidney disease. N Engl J Med 383:1436–1446. https://doi.org/10.1056/nejmoa2024816

    Article  CAS  PubMed  Google Scholar 

  6. Kimura T, Sanada J, Shimoda M et al (2018) Switching from low-dose thiazide diuretics to sodium–glucose cotransporter 2 inhibitor improves various metabolic parameters without affecting blood pressure in patients with type 2 diabetes and hypertension. J Diabetes Investig 9:875–881. https://doi.org/10.1111/jdi.12774

    Article  CAS  PubMed  Google Scholar 

  7. Van Raalte DH, Bjornstad P, Persson F et al (2019) The impact of sotagliflozin on renal function, albuminuria, blood pressure, and hematocrit in adults with type 1 diabetes. Diabetes Care 42:1921–1929. https://doi.org/10.2337/dc19-0937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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. https://doi.org/10.1161/CIRCULATIONAHA.118.038881

    Article  CAS  PubMed  Google Scholar 

  9. Maruyama T, Takashima H, Oguma H et al (2019) Canagliflozin improves erythropoiesis in diabetes patients with anemia of chronic kidney disease. Diabetes Technol Ther 21:713–720. https://doi.org/10.1089/dia.2019.0212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tian Q, Guo K, Deng J et al (2022) Effects of SGLT2 inhibitors on haematocrit and haemoglobin levels and the associated cardiorenal benefits in T2DM patients: a meta-analysis. J Cell Mol Med 26:540–547. https://doi.org/10.1111/jcmm.17115

    Article  CAS  PubMed  Google Scholar 

  11. Lambers Heerspink HJ, de Zeeuw D, Wie L et al (2013) Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 15:853–862

    Article  CAS  PubMed  Google Scholar 

  12. 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. https://doi.org/10.2337/dc17-1096

    Article  CAS  PubMed  Google Scholar 

  13. David Mazer C, Hare GMT, Connelly PW et al (2020) Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.119.044235

    Article  PubMed  Google Scholar 

  14. Ghanim H, Abuaysheh S, Hejna J et al (2020) Dapagliflozin suppresses hepcidin and increases erythropoiesis. J Clin Endocrinol Metab 105:E1056–E1063. https://doi.org/10.1210/clinem/dgaa057

    Article  Google Scholar 

  15. Packer M (2022) How can SGLT2 inhibitors stimulate erythrocytosis in patients who are iron deficient? Implications for understanding iron hemostasis in heart failure. Eur J Heart Fail. https://doi.org/10.1002/ejhf.2731

    Article  PubMed  Google Scholar 

  16. Li J, Neal B, Perkovic V et al (2020) Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes. Kidney Int 98:769–777. https://doi.org/10.1016/j.kint.2020.04.051

    Article  CAS  PubMed  Google Scholar 

  17. Li J, Woodward M, Perkovic V et al (2020) Mediators of the effects of canagliflozin on heart failure in patients with type 2 diabetes. JACC Heart Fail 8:57–66. https://doi.org/10.1016/j.jchf.2019.08.004

    Article  PubMed  Google Scholar 

  18. Irace C, Casciaro F, Scavelli FB et al (2018) Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy. Cardiovasc Diabetol 17:1–9. https://doi.org/10.1186/s12933-018-0695-y

    Article  CAS  Google Scholar 

  19. Packer M (2023) Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium-glucose cotransporter 2 inhibitors. Eur Heart J. https://doi.org/10.1093/eurheartj/ehad235

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kim I-S, Lee BK, Yang P-S et al (2022) Sex-based approach for the clinical impact of polycythaemia on cardiovascular outcomes in the general population. Eur J Prev Cardiol 29:869–879. https://doi.org/10.1093/eurjpc/zwaa071

    Article  PubMed  Google Scholar 

  21. Sano M, Takei M, Shiraishi Y, Suzuki Y (2016) Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res 8:844–847. https://doi.org/10.14740/jocmr2760w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zinman B, Inzucchi SE, Lachin JM et al (2017) Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke 48:1218–1225. https://doi.org/10.1161/STROKEAHA.116.015756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wong CKH, Lau KTK, Tang EHM et al (2022) Cardiovascular benefits of SGLT2 inhibitors in type 2 diabetes, interaction with metformin and role of erythrocytosis: a self-controlled case series study. Cardiovasc Diabetol 21:1–14. https://doi.org/10.1186/s12933-022-01520-w

    Article  CAS  Google Scholar 

  24. Rosen B, Waitzberg R, Merkur S (2015) Israel: health system review. Health Syst Transit 17:1–212

    PubMed  Google Scholar 

  25. Maccbitech Data&Disease registries. https://www.ksminnovation.com/maccabitech-data-and-disease

  26. MacHtinger R, Fallach N, Goldstein I et al (2022) Ovarian stimulation for fertility treatments and risk of breast cancer: a matched cohort study. Hum Reprod 37:577–585. https://doi.org/10.1093/humrep/deab270

    Article  CAS  PubMed  Google Scholar 

  27. Heymann AD, Chodick G, Halkin H et al (2007) Description of a diabetes disease register extracted from a central database. Harefuah 146(15–17):79

    PubMed  Google Scholar 

  28. Ayalew T (2022) Diagnostic approach to the patient with polycythemia. In: RA L (ed) Uptodate. UpToDate, Waltham

  29. AlDallal SM, Jena N (2018) Prevalence of anemia in type 2 diabetic patients. J Hematol 7:57–61. https://doi.org/10.14740/jh411w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weiss G, Schett G (2013) Anaemia in inflammatory rheumatic diseases. Nat Rev Rheumatol 9:205–215. https://doi.org/10.1038/nrrheum.2012.183

    Article  CAS  PubMed  Google Scholar 

  31. Li M, Cao Y, Olsson L (2021) A population-based study on time trends of hemoglobin in primary care comparing prediagnostic colorectal cancer patients versus age- and sex-matched controls. Scand J Gastroenterol 56:266–273. https://doi.org/10.1080/00365521.2021.1879245

    Article  CAS  PubMed  Google Scholar 

  32. Edgren G, Bagnardi V, Bellocco R et al (2010) Pattern of declining hemoglobin concentration before cancer diagnosis. Int J Cancer 127:1429–1436. https://doi.org/10.1002/ijc.25122

    Article  CAS  PubMed  Google Scholar 

  33. Kinar Y, Akiva P, Choman E et al (2017) Performance analysis of a machine learning flagging system used to identify a group of individuals at a high risk for colorectal cancer. PLoS ONE 12:1–8. https://doi.org/10.1371/journal.pone.0171759

    Article  CAS  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sector.

Author information

Author notes

  1. Yair Schwarz and Pinchas Klein are equal contributors.

Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Derech Sheba 2, 5266202, Ramat Gan, Israel

    Yair Schwarz & Pinchas Klein

  2. Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel

    Yair Schwarz & Pinchas Klein

  3. Maccabi Health Care Services, Tel-Avia-Jaffa, 6812509, Israel

    Pinchas Klein & Liat Lev-Shalem

Authors
  1. Yair Schwarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pinchas Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liat Lev-Shalem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yair Schwarz.

Ethics declarations

Conflict of interest

The authors declare they have no conflict of interest.

Ethical approval

The study was approved by MHS ethics committee.

Informed consent

As our study is based on a data registry, the need for informed consent was waived by the ethical committee.

Additional information

Managed By Antonio Secchi.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schwarz, Y., Klein, P. & Lev-Shalem, L. Masked anemia and hematocrit elevation under sodium glucose transporter inhibitors: findings from a large real-world study. Acta Diabetol 61, 99–105 (2024). https://doi.org/10.1007/s00592-023-02174-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-023-02174-0

Keywords

Search

Navigation