Published: 1 June 2023

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Sodium-glucose co-transporter 2 (SGLT2) inhibitors and potential risk for polycythaemia

Published: 1 June 2023
Prescriber Update 44(2): 35–37
June 2023

The Centre for Adverse Reactions Monitoring (CARM) has received a case report of polycythaemia with empagliflozin (CARM ID 142929).

This article highlights information about the potential risk of polycythaemia with sodium-glucose co-transporter 2 (SGLT2) inhibitor medicines.

What is polycythaemia?^1,2

Polycythaemia (erythrocytosis) is an elevation of haemoglobin and/or haematocrit levels above the normal range due to an abnormally high concentration of red blood cells (erythrocytes).

Depending on the cause, polycythaemia is subclassified into relative or absolute polycythaemia.

Relative polycythaemia refers to plasma volume depletion (ie, haemoconcentration without an increase in erythrocyte mass), most commonly caused by diuretics, vomiting or diarrhoea.

Absolute polycythaemia refers to increased erythrocyte mass and is categorised into primary or secondary. Mutations in erythrocyte progenitor cells cause primary polycythaemia and elevated serum erythropoietin levels cause secondary polycythaemia. Polycythaemia vera is a type of primary polycythaemia associated with a Janus Kinase-2 (JAK2) mutation. Elevated erythropoietin in secondary polycythaemia may be due to hypoxia, erythropoietin-producing solid tumours or some medicines, such as erythropoietin or testosterone.

Some types of polycythaemias, particularly polycythaemia vera, are associated with an increased risk of thrombosis.

SGLT2 inhibitors may increase haematocrit by stimulating erythropoiesis

In type 2 diabetes, increased glucose uptake via the SGLT2 in the kidney causes metabolic stress. Damage to erythropoietin-secreting cells in the kidney may occur, subsequently reducing serum erythropoietin levels.³

SGLT2 inhibitors may help alleviate this metabolic stress in the kidneys through inhibition of SGLT2. As a result, the kidneys may increase secretion of erythropoietin, stimulating red blood cell production (erythropoiesis).³

SGLT2 inhibitors are thought to increase haematocrit levels secondary to increasing erythropoietin levels.³ In clinical trials, participants taking empagliflozin or dapagliflozin were reported to have increased haematocrit levels from baseline compared to the placebo group.^4,5

Identifying the underlying cause of polycythaemia is important

Diagnosing the specific cause of polycythaemia is needed for appropriate management.^1,2 In some cases, specialist input may be needed.² Follow local guidelines.

SGLT2 inhibitors may increase a patient’s haematocrit and/or haemoglobin levels. In some patients, these elevations may be above normal levels.⁶ Cases of polycythaemia associated with SGLT2 inhibitor use have been reported in the literature.⁷

Consider SGLT2 inhibitors as a potential cause for secondary polycythaemia.⁶

More information

For more information, see the empagliflozin and dapagliflozin data sheets and consumer medicines information (CMI).

• Search for a data sheet or CMI

References

1. Tefferi A. 2022. Diagnostic approach to the patient with erythrocytosis/polycythemia. In: UpToDate 21 November 2022. URL: uptodate.com/contents/diagnostic-approach-to-the-patient-with-erythrocytosis-polycythemia (accessed 5 April 2023).
2. Mithoowani S, Laureano M, Crowther MA, et al. 2020. Investigation and management of erythrocytosis. Canadian Medical Journal 192(32): E913-18. DOI: 10.1503/cmaj.191587 (accessed 13 April 2023).
3. Sano M and Goto S. 2019. Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 Inhibitors and associated beneficial renal and cardiovascular effects. Circulation 139(17): 1985-87. DOI: 10.1161/circulationaha.118.038881 (accessed 5 April 2023).
4. Boehringer Ingelheim (N.Z) Limited. 2022. Jardiance New Zealand Data Sheet 29 August 2022. URL: medsafe.govt.nz/profs/Datasheet/j/jardiancetab.pdf (accessed 5 April 2023).
5. AstraZeneca Limited. 2022. Forxiga New Zealand Data Sheet 18 July 2022. URL: medsafe.govt.nz/profs/Datasheet/f/forxigatab.pdf (accessed 5 April 2023).
6. Gangat N, Szuber N, Alkhateeb H, et al. 2021. JAK2 wild-type erythrocytosis associated with sodium-glucose cotransporter 2 inhibitor therapy. Blood 138(26): 2886–9. DOI: doi.org/10.1182/blood.2021013996 (accessed 5 April 2023).
7. Chin-Yee B, Solh Z and Hsia C. 2020. Erythrocytosis induced by sodium-glucose cotransporter-2 inhibitors. Canadian Medical Journal 192(42): E1271. DOI: 10.1503/cmaj.76686 (accessed 29 April 2023).