SAT-630 - SGLT2 Inhibitor-Associated Erythrocytosis

Background:
Sodium–glucose cotransporter-2 (SGLT2) inhibitors are widely prescribed for the management of type 2 diabetes mellitus and heart failure with reduced ejection fraction, with established cardiovascular and renal benefits. Use of SGLT2 inhibitors has been associated with modest increases in hemoglobin and hematocrit, attributed to hemoconcentration and increased erythropoiesis. While modest elevations in hematocrit are commonly observed in clinical trials, clinically significant polycythemia has been infrequently reported and remains poorly characterized.

Case Presentation:
We report the case of a 49-year-old man with a history of type 2 diabetes mellitus, hypertension, coronary artery disease, ischemic cardiomyopathy with heart failure with reduced ejection fraction, and hyperlipidemia who was noted to have erythrocytosis with a hemoglobin of 18.2 g/dL and hematocrit of 55.1%. He had been receiving empagliflozin 25 mg once daily for approximately one year. Prior to initiation of empagliflozin, hemoglobin was within the normal range at 15.5 g/dL.

An extensive evaluation for primary and secondary causes of erythrocytosis was performed. Iron studies, vitamin B12 and folate levels, erythropoietin level, serum protein electrophoresis, immunofixation electrophoresis, serum free kappa and lambda light chains, erythrocyte sedimentation rate, and carboxyhemoglobin levels were all within normal limits. There was no evidence of hypoxia, smoking, testosterone use, or other secondary causes of polycythemia. Findings were not suggestive of a myeloproliferative disorder. Room-air oxygen saturation was normal, and testing for JAK2 mutation was not approved by insurance. Given the temporal relationship between empagliflozin initiation and development of erythrocytosis, along with exclusion of alternative etiologies, SGLT2 inhibitor–associated polycythemia was considered the most likely diagnosis.

Discussion:
SGLT2 inhibitors are known to increase hemoglobin and hematocrit through a combination of intravascular volume contraction and stimulation of erythropoiesis, potentially mediated by altered renal oxygen sensing and hypoxia-inducible factor signaling. While mild hematocrit elevations are commonly reported, clinically significant polycythemia remains infrequently described. In this case, the development of marked erythrocytosis following prolonged empagliflozin therapy, along with exclusion of primary and secondary causes, supports a medication-related etiology. Recognition of SGLT2 inhibitors as a potentially reversible cause of secondary polycythemia is important to avoid unnecessary diagnostic evaluation and to mitigate potential thrombotic risk, particularly in patients with underlying cardiovascular disease.

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