Erythrocytosis during SGLT2 Inhibitor Therapy: Should We Be Concerned?

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have become a cornerstone in the management of type 2 diabetes mellitus, chronic kidney disease and heart failure because of their established cardiovascular and renal benefits. Alongside these effects, consistent increases in hemoglobin and hematocrit have emerged as a characteristic hematologic response. Initially attributed primarily to hemoconcentration resulting from osmotic diuresis, accumulating evidence indicates that enhanced erythropoiesis, driven predominantly by increased erythropoietin production and improved iron availability, represents the principal mechanism. While these changes are usually modest, a subset of patients develops erythropoiesis exceeding conventional diagnostic thresholds, raising important questions regarding differential diagnosis, thrombotic risk, and clinical management. Recent observational studies, systematic evidence syntheses, and emerging hematologic data have refined our understanding of SGLT2 inhibitor-associated erythropoiesis. Reported incidence varies considerably according to the population studied, follow-up duration, and diagnostic criteria. Although most available evidence does not demonstrate a consistent association between SGLT2 inhibitor-associated erythropoiesis and arterial or venous thromboembolic events, recent studies suggest that increased risk in selected subgroups cannot be excluded. Consequently, the clinical significance of this increasingly recognized phenomenon remains incompletely defined. This narrative review critically appraises the current evidence regarding the incidence, pathophysiological mechanisms, thrombotic implications, differential diagnosis, and management of SGLT2 inhibitor-associated erythropoiesis. We also present four real-world clinical cases illustrating its heterogeneous presentation, the frequent coexistence of alternative contributors to secondary erythropoiesis, and its reversibility following drug withdrawal. Integrating current evidence with these clinical observations, we propose a pragmatic diagnostic approach aimed at excluding primary hematologic disorders and alternative secondary causes while supporting individualized decisions regarding continuation of SGLT2 inhibitor therapy. Given the substantial cardiorenal benefits of these agents, management should remain individualized, balancing the degree and clinical context of erythropoiesis against the expected benefits of continued treatment.