Uncoupling erythropoiesis from cardiorenal effects: SGLT2 inhibition in non-diabetic heart failure
D Magureanu, I C Bocsan, M A Neag, R M Pop, A Cozma, A D BuzoianuAbstract
Background
Sodium–glucose cotransporter 2 (SGLT2) inhibitors consistently increase hemoglobin and hematocrit across cardiovascular and renal disease states. Although initially attributed to hemoconcentration, growing evidence supports a true stimulation of erythropoiesis. However, most mechanistic data derive from diabetic populations, where hyperglycemia-related metabolic unloading may confound interpretation. Whether SGLT2 inhibitors stimulate erythropoiesis independently of diabetes and independently of cardiorenal improvement remains insufficiently explored.
Objective
To evaluate the erythropoietic effects of dapagliflozin in non-diabetic patients with heart failure and to determine whether hematologic changes are associated with concurrent changes in renal function or cardiac status.
Methods
In this retrospective–prospective observational study, each of 68 non-diabetic heart failure patients served as their own control. Hematologic, renal, and cardiac parameters were assessed at three time points: one year prior to dapagliflozin initiation, at baseline, and one year after initiation of therapy. Changes were analyzed using paired tests and correlation analyses.
Results
After one year of dapagliflozin therapy, hemoglobin increased from a median of 13.0 g/dL at baseline to 14.3 g/dL, hematocrit from 40.4% to 43.65%, and red blood cell count from 4.43 to 4.75 ×10⁶/µL (all p < 0.001). These increases reversed a declining hematologic trajectory observed during the year preceding treatment. Mean corpuscular indices remained stable, indicating a quantitative increase in erythrocytes rather than altered erythrocyte morphology. Changes in hemoglobin showed no significant correlation with changes in estimated glomerular filtration rate (rho = 0.202, p = 0.098) or NT-proBNP (rho = –0.003, p = 0.981), despite modest improvements in both renal and cardiac parameters. In contrast, hematologic variables were strongly intercorrelated (e.g., Δhemoglobin – Δhematocrit rho = 0.875, p < 0.001), supporting a coherent erythropoietic response evolving independently of cardiorenal changes.
Conclusion
In non-diabetic patients with heart failure, dapagliflozin induces a robust erythropoietic response that is independent of glycemic status and uncoupled from improvements in renal or cardiac function. These findings support the concept that erythropoiesis stimulation represents a direct, glycemia-independent pharmacologic effect of SGLT2 inhibition rather than a secondary consequence of decongestion or cardiorenal recovery. By demonstrating a comparable hematologic response in a non-diabetic cohort, our results extend mechanistic hypotheses, largely derived from diabetic populations, implicating renal metabolic unloading, iron mobilization, inflammatory modulation, and cellular stress signaling beyond hyperglycemic physiology. Dedicated mechanistic studies in non-diabetic populations are warranted to elucidate the underlying pathways and clinical implications.Evolution of parameters during therapyFor image description, please refer to the figure legend and surrounding text.Correlations ΔHGB-ΔeGFR/ΔNT-proBNPFor image description, please refer to the figure legend and surrounding text.