Uncoupling Erythropoiesis from Cardiorenal Effects: SGLT2 Inhibition in Non-Diabetic Heart Failure

Background and Objectives: SGLT2 inhibitors increase hemoglobin and hematocrit in multiple clinical settings, an effect increasingly attributed to stimulation of erythropoiesis rather than hemoconcentration. However, most mechanistic evidence derives from diabetic populations, leaving uncertainty as to whether this response depends on diabetes-related metabolic changes. To evaluate whether dapagliflozin stimulates erythropoiesis in non-diabetic patients with heart failure and to determine whether hematologic changes correlate with renal, cardiac, inflammatory, hepatic, or iron-related parameters. Materials and Methods: In this retrospective observational study, each of 68 non-diabetic heart failure patients served as their own control. Hematologic, renal, cardiac, inflammatory, hepatic, and iron 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: Hemoglobin, hematocrit, and red blood cell count were significantly lower at the baseline compared with values recorded one year before dapagliflozin initiation and increased significantly during the year following treatment (all p < 0.001), while mean corpuscular indices remained stable. Serum iron decreased before treatment and increased significantly after dapagliflozin initiation (p < 0.05 vs. baseline); however, changes in serum iron did not correlate significantly with changes in hemoglobin after treatment. Inflammatory markers showed a modest reduction in C-reactive protein after treatment, while composite inflammatory indices remained largely stable. Liver enzymes showed no significant longitudinal changes. Correlation analyses demonstrated no association between changes in hemoglobin and changes in eGFR (ρ = 0.202, p = 0.098) or NT-proBNP (ρ = −0.003, p = 0.981) after treatment. Hematologic variables remained strongly intercorrelated, whereas cross-system correlations were minimal, indicating that erythropoietic stimulation occurred largely independently of renal or cardiac functional trajectories. Conclusions: Dapagliflozin robustly stimulates erythropoiesis in non-diabetic patients with heart failure, independent of improvements in kidney or cardiac function. Although serum iron levels improved after treatment, the absence of a direct correlation with hemoglobin suggests that iron mobilization may act as a permissive rather than a primary driver of erythropoietic response. These findings support the concept that erythropoiesis represents a diabetes-independent pharmacologic action of SGLT2 inhibitors and may involve renal, hepatic, inflammatory, and iron-regulatory pathways beyond those described in diabetic physiology. Dedicated mechanistic studies in non-diabetic populations are warranted.