How does Empagliflozin affect hematocrit levels?

Empagliflozin Raises, Not Lowers, Hematocrit

Empagliflozin consistently increases hematocrit levels, not decreases them—this effect is well-documented across multiple clinical trials and appears to be mediated primarily through increased erythropoiesis rather than simple hemoconcentration. 1, 2, 3

Mechanism of Hematocrit Increase

The rise in hematocrit with empagliflozin occurs through two distinct mechanisms:

Primary Mechanism: Enhanced Erythropoiesis

• Empagliflozin stimulates erythropoietin production, with a significant increase of 2.6 IU/L observed at 12 weeks compared to placebo in heart failure patients 1
• The effect on erythropoiesis is delayed, with hematocrit increases becoming significant only after 3 months of treatment, despite immediate diuretic effects occurring within 1 day 3
• Empagliflozin reduces hepcidin levels (adjusted ratio 0.76), which augments early iron utilization for red blood cell production 1
• Increased urinary glucose excretion correlates with erythropoietin induction (Spearman rho 0.64; P = 0.008), suggesting reduced tubular glucose reabsorption may decrease cellular stress and increase renal erythropoietin secretion 3

Secondary Mechanism: Volume Contraction

• Osmotic diuresis contributes modestly to hematocrit elevation, but the delayed time course (3 months vs. 1 day for diuresis) indicates this is not the primary mechanism 3
• Hematocrit increases are consistent regardless of baseline diuretic dose, suggesting the effect is independent of volume status 4

Clinical Evidence Across Populations

Magnitude of Effect

• In heart failure patients, empagliflozin increases hematocrit at 52 weeks regardless of baseline diuretic therapy 4
• In type 2 diabetes patients, dapagliflozin (same drug class) produces consistent hematocrit increases across all eGFR levels (≥45 to <60, ≥60 to <90, and ≥90 mL/min/1.73 m²) 5
• The hematocrit increase is accompanied by rises in hemoglobin (baseline 136 g/L to 142 g/L at 3 months, P = 0.008) and red blood cell count 3

Prognostic Significance

• Hematocrit changes mediate 99.5% of empagliflozin's kidney protective effects in time-dependent analyses and 40.7% in landmark analyses, making it the strongest mediator of renal benefit 2
• Hemoglobin changes mediate 79.4% of kidney benefits, further supporting the importance of erythropoietic effects 2

Iron Metabolism Changes

Empagliflozin increases iron utilization for erythropoiesis, evidenced by:

• Decreased ferritin levels (P = 0.017) 3
• Decreased total iron (P = 0.053) 3
• Decreased transferrin saturation (P = 0.030) 3
• Increased transferrin concentrations (P = 0.063), indicating enhanced iron transport capacity 3

Clinical Implications

Monitor for anemia improvement rather than worsening when initiating empagliflozin, particularly in heart failure patients where baseline anemia prevalence was 28% 1

The hematocrit increase occurs independently of:

• Baseline diabetes status 1
• Baseline anemia status 1
• Baseline chronic kidney disease status 1
• Baseline diuretic dose 4
• eGFR level (effects consistent across renal function ranges) 5

This erythropoietic effect may contribute to the cardiovascular and renal protective properties of SGLT2 inhibitors, as the hematocrit increase independently predicts clinical benefit 2, 3