Can Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, such as canagliflozin (SGLT2 inhibitor), dapagliflozin (SGLT2 inhibitor), or empagliflozin (SGLT2 inhibitor), cause polycythemia in patients with type 2 diabetes, especially those with a history of cardiovascular disease or other comorbidities?

SGLT2 Inhibitors and Polycythemia

SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) do cause a modest increase in hematocrit and hemoglobin levels through hemoconcentration, but this is not true polycythemia and does not require treatment discontinuation in most patients.

Mechanism of Hematocrit Elevation

The increase in hematocrit with SGLT2 inhibitors occurs through volume contraction rather than increased red blood cell production 1. These medications cause:

• Osmotic diuresis and natriuresis leading to intravascular volume depletion 1
• Hemoconcentration that typically results in a 2-5% increase in hematocrit from baseline 1
• This effect appears within the first weeks of therapy and stabilizes thereafter 2

Clinical Significance and Safety

This hematocrit elevation is generally not clinically concerning and does not represent true polycythemia 1. The cardiovascular outcome trials that demonstrated mortality benefits included patients who experienced these hematocrit changes:

• Empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49-0.77) despite hematocrit increases 1
• Canagliflozin reduced MACE by 14% (HR 0.86, p<0.01) with similar hematocrit effects 1
• Dapagliflozin reduced cardiovascular death or heart failure hospitalization by 29% (HR 0.71,95% CI 0.55-0.92) 2, 3

When to Exercise Caution

Monitor volume status carefully in patients at higher risk for volume depletion 1:

• Elderly patients (>65 years) who have higher baseline risk of volume-related adverse effects 2
• Patients on concurrent loop diuretics who may experience excessive volume contraction 1, 2
• Those with low baseline systolic blood pressure (<110 mmHg) 1
• Patients with baseline eGFR 30-60 mL/min/1.73 m² who are more susceptible to volume changes 1, 2

Practical Management Algorithm

For patients developing elevated hematocrit on SGLT2 inhibitors:

1. Assess volume status clinically - check for orthostatic hypotension, signs of dehydration, or excessive diuresis 1, 2

2. If volume depleted: Reduce concurrent diuretic doses first before considering SGLT2 inhibitor discontinuation 1, 2

3. If euvolemic with modest hematocrit elevation (2-5% increase): Continue SGLT2 inhibitor given proven mortality benefits 1, 4

4. If hematocrit rises >5% from baseline with symptoms: Consider temporary discontinuation, correct volume status, then rechallenge at lower diuretic doses 1, 2

Common Pitfall to Avoid

Do not discontinue SGLT2 inhibitors solely based on laboratory hematocrit elevation without clinical assessment 1. The cardiovascular and renal protective benefits (32% reduction in all-cause mortality with empagliflozin) far outweigh the risk from hemoconcentration in most patients 1, 5. The hematocrit changes observed in clinical trials did not result in increased thrombotic events or adverse outcomes 4, 5.