Do sodium‑glucose cotransporter‑2 (SGLT2) inhibitors cause true polycythemia?

SGLT2 Inhibitors and Polycythemia

SGLT2 inhibitors do cause an increase in hematocrit and hemoglobin, but this represents increased erythropoiesis (true erythrocytosis) rather than hemoconcentration from diuresis, and the clinical significance depends on baseline hematocrit levels, particularly in males. 1

Mechanism: True Erythrocytosis, Not Hemoconcentration

The increase in hematocrit with SGLT2 inhibitors was historically attributed to volume contraction from their diuretic effect, but this explanation is inconsistent with the observed preservation of renal function. If hemoconcentration were the mechanism, we would expect volume contraction and deteriorating renal function similar to chronic diuretic use—the opposite of what occurs with SGLT2 inhibitors. 1

The current evidence indicates that SGLT2 inhibitors stimulate true erythropoiesis through:

• Amelioration of renal hypoxia 1
• More efficient erythropoietin production 1, 2
• Increased red blood cell count that improves myocardial and renal tissue oxygenation 1

This mechanism explains why hematocrit increase is the best predictor of cardio-renal benefits with SGLT2 inhibitors. 1

Prevalence and Magnitude

• Erythrocytosis occurs in approximately 16.9% of patients on SGLT2 inhibitors over a median follow-up of 530 days 3
• The median hemoglobin rise is 1.0 g/dL (IQR 0.4-1.8 g/dL) 3
• At one year, the proportion with erythrocytosis increases significantly: 16.9% vs 5.5% in males and 5.2% vs 1.0% in females compared to placebo 4

Risk Factors for Developing Erythrocytosis

Increased risk:

• Male sex (OR 3.24,95% CI 2.47-4.26) 3
• BMI ≥25 kg/m² (OR 1.97,95% CI 1.63-2.39) 3
• Current smoking (OR 2.41,95% CI 1.96-2.96) 3

Decreased risk:

• Age ≥70 years 3
• Hypertension 3
• Chronic kidney disease 3

Thrombotic Risk: Critical Sex-Based Differences

Males with Baseline Erythrocytosis

In males with pre-existing erythrocytosis (hematocrit >49%), canagliflozin may increase thrombotic risk. 4 Fractional polynomial analysis demonstrates treatment benefits in anemic males but potential harm in those with erythrocytosis, primarily driven by increased myocardial infarction risk. 4

Females

No heterogeneity in thrombotic outcomes was observed in females across hematocrit levels. 4

Overall Thrombotic Risk

• Thrombosis is rare overall (0.5%, 33/6787 patients) 3
• When thrombosis occurs, it is primarily associated with pre-existing conditions (atrial fibrillation, coronary calcification, atherosclerosis) rather than directly attributable to SGLT2-induced erythrocytosis 3
• Thrombosis risk factors include antiplatelet use (OR 3.57), anticoagulant use (OR 5.93), and baseline erythrocytosis (OR 3.75) 3

Clinical Management Algorithm

Before Initiating SGLT2 Inhibitors

Check baseline hematocrit/hemoglobin in all patients, particularly males. 4, 3

For males with baseline erythrocytosis (hematocrit >49%):

• Exercise caution when prescribing SGLT2 inhibitors 4
• Consider alternative agents (GLP-1 receptor agonists) if cardiovascular protection is the primary goal 5
• If SGLT2 inhibitor is essential for cardiorenal protection, proceed with enhanced monitoring 4

For females and males without baseline erythrocytosis:

• Initiate SGLT2 inhibitor per standard indications 5, 6

During Treatment

Monitor hematocrit at 3-6 months after initiation, then annually. 3, 2

If erythrocytosis develops during treatment:

• Assess for thrombotic risk factors (antiplatelet/anticoagulant use, atrial fibrillation, atherosclerotic disease) 3
• In males with new erythrocytosis and high thrombotic risk, consider phlebotomy or discontinuation 2
• In females or males without additional risk factors, continue SGLT2 inhibitor given the substantial cardiovascular and renal mortality benefits 5, 1

Balancing Benefits vs. Risks

The cardiovascular and renal benefits of SGLT2 inhibitors are substantial and generally outweigh the erythrocytosis risk. 5 For adults at high or very high risk of CKD progression, SGLT2 inhibitors reduce all-cause mortality, cardiovascular mortality, heart failure hospitalization, and kidney failure with high certainty evidence. 5

Common Pitfalls to Avoid

• Do not assume hematocrit increase is simply hemoconcentration—it represents true erythropoiesis with potential clinical implications 1
• Do not ignore baseline hematocrit in males—this is a critical risk stratification tool 4
• Do not reflexively discontinue SGLT2 inhibitors for mild erythrocytosis—the cardiorenal benefits are substantial and thrombotic risk is primarily driven by pre-existing conditions 3
• Do not apply male thrombotic risk data to females—sex-specific differences are significant 4