SGLT2 inhibitors and secondary polycythemia: a systematic review and meta-analysis of hematologic effects in patients with type 2 diabetes

Abstract

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used in the management of type 2 diabetes mellitus (T2DM) due to their survival benefits. However, these agents are associated with increases in hemoglobin (Hgb) and hematocrit (Hct), raising concern for secondary polycythemia or erythrocytosis and potential thrombotic risk. The clinical significance of these hematologic changes remains unclear. Methods We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines. PubMed, Scopus, and Embase were searched up to February 2026 for studies evaluating the effect of SGLT2 inhibitors on hematologic parameters in adults with T2DM. Patients with primary polycythemia, end-stage renal disease (ESRD), or heart failure were excluded. Primary outcomes were changes in Hgb and Hct. Secondary outcomes included the incidence of erythrocytosis/polycythemia and thrombotic events. Results A total of 10 studies met inclusion criteria, comprising randomized and observational studies, with follow-up ranging from 8 weeks to 24 months. SGLT2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, were consistently associated with increases in Hgb and Hct. Across three randomized controlled trials, SGLT2 inhibitors significantly increased hematocrit (3 studies, 171 patients, pooled mean difference + 2.29%, 95% CI 1.48 to 3.09) and hemoglobin (3 studies, 171 patients, pooled mean difference + 0.51 g/dL, 95% CI 0.28 to 0.74) compared with placebo. Real-world data (9,646 patients) reported an increase in polycythemia prevalence from 2.4% to 9.7%, with severe cases in 1.4% of patients. Limited data suggested a potential association with thrombotic events, with one observational study of 100 patients with JAK2-unmutated erythrocytosis reporting a 10% event rate. Hematologic changes were observed early after treatment initiation and appeared reversible following drug discontinuation. Conclusions In patients with type 2 diabetes, ESRD, or heart failure, SGLT2 inhibitor use is associated with consistent increases in hemoglobin and hematocrit. Although these effects may contribute to cardiovascular benefit, a subset of patients may develop clinically significant erythrocytosis. Clinicians should be aware of this potential effect and monitor high-risk individuals. Larger prospective studies are needed to better define the clinical significance of these findings.