Sodium-Glucose Cotransporter 2 Inhibitors, Erythrocytosis, and Thrombosis in Adults With Type 2 Diabetes

Abstract

Importance: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are widely used and have been shown to induce erythrocytosis. However, the clinical implications of this phenomenon, particularly its association with venous and arterial thrombotic events, remain uncertain.

Objective: To assess the extent, temporal course, and thrombotic complications of SGLT2i-induced erythrocytosis.

Design, setting, and participants: This retrospective cohort study used patient data from Israel's largest health care organization from January 1, 2015, through June 30, 2024. Adult patients aged 18 years or older with type 2 diabetes who initiated SGLT2is were identified and compared with those who initiated dipeptidyl peptidase 4 inhibitors (DPP-4is) or glucagon-like peptide 1 receptor agonists (GLP-1RAs) using a propensity score-matched, active-comparator, new-user cohort design.

Exposure: New initiation of an SGLT2i, a GLP-1RA, or a DPP-4i.

Main outcomes and measures: Outcomes included erythrocytosis within 1 year of initiating SGLT2is, as well as arterial and venous thrombotic events until the end of follow-up. Prevalence rates, rate differences, and odds ratios (ORs) for new-onset erythrocytosis and hemoglobin increase greater than 0.5 g/dL with 95% CIs were calculated. Hazard ratios (HRs) and 95% CIs for thrombotic outcomes were estimated using time-varying Cox proportional hazards regression models.

Results: After 1:1 propensity score matching, a total of 137 552 adults were included in the SGLT2i vs DPP-4i cohort (68 776 pairs; SGLT2i initiators: mean [SD] age, 64.55 [12.03] years; 55.3% male; DPP-4i initiators: mean [SD] age, 64.73 [13.08] years; 53.5% male) and 131 512 adults in the SGLT2i vs GLP-1RA cohort (65 756 pairs; SGLT2i initiators: mean [SD] age, 63.73 [11.87] years; 52.0% male; GLP-1RA initiators: mean [SD] age, 62.77 [11.56] years; 51.4% female). Among SGLT2i initiators, erythrocytosis prevalence in the SGLT2i vs DPP-4i cohort increased by 5.5% (95% CI, 5.1%-5.8%) and in the SGLT2i vs GLP-1RA cohort by 5.8% (95% CI, 5.4%-6.2%). In the SGLT2i vs GLP-1RA cohort, hemoglobin increased by 0.37 g/dL (95% CI, 0.36-0.38 g/dL) and hematocrit by 1.50% (95% CI, 1.48%-1.53%). Male sex (adjusted OR [AOR], 4.12; 95% CI, 3.80-4.48), smoking (AOR, 2.00; 95% CI, 1.85-2.16), and the use of empagliflozin vs dapagliflozin (AOR, 1.16; 95% CI, 1.09-1.25) were associated with an increased risk of developing erythrocytosis. New-onset erythrocytosis was not associated with an increased risk of myocardial infarction (HR, 0.92; 95% CI, 0.58-1.44), venous thromboembolism (HR, 1.56; 95% CI, 0.68-3.60), or stroke (HR, 1.26; 95% CI, 0.84-1.90).

Conclusions and relevance: In this cohort study of patients with type 2 diabetes, SGLT2i use was associated with a higher risk of erythrocytosis compared with DPP-4is and GLP-1RAs; however, erythrocytosis was not associated with thrombotic events. These findings provide important reassurance regarding the safety of SGLT2i-induced erythrocytosis.

Figure 1.. Hemoglobin and Hematocrit Levels Over Time Among Patients With Type 2 Diabetes Initiating Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2is) vs Dipeptidyl Peptidase 4 Inhibitors (DPP-4is) or Glucagon-Like Peptide 1 Receptor Agonists (GLP-1RAs) After Propensity Score Matching

Lines were smoothed using the locally weighted scatterplot smoothing method. The shaded areas around the curves indicate 95% CIs.

Figure 2.. Kaplan-Meier Curves for Thrombotic Events (Myocardial Infarction, Venous Thromboembolism, and Stroke) in Sodium-Glucose Cotransporter 2 Inhibitor Initiators With and Without New-Onset Erythrocytosis

Lenient criteria included hemoglobin greater than 16.5 g/dL or hematocrit greater than 49% in men and hemoglobin greater than 16.0 g/dL or hematocrit greater than 48% in women based on the 2016 World Health Organization classification. Strict criteria included hemoglobin greater than 18.5 g/dL or hematocrit of at least 52% in men and hemoglobin greater than 16.5 g/dL or hematocrit of at least 48% in women based on 2005 British Society of Hematology criteria. To convert hemoglobin values to grams per liter, multiply by 10; to convert hematocrit values to a proportion of 1.0, multiply by 0.01. The shaded areas around the curves indicate 95% CIs.