Effect of SGLT2 Inhibitors on Erythrocytosis and Arterial Thrombosis Risk in Patients with Type 2 Diabetes Mellitus: A Real-World Multi-Center Cohort Study across the United States
Authors: Chen Yu-Han , Hsieh Tina Yi Jin , Sun Andrea Yue-En , Rastogi Natasha , Wei James Cheng-Chung , Lee Cho-Hao 
Published: December 2024

Background
Recent clinical studies have indicated a connection between Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i) and erythrocytosis. Little is known about the mechanism of medication-induced erythrocytosis and the relationship between secondary erythrocytosis, specifically SGLT2i-induced erythrocytosis, and the risk of thrombosis.
This study aims to 1) identify a potential correlation between the use of SGLT2i in patients with type 2 diabetes mellitus (T2DM) and erythrocytosis 2) examine whether a correlation would increase the incidence of arterial thrombosis.
Method
This retrospective study included electronic health records from over 50 U.S. healthcare organizations within the TriNetX Network. The baseline cohort consisted of adults aged ≥18 with Glucagon-Like Peptide-1 Receptor Agonists (GLP1RA), Dipeptidyl Peptidase 4 Inhibitors (DPP4i), or SGLT2i prescriptions following a T2DM diagnosis after 5/1/2005 (first GLP1RA approval) or 5/1/2014 (first SGLT2i approval) to 12/31/2021. The group of interest were patients on monotherapy of SGLT2i, while the control group were those on DPP4i or GLP1RA.
The exclusion criteria included patients with stage 4-5 chronic kidney disease, end-stage renal disease, post-renal transplant status, pre-existing erythrocytosis before initiation of GLP1RA, DPP4i, or SGLT2i, and underlying hematologic malignancies. Patients were observed until one of the following conditions was met 1) outcome development 2) study end date of 6/24/2024 3) loss follow-up.
Primary outcomes included the risk of hemoglobin (Hb) levels exceeding 16.0 g/dL in females and 16.5 g/dL in males, as well as hematocrit levels exceeding 48% in females and 54% in males. The study also analyzed the risk of arterial thromboembolic events including stroke or transient ischemic attack (TIA), myocardial infarction (MI), and major adverse cardiovascular events (MACE).
1:1 propensity score matching was conducted to balance the cohorts on demographics, comorbidities, socioeconomic factors, medication usage, laboratory results, HbA1C, and BMI. Cox regression model generated hazard ratios (HR) and 95% confidence intervals (CI) for the events between the comparison groups.
Results
The female T2DM patients treated with SGLT2i (n=137,478) had a significantly higher risk of hematocrit &gt; 48% and Hb &gt; 16.0 g/dL compared to the DPP4i cohort (n=136,874), with a HR of 2.16 (95% CI: 2.08-2.25) and HR of 2.00 (95% CI: 1.91-2.10), respectively. However, the SGLT2i cohort had a significantly lower risk of stroke or TIA (HR 0.80, 95% CI: 0.78-0.83), MI (HR 0.88, 95% CI: 0.84-0.92), and MACE (HR 0.75, 95% CI: 0.73-0.77).
The male T2DM patients treated with SGLT2i (n=129,503) had a significantly higher risk of hematocrit &gt; 54% and Hb &gt; 16.5 g/dL compared to the DPP4i cohort (n=129,855), with a HR of 2.06 (95% CI: 1.94-2.20) and HR of 1.92 (95% CI: 1.86-1.97). The risk of stroke or TIA and MACE was lower with SGLT2i compared to DPP4i (HR 0.65, 95% CI: 0.63-0.67 and HR 0.70, 95% CI: 0.67-0.73).
The female T2DM patients treated with SGLT2i (n=114,249) had a significantly higher risk of hematocrit &gt; 48% and Hb &gt; 16.0 g/dL compared to those treated with GLP1RA (n=115,159), with a HR of 1.97 (95% CI: 1.86-2.06) and HR of 1.82 (95% CI: 1.73-1.93). The SGLT2i cohort had a significantly lower risk of MACE (HR 0.93, 95% CI: 0.90-0.96).
Similarly, the male T2DM patients treated with SGLT2i (n=145,545) had a significantly higher risk of hematocrit &gt; 54% and Hb &gt; 16.5 g/dL compared to those treated with GLP1RA (n=145,467), with a HR of 1.61 (95% CI: 1.53-1.70) and HR of 1.60 (95% CI: 1.56-1.66). The SGLT2i cohort had a significantly lower risk of MACE (HR 0.95, 95% CI: 0.93-0.98).
Conclusion
Our study demonstrated an association between SGLT2i and erythrocytosis, potentially due to hemoconcentration, changes in iron metabolism, or increased erythropoietin production, as noted in other studies. Despite this association, SGLT2i initiators had lower risk of thromboembolic events compared to DPP4i, and lower risk of MACE compared to GLP1RA group.
Further research is needed to explore if increased hemoglobin levels in patients with T2DM on SGLT2i are associated with thromboembolic risks. Additionally, studies should investigate other adverse effects, such as venous thromboembolic events, and assess whether clinicians should implement interventions to manage erythrocytosis in SGLT2i patients to prevent adverse outcomes.