A comprehensive study published in JAMA Network Open reveals that sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with increased red blood cell counts in patients with type 2 diabetes, but importantly, this condition does not elevate the risk of dangerous blood clots. The findings provide reassurance about the safety profile of these widely prescribed diabetes medications while highlighting the need for targeted monitoring in certain patient populations.
Study Findings on Erythrocytosis Prevalence
The population-based study analyzed over 134,000 patients with type 2 diabetes, comparing those who initiated SGLT2 inhibitors with patients using alternative treatments including DPP-4 inhibitors and GLP-1 receptor agonists. Researchers found that 6.6% of patients starting SGLT2 inhibitors developed erythrocytosis within 12 months, significantly higher than the 2.4% rate observed in patients using other glucose-lowering medications.
Treatment with SGLT2 inhibitors was associated with a mean increase of 0.35 and 0.37 g/dL in hemoglobin and a 1.4% and 1.5% increase in hematocrit compared with DPP-4 inhibitors and GLP-1 receptor agonists, respectively. The study authors noted that "the rise in hemoglobin was slightly lower than in previous randomized clinical trials and observational studies that reported an increase in hemoglobin, ranging between 0.5 and 1.0 g/dL."
Risk Factors and Medication Differences
The research identified specific patient populations at higher risk for developing erythrocytosis. Men demonstrated more than four times the rate of erythrocytosis compared to women, while smokers also showed significantly elevated risk. Among the SGLT2 inhibitor class, empagliflozin users had a higher likelihood of developing erythrocytosis compared to those taking dapagliflozin.
Before treatment initiation, the prevalence of erythrocytosis was 6.7% in the SGLT2 inhibitor group and 5.6% in the DPP-4 inhibitor comparison group. After treatment, the SGLT2 inhibitor group showed an increase to 12.1%, while the DPP-4 inhibitor group decreased to 3.5%. Similar patterns emerged when comparing SGLT2 inhibitors to GLP-1 receptor agonists.
Mechanism and Clinical Implications
Research presented at the American Society of Hematology in 2024 provided mechanistic insights, confirming that SGLT2 inhibitors raise erythropoietin levels. This finding suggests the increase in red blood cells results from a direct physiological effect rather than dehydration, as some had previously theorized.
The hemoglobin levels for the SGLT2 inhibitor group increased from 13.37 g/dL at baseline to 13.72 g/dL one year after treatment, while the DPP-4 inhibitor comparison group showed levels of 13.28 g/dL decreasing to 13.09 g/dL. Hematocrit levels in SGLT2 inhibitor users increased from 41.07% to 42.49% at one year of treatment.
Thrombotic Risk Assessment
Despite theoretical concerns that elevated red blood cell counts could increase thrombotic risk, the study found no evidence of increased danger. New-onset erythrocytosis was not associated with an increased risk of myocardial infarction, venous thromboembolism, or stroke when evaluating strict criteria. Notably, for more lenient criteria, erythrocytosis was actually associated with a reduced risk of stroke.
The study authors concluded that "SGLT2i-induced erythrocytosis was not associated with an increased risk of arterial or venous thrombosis. These findings strengthen the limited existing literature that previously explored the association between SGLT2i-induced erythrocytosis and thrombotic events."
Clinical Monitoring Considerations
The findings have important implications for clinical practice, particularly for pharmacists and healthcare providers monitoring patients on SGLT2 inhibitors. The research suggests that while erythrocytosis occurs in a meaningful subset of patients, it does not warrant discontinuation of these beneficial medications due to thrombotic concerns.
SGLT2 inhibitors, including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, are approved for glycemic control, reduction of major adverse cardiovascular events, and reduction in risk of cardiovascular hospitalization and death for patients with heart failure. The medications work by preventing reabsorption of filtered glucose from the tubular lumen.
The study reinforces the importance of regular laboratory monitoring, particularly for male patients and smokers who may be at higher risk for developing erythrocytosis. However, the absence of increased thrombotic risk provides reassurance that SGLT2 inhibitors can continue to be prescribed safely while maintaining appropriate clinical surveillance.
