Increased risk of erythrocytosis in men with type 2 diabetes treated with combined sodium-glucose cotransporter-2 inhibitor and testosterone replacement therapy.

Combined SGLT-2i and TRT therapy was associated with significantly higher odds of erythrocytosis compared to SGLT-2i alone in adjusted analyses.

• Adjusted OR of erythrocytosis for combination therapy vs. SGLT-2i alone was 3.80 (95% CI 2.27-6.11)
• Unadjusted OR for combination vs. SGLT-2i alone was 4.99 (95% CI 3.10-7.71)
• Logistic regression model was adjusted for baseline hematocrit, age, BMI, obstructive sleep apnea, diuretic use, and smoking status
• Erythrocytosis was defined as hematocrit level >54% within 365 days of therapy initiation

Combined SGLT-2i and TRT therapy was associated with significantly higher odds of erythrocytosis compared to TRT alone in adjusted analyses.

• Adjusted OR of erythrocytosis for combination therapy vs. TRT alone was 2.49 (95% CI 1.51-3.59)
• Unadjusted OR for combination vs. TRT alone was 2.91 (95% CI 1.87-4.31)
• Analysis was conducted in a retrospective nationwide cohort of US Veterans with type 2 diabetes

The overall rate of new-onset erythrocytosis in the entire cohort of patients with type 2 diabetes was 1.4%.

• Total cohort size was 53,971 people with type 2 diabetes
• 756 patients (1.4%) developed erythrocytosis across all treatment groups
• Patients were required to have baseline hematocrit between 38% and 50%
• Adequate medication adherence was defined as proportion of days covered >80%
• Study period was between March 2013 and October 2022

Testosterone delivery route did not modify the increased odds of erythrocytosis in the combination therapy group.

• Topical versus injectable testosterone administration routes were compared
• Neither delivery route modified the increased odds of erythrocytosis associated with combination therapy
• This finding suggests the erythrocytosis risk is a class effect of TRT rather than route-specific

Both SGLT-2i and TRT have individually been shown in clinical trials to stimulate red blood cell production.

• The erythropoietic effects of each therapy alone are established from prior clinical trial data
• Little was previously known about whether combination therapy poses additional erythrocytosis risk in real-world clinical practice
• This study represents the first large cohort demonstration of the combined erythrocytosis risk