The Relationship between Sodium-Glucose Co-Transporter 2 Inhibitors and Erythrocytosis: A Retrospective Review from a Large Urban Center

Introduction

Sodium-Glucose Co-Transporter 2 inhibitors (SGLT2i), FDA-approved for treating diabetes mellitus, have gained popularity for their benefits in patients with heart failure and chronic kidney disease. However, they are also associated with erythrocytosis. The mechanism behind this could be explained by increased production of erythropoietin (EPO). The use of SGLT2i reduces renal cortical oxidative stress, thereby leading to a rise in EPO production. The diuretic properties associated with SGLT2i can also cause hemoconcentration (Shah et al., 2022). The current literature on the effect of SGLT2i and erythrocytosis in real-world patients is limited. Additionally, many of these patients are referred to hematology clinics and undergo extensive workup for erythrocytosis (e.g., bone marrow biopsies, mutation analysis testing). Therefore, our study sought to determine the effects of SGLT2i on hemoglobin (Hb) and hematocrit (Hct) levels within our own institution’s population.

Methods

A retrospective review was conducted on 57 patients with diabetes mellitus referred to our center with concomitant SGLT2i usage and erythrocytosis. Erythrocytosis was defined as Hb >16 g/dL in females and Hb >16.5 g/dL in males. Patients with JAK 2 mutations or incomplete data were excluded. 3 out of 57 patients had Post-Transplant Erythrocytosis and were also excluded. Resulting in 34 patients in the dataset. Data was collected regarding age, gender, type of SGLT-2 inhibitor, baseline Hb, baseline Hct, peak Hb, peak Hct, and erythropoietin (EPO) level, history of smoking, Obstructive Sleep Apnea (OSA) diagnosis, and thrombosis events. Descriptive statistics and paired t-tests were used to analyze the data.

Results

The mean age of patients was 61.2 years, with 59% males and 41% females. Of the patients, 35% had a history of OSA, while 47% had a smoking history (32.3% former smokers and 14.7% current smokers). Mean EPO level was 22.84 mU/mL (N=30). 26 out of 30 patients had normal EPO levels (5-30 mU/mL). The most popular SGLT-2 inhibitor was empagliflozin (79.4%) followed by dapagliflozin (8.8%), ertugliflozin (8.8%), and canagliflozin ( 3%). One patient had a history of DVT, but it was prior to initiation of SGLT-2 inhibitor therapy. Mean Baseline Hb/Hct was 15.3 g/dL with a standard deviation (SD) of 1.34 g/dL and 47.2% (SD 3.59%) respectively. Mean peak Hb/HCT was 17.48 g/dL (SD 1.03 g/dL) and 53.42 % (SD 4.09%) respectively. There was a significant difference between baseline and peak Hb (p<0.001) and Hct (p<0.001) values after starting an SGLT-2 inhibitor. Mean Time to peak Hb and Hct levels was 25.9 months. Additionally, there was a significant difference between baseline and peak Hb (p<0.001) and Hct (p<0.001) levels across all subgroups (males, females, OSA history, and smoking history).

Of the original 57 patients, one patient was discovered to be Jak 2 (V617F) positive after initiation of SGLT2i. Their baseline Hb was 16.3 g/dL and peak Hb was 17.2 g/dL. Their baseline Hct was 49.1 and peak Hct was 51.9. Additionally, out of the original 57 patients, 44 patients had JAK 2 mutation testing.

Conclusions

We observed a significant difference between baseline and peak Hb and Hct levels following initiation of SGLT-2 inhibitor. Despite the increase in Hb/Hct levels, there were no reports of thrombosis during SGLT-2 inhibitor therapy. Furthermore, one meta-analysis showed there was no association between venous thromboembolism events in patients treated with SGT2i (Wang et al., 2019). Given the considerable benefit of SGLT2i, further studies could focus on long-term patient monitoring, as the benefits of continuing SGLT2i may outweigh the risks of discontinuation. Additionally, further education should be provided to primary care providers regarding the possibility of erythrocytosis while on SGLT2i to prevent unnecessary workup, especially if the time to peak Hb/HCT levels is around two years, as our study showed.