Evaluating Erythrocytosis Incidence and Thromboembolic Risk in HFrEF Patients Treated with SGLT2 Inhibitors

Introduction

Heart failure with reduced ejection fraction (HFrEF) poses a significant clinical challenge, characterized by a state of chronic inflammation and neurohormonal activation. Recent advances in pharmacotherapy, particularly the advent of sodium-glucose cotransporter-2 inhibitors (SGLT2i), have transformed management strategies for HFrEF. Among these benefits are improvements in cardiovascular outcomes. However, there are concerns about potential side effects associated with these agents, particularly regarding hematological changes such as erythrocytosis, which may elevate thromboembolic risk.

Study Background and Disease Burden

Erythrocytosis, defined as elevated hemoglobin levels (>16.5 g/dL in men and >16.0 g/dL in women), can develop as a secondary condition in various contexts, including chronic hypoxia and pharmacological interventions. SGLT2 inhibitors have been found to increase hemoglobin and hematocrit levels, suggesting a propensity for erythrocytosis. The potential for an increased thromboembolic risk elevates the urgency of studying this association, particularly in HFrEF patients, who are already at heightened risk for complications including myocardial infarction and stroke. The aim of this nationwide register-based cohort study was to investigate the incidence of erythrocytosis in HFrEF patients treated with SGLT2 inhibitors and its correlation with thromboembolic events.

Study Design

This study was structured as a nationwide cohort analysis, encompassing 3,138 patients diagnosed with new-onset HFrEF who commenced treatment with SGLT2 inhibitors and 3,138 matched untreated controls based on propensity scores. Key assessments included measuring hemoglobin levels at baseline and following a six-month treatment period, and evaluating erythrocytosis incidence using Poisson regression models. To explore the relationship between erythrocytosis and thromboembolic outcomes, Cox proportional hazards models were applied, specifically stratifying by SGLT2i treatment status and considering events such as myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis over a one-year follow-up.

Key Findings

The results indicated that 207 patients (3.3%) developed erythrocytosis over the six-month follow-up period. Significantly, the incidence of erythrocytosis was higher among SGLT2i-treated patients, reported at 109.5 cases per 1000 person-years compared to 26.8 per 1000 person-years in the control group. After adjusting for confounding variables, the study demonstrated an incidence rate ratio (IRR) of 4.10 (95% CI: 2.95-5.83), highlighting a marked increase in risk among treated individuals.

Despite the observed incidence of erythrocytosis, there was no significant association noted between erythrocytosis and the risk of one-year thromboembolic events across the total study population. The hazard ratios were 0.85 (95% CI: 0.44-1.65) for the overall cohort, with no differing significance in SGLT2i-treated (HR: 0.81; 95% CI: 0.38-1.74) versus untreated patients (HR: 0.75; 95% CI: 0.19-3.05), and an interaction P-value of 0.77 underscored the consistency of the findings across groups.

Expert Commentary

The nuances of this study raise several pivotal points for clinical practice. While SGLT2 inhibitors exhibit a favorable safety profile, vigilance for hematological changes, particularly erythrocytosis, remains crucial. The elevated incidence in treated patients mandates close monitoring, although this study provides reassurance regarding the absence of a corresponding increment in thromboembolic risks. Further investigation is warranted to understand the biological mechanisms behind erythrocytosis in SGLT2 inhibitor therapy. Additionally, empowering healthcare providers with guidelines on monitoring parameters may optimize patient outcomes, especially in a high-stakes population like those with HFrEF.

Conclusion

The increased incidence of erythrocytosis in HFrEF patients receiving SGLT2 inhibitors reflects a peculiar hematological response linked to these therapies. Importantly, this change does not appear to elevate thromboembolic risk within one year, suggesting that while monitoring for erythrocytosis is necessary, it alone should not deter the use of SGLT2 inhibitors in clinical practice. Nevertheless, the study highlights key research gaps regarding long-term impacts of erythrocytosis and the interplay of heart failure treatments, necessitating ongoing research to corroborate these findings in diverse populations.

References

1. Mohamed AA, Andersen CF, Christensen DM, et al. Erythrocytosis incidence and thromboembolic risk in heart failure with reduced ejection fraction treated with SGLT2 inhibitors: a nationwide register-based cohort study. Cardiovasc Diabetol. 2025;24(1):314. doi:10.1186/s12933-025-02871-w.
2. [Additional literature on SGLT2 inhibitors and hematological effects].