Sodium glucose cotransporter 2 inhibitors (SGLT2-i) are one of the four pillars of guideline-directed medical therapy in all patients with heart failure according to the current guidelines. Although SGLT2-i are known to increase hemoglobin (Hb) and hematocrit (Ht) levels, there is a lack of data on the burden of erythrocytosis in pivotal trials and real-world heart failure (HF) populations. ,, We have previously described a case of chronic HF with severe secondary, reversible SGLT2-i erythrocytosis in which the patient experienced HF exacerbation. Therefore, this multicenter study was designed to assess the real-world prevalence and potential adverse events of secondary erythrocytosis in patients with chronic HF.
This retrospective study included adult heart failure patients who visited the outpatient heart failure clinics of the Catharina Hospital (between 2021 and 2022) and the Erasmus MC (between 2020 and 2024). Patients were included if they had received at least 1 month of treatment with an SGLT2 inhibitor and if hemoglobin/hematocrit data was available at baseline and at follow-up visits every 6 months for 2 years. Those with baseline erythrocytosis or JAK2 mutations were excluded from the study. Erythrocytosis was defined according to the 2017 WHO classification as Hb >10.3 mmol/L (>16.5 g/dl) and/or Ht >0.49 L/L in men and Hb >10.0 mmol/L (>16.0 g/dl) and/or Ht >0.48 L/L in women. Logistic regression analysis was performed to analyze the effect size of covariates on developing erythrocytosis. Univariate and multivariate Cox proportional hazard regression analysis were performed to analyze the effect size of erythrocytosis and confounders on thromboembolic events and HF exacerbation in HF patients using SGLT2-i.
A total of 793 patients with HF was included ( Table 1 ). The overall prevalence of SGLT2-i-related erythrocytosis was 153 of 793 (19.3%; mean age 63.3 ± 11.6 years and 83% males). No differences in baseline characteristics were seen between the two groups except for the proportion of males was significantly higher in the erythrocytosis group (83% vs 67%; p < 0.001), as was the BMI (28.0 vs 26.8; p = 0.024), and the prevalence of obstructive sleep apnea syndrome (OSAS) (25% vs 16%; p = 0.006). The population consisted mainly of heart failure with reduced ejection fraction (HFrEF) patients, with a higher prevalence in the group with erythrocytosis (82% vs 68%) and higher baseline eGFR (64 ml/min/1.73m 2 vs 54 ml/min/1.73m 2; p = 0.007).
Table 1
Comparison of baseline characteristics and clinical outcomes between patients with and without erythrocytosis
|
No erythrocytosis
(n = 640) |
Erythrocytosis
(n = 153) |
p-value | |
|---|---|---|---|
| Age- years (SD) | 63.6 (±14.4) | 63.3 (±11.6) | 0.791 |
| Male gender, n (%) | 427 (66.7) | 127 (83.0) | <0.001 |
| BMI- Median (IQR) | 26.8 (23.8 to 30.8) | 28.0 (25.0 to 31.4) | 0.024 |
| Heart failure type, n (%) n = 792 | <0.001 | ||
| • HFrEF | 433 (67.8) | 126 (82.4) | |
| • HFmrEF | 115 (18.0) | 19 (12.4) | |
| • HFpEF | 91 (14.2) | 8 (5.4) | |
| Current smoker, n (%) | 97 (15.2) | 24 (15.7) | 0.473 |
| Medical history, n (%) | |||
| • Diabetes mellitus | 230 (35.9) | 59 (38.6) | 0.545 |
| • OSAS | 99 (15.5) | 38 (24.8) | 0.006 |
| • COPD | 91 (14.2) | 21 (13.7) | 0.910 |
| • CVA | 118 (18.4) | 23 (15.0) | 0.322 |
| • ACS | 275 (43.0) | 76 (49.7) | 0.134 |
| • PAD | 76 (11.9) | 12 (7.8) | 0.154 |
| • DVT | 28 (4.4) | 6 (3.9) | 0.804 |
| • PE | 41 (6.4) | 9 (5.9) | 0.811 |
| Heart failure medication, n (%) | |||
| • Dapagliflozin | 487 (76.1) | 122 (79.7) | 0.337 |
| • Empagliflozin | 153 (23.9) | 31 (20.3) | 0.337 |
| • ACE-inhibitor | 154 (24.1) | 42 (27.5) | 0.383 |
| • ARB | 83 (13.0) | 16 (10.5) | 0.399 |
| • Beta-blocker | 508 (79.4) | 124 (81.0) | 0.644 |
| • Diuretics | 575 (89.8) | 136 (88.9) | 0.727 |
| • Sacubitril-valsartan | 282 (44.1) | 67 (43.8) | 0.952 |
| Ferric carboxymaltose within 6 months prior to baseline, n (%) | 38 (5.9) | 6 (3.9) | 0.328 |
| Antithrombotic therapy, n (%) | |||
| • Vitamin K antagonist | 194 (30.3) | 48 (31.4) | 0.798 |
| • DOAC | 227 (35.5) | 53 (34.6) | 0.847 |
| • ASA | 113 (17.7) | 34 (22.2) | 0.192 |
| • P2Y12 inhibitor | 83 (13.0) | 20 (13.1) | 0.973 |
| Baseline NTproBNP (pg/ml)– median (IQR) | 423 (110 to 1,760) | 513 (138 to 1,527) | 0.904 |
| Baseline eGFR (ml/min/1.73 m 2)– median (IQR) | 54 (39 to 73) | 64 (46 to 75) | 0.007 |
|
Baseline hemoglobin (mmol/l)–
median (IQR) |
|||
| • Male | 8.3 (7.5 to 9.0) | 9.2 (8.6 to 9.6) | <0.001 |
| • Female | 7.8 (7.1 to 8.4) | 8.9 (8.5 to 9.2) | <0.001 |
|
Baseline hematocrit (L/L)–
median (IQR) |
|||
| • Male | 0.40 (0.37 to 0.44) | 0.45 (0.42 to 0.47) | <0.001 |
| • Female | 0.39 (0.36 to 0.42) | 0.44 (0.42 to 0.46) | <0.001 |
|
Peak hemoglobin (mmol/l)–
median (IQR) |
|||
| • Male | 9.1 (8.4 to 9.6) | 10.5 (10.2 to 10.8) | <0.001 |
| • Female | 8.7 (8.1 to 9.1) | 10.3 (9.9 to 10.6) | <0.001 |
|
Peak hematocrit (L/L)–
median (IQR) |
|||
| • Male | 0.44 (0.41 to 0.47) | 0.51 (0.50 to 0.53) | <0.001 |
| • Female | 0.42 (0.40 to 0.45) | 0.50 (0.49 to 0.52) | <0.001 |
| Time to peak hemoglobin, months median (IQR) | 7.0 (3.6 to 13.4) | 9.6 (5.5 to 17.1) | <0.001 |
| Time to peak hematocrit, months– median (IQR) | 9.8 (4.3 to 15.6) | 12.9 (6.9 to 18.8) | <0.001 |
| Delta hemoglobin– median (IQR) | 0.70 (0.20 to 1.2) | 1.30 (1.0 to 2.0) | <0.001 |
| Delta hematocrit– median (IQR) | 0.04 (0.01 to 0.06) | 0.07 (0.05 to 0.10) | <0.001 |
| Heart failure exacerbation during FU, n (%) | 146 (22.8) | 50 (32.7) | 0.011 |
| Blood transfusion, n (%) | 34 (5.3) | 3 (2.0) | 0.077 |
| Ferric carboxymaltose during FU, n (%) | 122 (19.1) | 34 (22.2) | 0.538 |
| Thromboembolic events during FU, n (%) | |||
| • CVA | 16 (2.5) | 5 (3.3) | 0.577 |
| • ACS | 18 (2.8) | 8 (5.2) | 0.132 |
| • PAD | 5 (0.8) | 1 (0.7) | 1.000 |
| • DVT | 1 (0.2) | 0 (0) | 1.000 |
| • PE | 5 (0.8) | 2 (1.3) | 0.626 |
| Death during FU, n (%) | 106 (16.9) | 14 (9.2) | 0.017 |
| Death cause, n (%) | 1.000 | ||
| • Cardiac | 56 (51.9) | 8 (57.1) | |
| • Non-cardiac | 25 (23.1) | 4 (28.6) | |
| • Unknown | 27 (25.0) | 2 (14.3) |
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