DENVER — Treatment with SGLT2 inhibitors was linked with modest but statistically significant increases in hemoglobin and hematocrit levels across a broad spectrum of patient populations, according to a systematic review and meta-analysis.
Across 85 randomized clinical trials encompassing over 70,000 patients with chronic kidney disease (CKD), heart failure, type 2 diabetes, cardiovascular disease, or combinations thereof, hemoglobin increased by an average of 0.55 g/dL in SGLT2 inhibitor groups and dropped by 0.08 g/dL in control groups over a median of 24 weeks (between-group difference 0.60 g/dL, 95% CI 0.55-0.66, P<0.001).
Additionally, hematocrit rose by 2.17% with SGLT2 inhibitors compared with a 0.13% decline in control arms (between-group difference 2.36%, 95% CI 2.19-2.52, P<0.001), reported Michele F. Eisenga, MD, PhD, of University Medical Center Groningen in the Netherlands, and colleagues.
The findings were presented at the American Society of Nephrology Kidney Week annual meeting and simultaneously published in JAMA.
“This is the largest and most comprehensive analysis to date of the effects of SGLT2 inhibitors on hematologic and iron-related parameters,” Eisenga told MedPage Today.
“Previous trials had already shown that SGLT2 inhibitors increase hemoglobin and hematocrit, but we were surprised in our systematic review and meta-analysis by how consistent these effects were across more than 70,000 participants and a wide range of patient populations,” he added.
The authors noted that these increases “may explain the improvement in quality of life previously reported with SGLT2 inhibitors in patients with heart failure and CKD.” However, they cautioned that among patients with elevated baseline hemoglobin and hematocrit, further increases could potentially elevate the risk of thromboembolic events.
Four of six secondary outcomes also showed significant associations with SGLT2 inhibitor therapy:
- Increased erythropoietin (EPO): +2.35 mIU/mL vs +0.04 mIU/mL in control groups
- Increased red blood cell concentration: +0.23 × 1012/L vs +0.02 × 1012/L, respectively
- Decreased ferritin: -19.78 ng/mL vs -3.08 ng/mL
- Decreased transferrin saturation: -2.20% vs -0.10%
Changes in hepcidin (-15.00 ng/mL vs -0.96 ng/mL) and serum iron (-0.94 µmol/L vs -0.42 µmol/L) did not reach statistical significance.
“Doctors should recognize that the increase in hemoglobin seen with SGLT2 inhibitors is likely not just due to hemoconcentration,” Eisenga emphasized. “Beyond confirming increases in hemoglobin and hematocrit, we show a consistent pattern of higher erythropoietin levels alongside lower ferritin and transferrin saturation. This points toward a coordinated effect on iron metabolism and red blood cell production, rather than a simple effect of fluid loss.”
In an accompanying editorial, Kai-Uwe Eckardt, MD, of Charité-Universitätsmedizin Berlin, and Mark J. Koury, MD, of Vanderbilt University Medical Center in Nashville, noted that early observations initially attributed these rises primarily to hemoconcentration.
“However, the rise in hemoglobin concentrations only reached a maximum at 48 weeks of SGLT2 inhibitor treatment, suggesting a gradual adjustment of the feedback control of erythropoiesis rather than persistent volume contraction,” they wrote.
“Unfortunately, data on red blood cell indices in the SGLT2 inhibitor trials analyzed were very limited and measurements of red blood cell mass, plasma volume, and red blood cell lifespan were not reported,” Eckardt and Koury added. “Such evaluations are needed to confirm that the increases in hemoglobin and hematocrit are indeed due to increases in red blood cell mass.”
Nonetheless, “there are good reasons to believe that the modest rise of hemoglobin concentration associated with SGLT2 inhibitor treatment can contribute to anemia management,” they added.
The meta-analysis screened double-blind randomized trials evaluating SGLT2 inhibitors as monotherapy or add-on treatment. Across 70,543 participants, the mean age was 62.4, 35.9% were female, mean baseline hemoglobin was 13.6 g/dL, and mean hematocrit was 41.5%.
The majority of trials evaluated empagliflozin (Jardiance) and dapagliflozin (Farxiga), followed by canagliflozin (Invokana), ertugliflozin (Steglatro), ipragliflozin (not approved in the U.S.), luseogliflozin (not approved in the U.S.), sotagliflozin (Inpefa), and bexagliflozin (Brenzavvy).
Post hoc analyses suggested dose- and duration-dependent responses, with hemoglobin differences reaching 0.65 g/dL at 1.5 times the standard clinical dose and 0.71 g/dL at 48 weeks of follow-up.
Eisenga noted that future trials must evaluate whether these hematologic shifts directly drive cardiorenal benefits or reduce reliance on conventional anemia treatments.
