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A meta-analysis of 85 randomized trials involving 70,543 people found that SGLT2 inhibitors were associated with modest increases in hemoglobin and hematocrit over a median 24 weeks. The findings suggest changes in red blood cell production and iron measures, but do not establish that the drugs treat anemia or that the blood changes cause their cardiorenal benefits.
A meta-analysis of 85 randomized trials found that SGLT2 inhibitors were associated with modest increases in hemoglobin and hematocrit across more than 70,000 participants with kidney disease, heart failure, type 2 diabetes, cardiovascular disease, or overlapping conditions. The findings, presented at the American Society of Nephrology’s Kidney Week meeting and published in JAMA, point to a consistent blood-related effect but do not establish that the drugs should be used as anemia treatment.
Across 70,543 participants, hemoglobin rose by an average of 0.55 g/dL in SGLT2 inhibitor groups and fell by 0.08 g/dL in control groups over a median of 24 weeks. The reported between-group difference was 0.60 g/dL (95% CI 0.55-0.66; P<0.001). Hematocrit increased by 2.17% with the drugs and declined by 0.13% in control groups, a between-group difference of 2.36 percentage points (95% CI 2.19-2.52; P<0.001).
The review, led by Michele F. Eisenga of University Medical Center Groningen in the Netherlands, also found changes in several secondary measures. Erythropoietin increased by 2.35 mIU/mL compared with 0.04 mIU/mL in control groups, while red blood cell concentration rose by 0.23 × 1012/L compared with 0.02 × 1012/L. Ferritin and transferrin saturation declined more in the treatment groups. Changes in hepcidin and serum iron did not reach statistical significance.
The trial participants had a mean age of 62.4 years; 35.9% were female. Their mean starting hemoglobin was 13.6 g/dL and mean hematocrit was 41.5%. Most trials studied empagliflozin or dapagliflozin, though several other SGLT2 inhibitors were included. Post hoc analyses suggested larger differences at higher doses and longer follow-up, but those analyses do not establish how the drugs should be prescribed for anemia.
Why Blood-Count Changes Matter
The findings add evidence that the rise in hemoglobin seen with SGLT2 inhibitors may involve more than a short-term concentration effect from fluid loss. The accompanying pattern of higher erythropoietin and lower ferritin and transferrin saturation is consistent with changes in red blood cell production and iron handling. The analysis, however, did not directly establish the mechanism.
The authors said the modest hemoglobin increase could be relevant to chronic anemia management and might help explain quality-of-life improvements previously reported in some people with heart failure or chronic kidney disease. Those are possible implications, not proof that the blood changes cause better quality of life or account for the drugs’ established benefits in these conditions. The review also does not show that SGLT2 inhibitors can replace conventional anemia treatments.
Safety may matter for patients who already have elevated hemoglobin or hematocrit. The authors cautioned that further increases could potentially raise thromboembolic risk in that group. The analysis reported blood measurements, not evidence that the treatment caused an increase in clotting events. The clinical significance and risks of the changes need further study.
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How Researchers Interpret the Rise
Earlier explanations for the increase in hemoglobin and hematocrit focused largely on hemoconcentration—a rise in measured concentration when fluid volume falls. In comments to MedPage Today, Eisenga said the meta-analysis found a pattern that, in his view, suggests a coordinated effect involving iron metabolism and red blood cell production rather than fluid loss alone.
An accompanying editorial by Kai-Uwe Eckardt of Charité-Universitätsmedizin Berlin and Mark J. Koury of Vanderbilt University Medical Center noted that hemoglobin increases reached their maximum at 48 weeks in the cited observations. They said that timing suggests gradual adjustment of erythropoiesis, rather than ongoing volume contraction, may be involved. The editorial authors also stressed that the trial evidence has important measurement gaps.
The researchers screened double-blind randomized trials of SGLT2 inhibitors used alone or alongside other treatments. The drugs are used across several chronic conditions, including type 2 diabetes, heart failure and chronic kidney disease. This broad range of trial populations allowed the review to compare blood-related changes across different clinical settings, but it does not answer every question about individual patients or long-term outcomes.
“This is the largest and most comprehensive analysis to date of the effects of SGLT2 inhibitors on hematologic and iron-related parameters.”
— Michele F. Eisenga, MD, PhD, of University Medical Center Groningen, speaking to MedPage Today
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Mechanism and Patient Risks
The trials reviewed provided limited data on red blood cell indices and did not report measurements of red blood cell mass, plasma volume or red blood cell lifespan, according to the accompanying editorial. As a result, the review cannot confirm which mechanisms produced the higher hemoglobin and hematocrit levels.
It also remains unclear whether these changes directly contribute to the heart and kidney benefits associated with SGLT2 inhibitors, improve anemia outcomes, or change the need for established anemia treatments. The authors said future studies are needed to test those possibilities. The report does not establish a patient-specific clot risk from the observed changes; the concern about people with high starting levels was presented as a potential risk, not a demonstrated outcome.
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Studies Needed to Test Clinical Effects
Eisenga said future trials should determine whether the hematologic changes directly contribute to cardiorenal benefits or reduce reliance on conventional anemia treatments. Studies that directly measure red blood cell mass, plasma volume and related variables could help clarify the biological mechanism, as the editorial authors recommended.
For now, the report establishes an association across a large set of randomized trials, with statistically significant average differences in hemoglobin and hematocrit. It does not provide a new treatment recommendation. Further evidence will be needed to establish whether the changes lead to measurable anemia-related benefits and how they affect patients with elevated baseline blood counts.
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Key Questions
What did the meta-analysis find?
Across 85 randomized trials, SGLT2 inhibitor treatment was associated with an average hemoglobin difference of 0.60 g/dL and a hematocrit difference of 2.36 percentage points compared with control groups over a median of 24 weeks.
Does this prove SGLT2 inhibitors treat anemia?
No. The findings show average changes in blood measures, but do not establish that the drugs should be used as anemia treatment or can replace conventional therapies.
Were the blood changes caused only by fluid loss?
The review found changes in erythropoietin and iron-related measures that the authors said suggest effects beyond hemoconcentration. But direct measurements of red blood cell mass and plasma volume were not available to confirm the mechanism.
Did the study show an increase in blood clots?
No increase in clotting events was established by the reported findings. The authors cautioned that further increases in hemoglobin and hematocrit could potentially pose a risk for people whose levels are already high, but the analysis did not prove that risk.
What research is needed next?
Further studies are needed to test whether the blood changes contribute to cardiorenal benefits or improve anemia outcomes, and to clarify their mechanism and possible risks in people with elevated baseline blood counts.
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