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A meta-analysis of 85 randomized trials involving 70,543 participants found that SGLT2 inhibitor treatment was associated with modest increases in hemoglobin and hematocrit over a median 24 weeks. The findings may be relevant to anemia management, but the analysis does not establish that the drugs treat anemia or that the blood changes cause cardiorenal benefits.
A review of 85 randomized trials found that people assigned sodium-glucose cotransporter 2 (SGLT2) inhibitors had modestly higher hemoglobin and hematocrit levels than those in control groups. The analysis, involving 70,543 participants with conditions including chronic kidney disease, heart failure and type 2 diabetes, was presented at the American Society of Nephrology’s Kidney Week meeting and published in JAMA; the results may inform research into anemia but do not establish the drugs as anemia treatment.
Over a median 24 weeks, hemoglobin rose by an average of 0.55 grams per deciliter in the SGLT2 inhibitor groups and fell by 0.08 g/dL in control groups. The reported between-group difference was 0.60 g/dL (95% confidence interval 0.55 to 0.66; P<0.001). Hematocrit increased by 2.17% in the treatment groups and declined by 0.13% in controls, a between-group difference of 2.36 percentage points (95% CI 2.19 to 2.52; P<0.001).
The study team, led by Michele F. Eisenga, MD, PhD, of University Medical Center Groningen, also reported significant differences in four of six secondary measures. Compared with controls, SGLT2 inhibitor groups had higher erythropoietin and red blood cell concentration, and lower ferritin and transferrin saturation. Changes in hepcidin and serum iron did not reach statistical significance.
The trials included people with chronic kidney disease, heart failure, type 2 diabetes and cardiovascular disease, sometimes in combination. Most evaluated empagliflozin or dapagliflozin, alongside several other SGLT2 inhibitors. The average participant age was 62.4 years, 35.9% were female, and mean starting hemoglobin and hematocrit were 13.6 g/dL and 41.5%, respectively.
Possible Relevance to Anemia Care
The findings add evidence that SGLT2 inhibitors affect red blood cell production and iron-related measures, not just blood sugar or kidney and heart outcomes. The authors said the modest hemoglobin rise could help explain quality-of-life improvements previously reported in some people with heart failure or chronic kidney disease, but the meta-analysis did not test whether the blood changes caused those improvements.
The results may matter for clinicians monitoring blood counts, particularly when a patient already has elevated hemoglobin or hematocrit. The researchers cautioned that further increases in people with high starting levels could potentially raise thromboembolic risk. The analysis does not establish the size of that risk or show that the observed average changes lead to harmful events.
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How the Blood Changes Were Studied
SGLT2 inhibitors are used for conditions including type 2 diabetes, heart failure and chronic kidney disease. Previous trials had also reported increases in hemoglobin and hematocrit. The new work systematically reviewed double-blind randomized trials in which an SGLT2 inhibitor was used alone or added to other treatment, comparing blood measures with control groups.
Post hoc analyses suggested that the differences may vary with dose and duration: the hemoglobin difference reached 0.65 g/dL at 1.5 times the standard clinical dose and 0.71 g/dL at 48 weeks of follow-up. These analyses are not the same as a trial designed to establish a dose-response effect. The accompanying editorial also noted that hemoglobin increases reached their maximum only at 48 weeks in earlier observations, a pattern the editors said may fit gradual changes in red blood cell production better than lasting fluid contraction.
“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.”
— Michele F. Eisenga, MD, PhD, lead researcher
Mechanism and Clinical Effects Remain Open
The analysis found changes in blood concentrations and related markers, but it could not confirm that participants had a corresponding increase in total red blood cell mass. The editorial authors said trial data on red blood cell indices were limited and that measurements of red blood cell mass, plasma volume and red blood cell lifespan were not reported. Those gaps make it difficult to distinguish fully among possible mechanisms.
It also remains unclear whether the changes directly account for cardiorenal benefits, improve anemia outcomes, reduce the need for conventional anemia treatments or increase thromboembolic events in people with high baseline counts. The authors’ suggestion that the rise could contribute to anemia management is a potential implication, not proof of a treatment benefit.
Trials Must Test Patient Outcomes
Eisenga said future trials should examine whether the hematologic changes directly contribute to heart and kidney benefits and whether they reduce reliance on conventional anemia treatments. Studies with direct measurements of red blood cell mass and related factors could also help clarify the mechanism described in the editorial.
Until those questions are answered, the reported average rises should be read as trial findings rather than a recommendation to use SGLT2 inhibitors specifically for anemia. The source report does not identify a specific upcoming trial or date for further results.
Key Questions
How much did hemoglobin change in the analysis?
Across a median of 24 weeks, hemoglobin rose by an average of 0.55 g/dL in SGLT2 inhibitor groups and fell by 0.08 g/dL in control groups. The reported difference between groups was 0.60 g/dL.
Did hematocrit also increase?
Yes. Hematocrit rose by an average of 2.17% in the treatment groups and declined by 0.13% in controls, a between-group difference of 2.36 percentage points.
Does this show that SGLT2 inhibitors treat anemia?
No. The analysis found changes in hemoglobin, hematocrit and related measures, but it did not establish that the drugs treat anemia or reduce the need for other anemia treatments.
Why do researchers say the mechanism is uncertain?
The trials generally did not report direct measurements of red blood cell mass, plasma volume or red blood cell lifespan. The pattern of changes may point to altered red blood cell production and iron metabolism, but the available data do not confirm the precise mechanism.
What potential risk did the researchers mention?
The authors said further increases in people whose hemoglobin or hematocrit is already high could potentially increase thromboembolic risk. The analysis does not quantify that risk or show that the average changes caused such events.
Source: rss
