SGLT2 Inhibitors Tied to Lower Platelet Activation in HFrEF

Sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy was associated with a significant reduction in mean platelet volume (MPV) and a significant increase in platelet count among patients with heart failure with reduced ejection fraction (HFrEF), according to a real-world study published in Internal and Emergency Medicine.¹ The findings suggest a potential hematologic pathway that warrants further investigation as a contributor to the cardiovascular benefits of SGLT2 inhibitors in this population.

“Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as cornerstone therapies for heart failure with reduced ejection fraction (HFrEF), owing to their cardioprotective and hematologic effects. While their impact on hemoglobin and hematocrit levels is increasingly recognized, the influence of SGLT2 inhibitors on mean platelet volume (MPV), a surrogate marker of platelet activation and cardiovascular risk, remains underexplored in HFrEF patients,” wrote the researchers of the study.

Researchers retrospectively reviewed records of 80 patients with HFrEF treated at a single cardiology outpatient clinic in Turkey between January 2024 and December 2025. All patients were already receiving maximum tolerated doses of guideline-directed medical therapy when an SGLT2 inhibitor was added; no other medication changes were made during the 6-month follow-up period. Patients with significant valvular disease, morbid obesity, active infection, anticoagulant use, thyroid or hepatic disorders, malignancy, recent transfusion, advanced renal failure, or hematologic disorders were excluded.

MPV, platelet count, hemoglobin, hematocrit, and a panel of biochemical markers were measured at baseline and after 6 months using the same analyzer and assay protocols at both time points. The relationship between changes in platelet count and hematocrit was also assessed to determine whether platelet changes simply reflected hemoconcentration from the diuretic effects of SGLT2 inhibitors.

MPV Fell, Platelet Count Rose, Independent of Hemoconcentration

After 6 months of SGLT2 inhibitor therapy, MPV decreased significantly, from 11.4 ± 0.7 fL at baseline to 9.1 ± 0.9 fL (P < .001), while platelet count increased significantly, from 236 ± 74 ×10⁹/L to 256 ± 76 ×10⁹/L (P = .009). Hemoglobin and hematocrit both trended upward but did not reach statistical significance.

No correlation was found between changes in platelet count and changes in MPV (r = –0.1; P = .363) or between changes in hematocrit and platelet count (r = –0.08; P = .465)—the latter finding arguing against simple hemoconcentration as the explanation for the platelet count increase. The authors hypothesized that the discordant pattern of falling MPV alongside rising platelet count may reflect effects on platelet production or turnover rather than simple hemoconcentration, although the study did not directly evaluate underlying mechanisms.

In a subgroup analysis by SGLT2 inhibitor subtype, the MPV reduction was significantly greater with dapagliflozin than with empagliflozin (P = .003). No significant changes were observed in urea, creatinine, triglycerides, LDL cholesterol, mean corpuscular volume, troponin, N-terminal pro-B-type natriuretic peptide, or high-sensitivity C-reactive protein.

Elevated MPV has been independently associated with myocardial infarction risk and broader cardiovascular events in prior population-based research, and prior studies in patients with diabetes have similarly linked SGLT2 inhibitor therapy to reduced platelet activation markers, including decreased P-selectin expression and thrombin generation.² However, findings on platelet count specifically have been inconsistent across studies in diabetic populations, with some showing no change and others showing statistically significant increases. This study is the first, per its authors, to examine MPV change specifically in patients with HFrEF, independent of background diuretic therapy.¹

The researchers also noted several limitations. This was a small, single-center, retrospective study without randomization or a control group, limiting causal inference. Most patients were taking aspirin or clopidogrel, which can independently affect MPV, though doses were unchanged throughout follow-up. The small sample size precluded multivariable adjustment, and MPV was the sole platelet function marker assessed.

While modest in scope, these findings add to emerging evidence that SGLT2 inhibitors may influence hematologic parameters beyond erythropoiesis in patients with HFrEF. Whether reductions in MPV translate into meaningful changes in platelet activation or cardiovascular outcomes remains uncertain and will require prospective investigation.

“These hematological changes may represent an additional mechanism by which SGLT2 inhibitors exert cardiovascular benefit,” wrote the researchers. “However, prospective, randomized trials are needed to validate these findings and explore the clinical significance of MPV modulation in heart failure management.”

References

1. Orta H, Aydin C, Demirkiran A, et al. Effect of SGLT2 inhibitors on mean platelet volume in heart failure with reduced ejection fraction: a real-world analysis independent of diuretic therapy. Intern Emerg Med. Published online June 23, 2026. doi:10.1007/s11739-026-04398-8
2. Klovaite J, Benn M, Yazdanyar S, et al. High platelet volume and increased risk of myocardial infarction: 39531 participants from the general population. J Thromb Haemost. 2011;9(1):49-56. doi:10.1111/j.1538-7836.2010.04110.x