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Effects of SGLT2 Inhibitors on Circulating Stem and Progenitor Cells in Patients With Type 2 Diabetes

Context
Reduction in the levels of circulating stem cells (CSCs) and endothelial progenitor cells (EPCs) predicts development or progression of microangiopathy and macroangiopathy in patients with type 2 diabetes (T2D).


Objective
We tested whether treatment with sodium glucose cotransporter-2 (SGLT2) inhibitors affected the levels of CSCs and EPCs.


Design
A randomized trial of dapagliflozin vs placebo with open-label extension, and an open-label observational study of empagliflozin treatment.


Setting
Tertiary referral diabetes outpatient clinic.


Patients
Patients with T2D aged 18 to 75 years.


Intervention
Dapagliflozin at 10 mg vs placebo (n = 31); empagliflozin at 10 mg (n = 15).


Main Outcome Measures
We measured CSCs (CD34+) and EPCs (CD34+KDR+) by flow cytometry at baseline, at 12 weeks, and after the extension period.


Results
After 12 weeks, CSCs declined nonsignificantly in the dapagliflozin group, remained stable in the placebo group, and the change from baseline was not significantly different between the two groups. EPCs declined nonsignificantly in the dapagliflozin group, increased nonsignificantly in the placebo group, and the change from baseline was significantly different between the two groups. After an open-label extension period of about 1.5 years, CSCs remained stable over time, whereas EPCs significantly increased in patients who received dapagliflozin. In all patients, irrespectively of treatment, EPCs increased significantly from baseline to the end of observation, concomitantly with improvement in HbA1c. In a cohort of 15 patients who received open-label empagliflozin for 12 weeks, CSCs declined nonsignificantly, whereas EPCs remained stable.


Conclusion
SGLT2 inhibitors do not significantly increase CSCs or EPCs. Thus, cardiovascular protection by SGLT2 inhibitors may not directly involve stem/progenitor cells.