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Improved Erythrocyte Deformability Induced by Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetic Patients

Abstract

Purpose

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are antidiabetic drugs that improve cardiovascular outcomes. Hemoglobin and hematocrit values increase after SGLT-2 inhibitor administration. Although these factors increase blood viscosity and the risk of cardiovascular disease, SGLT-2 inhibitors have protective effects on the cardiovascular system. The mechanisms for this paradoxical phenomenon remain unclear, and the effect of SGLT-2 inhibitors on hemorheology has not been studied.

Methods

We evaluated the hemorheological parameters of 63 patients of whom 38 received metformin with a dipeptidyl peptidase 4 (DPP-4) inhibitor, while 25 received metformin with SGLT-2 inhibitor. Blood viscosity was measured using a cone-and-plate viscometer, erythrocyte aggregation was measured using a modified erythrocyte sedimentation rate method, and erythrocyte membrane fluctuation was measured as deformability, using a diffraction optical tomography.

Results

Both blood viscosity and erythrocyte aggregation increased in the SGLT-2 inhibitor group, although erythrocyte deformability was significantly improved compared with that of the DPP-4 inhibitor group (DPP-4 inhibitor 43.71 ± 5.13 nm; SGLT-2 inhibitor 53.88 ± 4.88 nm; p < 0.001). When the two groups were compared after propensity score matching, no differences in blood viscosity at high shear rates and erythrocyte aggregation were observed, although erythrocyte deformability was significantly improved in the SGLT-2 inhibitor group (DPP-4 inhibitor 45.01 ± 5.28 nm; SGLT-2 inhibitor 53.14 ± 4.72 nm; p = 0.001).

Conclusion

This study demonstrates that erythrocyte deformability was improved in the SGLT-2 inhibitor group compared with that in the DPP-4 inhibitor group. This improvement in erythrocyte deformability is expected to have a protective effect on the cardiovascular system.

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Fig. 1
Fig. 2

Abbreviations

BMI:

body mass index

CBC:

complete blood count

cDOT:

commercial diffraction optical tomography

DPP-4:

dipeptidyl peptidase 4

DBP:

diastolic blood pressure

eGFR:

estimated glomerular filtration rate

EMPA-REG OUTCOME:

Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients – Removing Excess Glucose

ESR:

erythrocyte sedimentation rate

HbA1c:

glycated hemoglobin

HDL:

high-density lipoprotein

LDL:

low-density lipoprotein

PSM:

propensity score matching

RBC:

red blood cell

SBP:

systolic blood pressure

SGLT-2:

sodium-glucose cotransporter 2

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Acknowledgments

We would like to thank Tomocube for assisting in the experiments. We also thank the members of the Hematology Department in Laboratory Medicine at Chonnam National University Hwasun Hospital for collecting the blood, and Cheol Soo Choi (Lee Gil Ya Cancer and Diabetes Institute, Gachon University) and Dae Ho Lee (Department of Internal Medicine, Gachon University Gil Medical Center) for helping with this project. We would like to thank Antonia Moreal (California Institute of Technology) for helping with the MATLAB code.

Funding

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2016M3A7B4910556).

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Contributions

M.K. conceptualized and designed the study; researched, analyzed, and interpreted the data; and drafted the manuscript. Y.S.L. researched, analyzed, and interpreted data and drafted the manuscript. A.R.H., J.H.Y., and H.K.K. contributed to study/data collection, discussion, and reviewed the manuscript. H.C.K. and Y.S. conceptualized and designed the study, analyzed and interpreted data, critically revised the manuscript for important intellectual content, and supervised the study. All authors approved the final version for submission.

Corresponding authors

Correspondence to Ho-Cheol Kang or Sung Yang.

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Institutional Review Board of Gwangju Institute of Science and Technology (20190726-BR-46-03-02), and the Institutional Review Board at Chonnam National University Hwasun Hospital (CNUHH-2019-093).

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Son, M., Lee, Y.S., Hong, A.R. et al. Improved Erythrocyte Deformability Induced by Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetic Patients. Cardiovasc Drugs Ther 36, 59–67 (2022). https://doi.org/10.1007/s10557-020-07067-w

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Keywords

  • SGLT-2 inhibitor
  • DPP-4 inhibitor
  • Hemorheology
  • Blood viscosity
  • Deformability
  • Type 2 diabetes