The synergistic effects of saxagliptin and metformin on CD34+ endothelial progenitor cells in early type 2 diabetes patients: a randomized clinical trial

Cardiovasc Diabetol. 2018 May 3;17(1):65. doi: 10.1186/s12933-018-0709-9.


Aims: Type 2 diabetes is associated with endothelial dysfunction leading to cardiovascular disease. CD34+ endothelial Progenitor Cells (EPCs) are responsible for endothelial repair and neo-angiogenesis and can be used as a cardiovascular disease risk biomarker. This study investigated whether the addition of saxagliptin, a DPP-IV inhibitor, to metformin, may reduce cardiovascular disease risk in addition to improving glycemic control in Type 2 diabetes patients.

Methods: In 12 week, double-blind, randomized placebo-controlled trial, 42 subjects already taking metformin 1-2 grams/day were randomized to placebo or saxagliptin 5 mg. Subjects aged 40-70 years with diabetes for < 10 years, with no known cardiovascular disease, BMI 25-39.9, HbA1C 6-9% were included. We evaluated EPCs number, function, surface markers and gene expression, in addition to arterial stiffness, blood biochemistries, resting energy expenditure, and body composition parameters. A mixed model regression to examine saxagliptin vs placebo, accounting for within-subject autocorrelation, was done with SAS (p < 0.05).

Results: Although there was no significant increase in CD34+ cell number, CD31+ cells percentage increased. Saxagliptin increased migration (in response to SDF1α) with a trend of higher colony formation count. MNCs cytometry showed higher percentage of CXCR4 double positivity for both CD34 and CD31 positive cells, indicating a functional improvement. Gene expression analysis showed an upregulation in CD34+ cells for antioxidant SOD1 (p < 0.05) and a downregulation in CD34- cells for IL-6 (p < 0.01). For arterial stiffness, both augmentation index and systolic blood pressure measures went down in saxagliptin subjects (p < 0.05).

Conclusion: Saxagliptin, in combination with metformin, can help improve endothelial dysfunction in early diabetes before macrovascular complications appear. Trial registration Trial is registered under, NCT02024477.

Keywords: Arterial stiffness; DPP-4 inhibitor; Diabetes; Endothelial progenitor cells; Saxagliptin.

Publication types

  • Clinical Trial, Phase IV
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / administration & dosage
  • Adamantane / adverse effects
  • Adamantane / analogs & derivatives*
  • Adult
  • Aged
  • Antigens, CD34 / blood*
  • Arterial Pressure / drug effects
  • Biomarkers / blood
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dipeptides / administration & dosage*
  • Dipeptides / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage*
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • District of Columbia
  • Double-Blind Method
  • Drug Synergism
  • Drug Therapy, Combination
  • Endothelial Progenitor Cells / drug effects*
  • Endothelial Progenitor Cells / metabolism
  • Endothelial Progenitor Cells / pathology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology
  • Female
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Male
  • Metformin / administration & dosage*
  • Metformin / adverse effects
  • Middle Aged
  • Time Factors
  • Treatment Outcome
  • Vascular Stiffness / drug effects


  • Antigens, CD34
  • Biomarkers
  • Dipeptides
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Metformin
  • saxagliptin
  • Adamantane

Associated data