Linagliptin, when compared to placebo, improves CD34+ve endothelial progenitor cells in type 2 diabetes subjects with chronic kidney disease taking metformin and/or insulin: a randomized controlled trial

Cardiovasc Diabetol. 2020 Jun 3;19(1):72. doi: 10.1186/s12933-020-01046-z.


Background: Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Cellular mechanisms of DPP4 inhibitors such as linagliptin (LG) on CVD risk, in patients with T2DM with established CKD has not been established. Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD) population.

Methods: 31 subjects taking metformin and/or Insulin were enrolled in this 12 weeks, double blind, randomized placebo matched trial, with 5 mg LG compared to placebo. Type 2 diabetes subjects (30-70 years old), HbA1c of 6.5-10%, CKD Stage 1-3 were included. CD34+ cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 6 and 12. A mixed model regression analysis was done with p value < 0.05 considered significant.

Results: A double positive CD34/CD184 cell count had a statistically significant increase (p < 0.02) as determined by flow cytometry in LG group where CD184 is SDF1a cell surface receptor. Though mRNA differences in CD34+ve was more pronounced CD34- cell mRNA analysis showed increase in antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and prominent endothelial markers (PECAM1, VEGF-A, vWF and NOS3). Arterial stiffness measures such as augmentation Index (AI) (p < 0.04) and pulse wave analysis (PWV) were improved (reduced in stiffness) in LG group. A reduction in LDL: HDL ratio was noted in treatment group (p < 0.04). Urinary exosome protein examining podocyte health (podocalyxin, Wilms tumor and nephrin) showed reduction or improvement.

Conclusions: In DKD subjects, Linagliptin promotes an increase in CXCR4 expression on CD34 + progenitor cells with a concomitant improvement in vascular and renal parameters at 12 weeks. Trial Registration Number NCT02467478 Date of Registration: 06/08/2015.

Keywords: CD34+; Diabetic kidney disease; EPC; Endothelium; Linagliptin; Type 2 diabetes.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antigens, CD34 / blood*
  • Biomarkers / blood
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / diagnosis
  • Diabetic Nephropathies / drug therapy*
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • District of Columbia
  • Double-Blind Method
  • Drug Therapy, Combination
  • Endothelial Progenitor Cells / drug effects*
  • Endothelial Progenitor Cells / metabolism
  • Endothelial Progenitor Cells / pathology
  • Female
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / adverse effects
  • Insulin / therapeutic use*
  • Linagliptin / adverse effects
  • Linagliptin / therapeutic use*
  • Male
  • Metformin / adverse effects
  • Metformin / therapeutic use*
  • Middle Aged
  • Pilot Projects
  • Receptors, CXCR4 / blood
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / diagnosis
  • Renal Insufficiency, Chronic / drug therapy*
  • Time Factors
  • Treatment Outcome


  • Antigens, CD34
  • Biomarkers
  • CXCR4 protein, human
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Insulin
  • Receptors, CXCR4
  • Linagliptin
  • Metformin

Associated data