title: Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy.
abstract: Cell culture and animal work indicate that dipeptidyl peptidase-4 (DPP-4) inhibition may exert cardiovascular benefits through favorable effects on the vascular endothelium. Prior human studies evaluating DPP-4 inhibition have shown conflicting results that may in part be related to heterogeneity of background anti-diabetes therapies. No study has evaluated the acute response of the vasculature to DPP-4 inhibition in humans. We recruited 38 patients with type 2 diabetes on stable background metformin therapy for a randomized, double-blind, placebo-controlled crossover trial of DPP-4 inhibition with sitagliptin (100 mg/day). Each treatment period was 8 weeks long separated by 4 weeks of washout. Endothelial function and plasma markers of endothelial activation (intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)) were measured prior to and 2 hours following acute dosing of sitagliptin or placebo, as well as following 8 weeks of intervention with each pill. Thirty subjects completed the study and were included in analyses. Neither acute nor chronic sitagliptin therapy resulted in significant changes in vascular endothelial function. While post-acute sitagliptin ICAM-1 levels were lower than that post-chronic sitagliptin, the ICAM-1 concentration was not significantly different than pre-acute sitagliptin levels or levels measured in relationship to placebo. There were no significant changes in plasma VCAM-1 levels at any time point. Acute and chronic sitagliptin therapies have neutral effects on the vascular endothelium in the setting of metformin background therapy. In conclusion, our findings suggest DPP-4 inhibition has a neutral effect on cardiovascular risk in patients without a history of heart failure or renal insufficiency.
  
  
  
  NCT01859793.
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Widlansky
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Venkata K
authors.initials: VK
authors.lastname: Puppala
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Tisha M
authors.initials: TM
authors.lastname: Suboc
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Mobin
authors.initials: M
authors.lastname: Malik
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Amberly
authors.initials: A
authors.lastname: Branum
authors.affiliation: 2 Medical College of Wisconsin School of Medicine, Milwaukee, WI, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Signorelli
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Jingli
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Ying
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tanner
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Sudhi
authors.initials: S
authors.lastname: Tyagi
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D000068900:Sitagliptin Phosphate / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D014664:Vasodilation / Q000187:drug effects; D014922:Wisconsin; D055815:Young Adult
chemical_list: D015415:Biomarkers; D054873:Dipeptidyl-Peptidase IV Inhibitors; C573420:ICAM1 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D008687:Metformin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate
keywords: DPP-4 inhibition; endothelium; inflammation; nitric oxide; sitagliptin; vascular