title: Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients.
abstract: BACKGROUND
  Endothelial dysfunction is an independent predictor for cardiovascular events in patients with type 2 diabetes (T2DM). Glucagon like peptide-1 (GLP-1) reportedly exerts vasodilatory actions, and inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme-degrading GLP-1, are widely used to treat T2DM. We therefore hypothesized that DPP-4 inhibitors (DPP-4Is) improve endothelial function in T2DM patients and performed 2 prospective, randomized crossover trials to compare the DPP-4I sitagliptin and an α-glucosidase inhibitor, voglibose (in study 1) and the DPP-4Is sitagliptin and alogliptin (in study 2).
  
  
  RESULTS
  In study 1, 24 men with T2DM (46±5 years) were randomized to sitagliptin or voglibose for 6 weeks without washout periods. Surprisingly, sitagliptin significantly reduced flow-mediated vasodilatation (FMD; -51% compared with baseline, P<0.05) of the brachial artery despite improved diabetic status. In contrast, voglibose did not affect FMD. To confirm this result and determine whether it is a class effect, we conducted another trial (study 2) to compare sitagliptin and alogliptin in 42 T2DM patients (66±8 years) for 6 weeks with 4-week washout periods. Both DPP-4Is improved glycemic control but significantly attenuated FMD (7.2/4.3%, P<0.001, before/after sitagliptin; 7.0/4.8%, P<0.001, before/after alogliptin, respectively). Interestingly, FMD reduction was less evident in subjects who were on statins or whose LDL cholesterol levels were reduced by them, but this was not correlated with parameters including DPP-4 activity and GLP-1 levels or diabetic parameters.
  
  
  CONCLUSIONS
  Our 2 independent trials demonstrated that DPP-4 inhibition attenuated endothelial function as evaluated by FMD in T2DM patients. This unexpected unfavorable effect may be a class effect of DPP-4Is.
  
  
  BACKGROUND
  URL: http://center.umin.ac.jp, Unique Identifiers: UMIN000005682 (sitagliptin versus voglibose) and UMIN000005681 (sitagliptin versus alogliptin).
authors.affiliation: Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan. ayaori@ndmc.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Ayaori
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Iwakami
authors.forename: Harumi
authors.initials: H
authors.lastname: Uto-Kondo
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sato
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Komatsu
authors.forename: Maki
authors.initials: M
authors.lastname: Iizuka
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Emi
authors.initials: E
authors.lastname: Yakushiji
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Makiko
authors.initials: M
authors.lastname: Yogo
authors.forename: Masatsune
authors.initials: M
authors.lastname: Ogura
authors.forename: Bonpei
authors.initials: B
authors.lastname: Takase
authors.forename: Takehiko
authors.initials: T
authors.lastname: Murakami
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007294:Inositol / Q000009:adverse effects / Q000031:analogs & derivatives*; D007564:Japan; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects*; D011446:Prospective Studies; D011719:Pyrazines / Q000009:adverse effects*; D012039:Regional Blood Flow; D000068900:Sitagliptin Phosphate; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects*; D014498:Uracil / Q000009:adverse effects / Q000031:analogs & derivatives*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D008078:Cholesterol, LDL; D054873:Dipeptidyl-Peptidase IV Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010880:Piperidines; D011719:Pyrazines; D014230:Triazoles; D007294:Inositol; D014498:Uracil; C520853:alogliptin; C102817:voglibose; D000068900:Sitagliptin Phosphate