Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients.

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). 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. 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. url: http://center.umin.ac.jp,unique identifiers: umin000005682 (sitagliptin versus voglibose) and umin000005681 (sitagliptin versus alogliptin).