Dipeptidyl Peptidase‐4 Inhibitors Attenuate Endothelial Function as Evaluated by Flow‐Mediated Vasodilatation in Type 2 Diabetic Patients

Abstract

BackgroundEndothelial 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).Methods and ResultsIn 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.ConclusionsOur 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.Clinical Trial RegistrationURL: http://center.umin.ac.jp, Unique Identifiers: UMIN000005682 (sitagliptin versus voglibose) and UMIN000005681 (sitagliptin versus alogliptin).

Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin

“…1,6 Additionally, DPP-4 inhibition with vildagliptin 14 potentiates endothelium-dependent vasodilation in response to acetylcholine, whereas others have reported that sitagliptin and alogliptin attenuated endothelial function based on changes in flow-mediated vasodilation in patients with type 2 diabetes mellitus. 15 These vascular findings have been implicated as a potential mechanism for augmented sympathetic activity that could have played a role in the increase in HF hospitalizations in the SAVOR TIMI 53 trial. 3,16 All of the aforementioned studies evaluating the hemodynamic and physiological responses to coadministered higher dose ACE inhibitors and DPP-4 inhibitors were performed using either acute or short-term study designs.…”

Effect of combination therapy with alogliptin and lansoprazole on glycemic control in patients with type 2 diabetes

“…However, it is unlike that lansoprazole influenced the decrease of these lipids levels, because it is reported that PPI therapy for 3 months significantly increased (but not decreased) TC and LDL-C levels with no change of HDL-C in patients with type 2 diabetes [25]. On the other hand, it is reported that alogliptin can reduce LDL-C levels [26][27][28], although these levels did not change in some studies [29,30]. Recently, Ayaori et al reported that alogliptin significantly reduced TC, LDL-C, and HDL-C (but not TG), and that it significantly deceased HDL-C, even when compared with sitagliptin [28].…”

“…On the other hand, it is reported that alogliptin can reduce LDL-C levels [26][27][28], although these levels did not change in some studies [29,30]. Recently, Ayaori et al reported that alogliptin significantly reduced TC, LDL-C, and HDL-C (but not TG), and that it significantly deceased HDL-C, even when compared with sitagliptin [28]. Thus, we speculate that decrease of TC, LDL-C, and HDL-C which were observed in this study was probably associated with the effect of alogliptin, although the precise mechanism is unknown.…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…In a double-blind study on patients with diabetes, treatment with vidagliptin for 4 weeks improved forearm blood flow in response to intra-arterially delivered acetylcholine [164]. On the contrary, other studies measuring FMD of the brachial artery have shown diametrically opposite results, suggesting that sitagliptin and alogliptin actually seem to worsen flow-mediated dilation (FMD) when used to treat diabetic patients [165]. At present, clinical evidence supporting the vascular protective effects of gliptins is uncertain, given the relatively short follow-up [166][167][168].…”