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 eight weeks long separated by four weeks of washout. Endothelial function and plasma markers of endothelial activation (ICAM-1 and VCAM-1) were measured prior to and two hours following acute dosing of sitagliptin or placebo, as well as following eight 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. Our findings suggest DPP-4 inhibition has a neutral effect on cardiovascular risk in patients without a history of heart failure or renal insufficiency.

<p>Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride</p>

“…The apparent effect of linagliptin to improve endothelial function, by a mechanism that is independent of any action on glucose concentration, is supported by observations that linagliptin treatment improves impaired endothelial function in mice with elevated lipid levels or where endothelium-dependent relaxation was impaired by sodium arsenite-induced oxidative stress 6. These findings are consistent with observations in diabetic patients, where DPP-4 inhibitors appear to improve endothelium-dependent relaxation in terms of increased flow-mediated dilatation of the brachial artery although it should be noted that not all studies with DPP-4 inhibitors have confirmed this effect 7–9…”

“…Treatment with linagliptin alone was reported not to affect FMD despite in one report being associated with improvements in microvascular function that were independent of any changes in glucose regulation 10. There are also reports in patients with type 2 diabetes where sitagliptin had no effect on FMD,7 and in another case even caused a deterioration in endothelial function.…”

Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets

“…FGF21 is a metabolic regulator that also affects nutrient preference in humans and may be used to treat metabolic diseases [64132133134]. DPP4 is increased in islets of T2DM patients and DDP4 inhibitor-based therapies have had moderate success in reducing glucose intolerance and insulin resistance [135], while GLP-1 receptor agonists have shown promise for the management of T2DM and reducing weight [136].…”

Clinical Pharmacology of Dipeptidyl Peptidase 4 Inhibitors: Comparative Review

“…Кроме того, на фоне приема ингибиторов ДПП-4 отмечалось уменьшение количества веществ клеточной адгезии -растворимой молекулы межклеточной адгезии 1 и Е-селектина [66]. Тем не менее протективный эффект ингибиторов ДПП-4 в отношении эндотелия сосудов подтвержден не во всех исследованиях [67][68][69]. Сообщалось также о негативном влиянии препаратов на эндотелиальную функцию [70].…”