GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Abstract

Objective— To assess the effects of glucagon-like peptide (GLP)-1–based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. Approach and Results— We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m 2 ; HbA 1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo ( P >0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P <0.05). After the meal, exenatide increased endothelial domain power ( P <0.05). In the 12-week study, no effects on vasomotion were observed. Conclusions— Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1–based therapies on glucose are not mediated through microvascular responses.

A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes

“…Taken together, this evidence suggests that linagliptin may improve microvascular function, which supports the results from several pooled analyses of phase III clinical trial data showing that linagliptin significantly reduced clinically relevant kidney disease endpoints in patients with T2D [39, 40]. Based on other clinical studies, it is unclear if improving microvascular function is a class effect of DPP-4 inhibitors: although vildagliptin improved retinal microvascular blood flow [41], saxagliptin reduced retinal blood flow [15], and sitagliptin had no effect on skin microvascular function [42]. …”

Diabetes, cardiovascular disease and the microcirculation

“…The microcirculation is a network of blood vessels < 150 µm in diameter, comprising arterioles, capillaries and venules. This network is responsible for the primary function of the vascular tree and regulation of tissue perfusion for optimal exchange of gases and removal of metabolic waste products [ 33 ] and may contribute to the unexplained variance in the association between T2DM and hypertension. There are significant differences in the way small arteries remodel in response to hypertension in people with or without T2DM.…”

PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients

“…Strict glycemic control reduces microvascular complications; however, no currently used antiglycemic agent directly increases microvascular perfusion (32). Exercise, as well as AMPK activation by AICAR and the indirect AMPK activator R118, increases microvascular perfusion in muscle (57,58), and O304 increased microvascular perfusion in hind legs of DIO mice and in calf muscle of T2D patients in the TEL-LUS study.…”

“…T2D is associated with devastating microvascular complications due to reduced capillary function and perfusion, which also reduce the supply of glucose and insulin to the muscle interstitium (4,31), but no currently used drug to treat T2D appears to directly increase microvascular blood flow (32). Notably, exercise stimulates peripheral blood flow, improves cardiac function, reduces blood pressure, and increases endurance capacity in man (33), and AMPK activation in endothelial and smooth muscle cells increases vasodilation and microvascular perfusion in muscle and reduces blood pressure (34).…”