GLP-1-Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus: An Acute and 12-Week Randomized, Double-Blind, Placebo-Controlled Trial.

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. 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); HbA1c [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. 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.

Smits MM ，Tonneijck L ，Muskiet MH ，Hoekstra T ，Kramer MH ，Diamant M ，Serné EH ，van Raalte DH ... -  《-》

The effects of GLP-1 based therapies on postprandial haemodynamics: Two randomised, placebo-controlled trials in overweight type 2 diabetes patients.

To assess the effects of glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors on postprandial haemodynamics. 57 patients with type 2 diabetes (mean±SD age 62.8±6.9years; BMI 31.8±4.1kg/m2; HbA1c 7.3±0.6%) were included in an acute (exenatide- or placebo-infusion) and 12-week (liraglutide, sitagliptin or placebo) randomised, placebo-controlled, double-blind trial. Systemic haemodynamics (oscillometric technique and finger photoplethysmography), vascular stiffness (tonometry), and sympathetic nervous system (SNS)-activity (heart rate variability) were determined in the fasting state and following a standardised mixed meal. In both studies, postprandial blood pressure (BP) decreased during placebo-intervention. Compared with placebo, acute exenatide-infusion increased postprandial diastolic BP (6.7 [95%-confidence interval 3.6-9.9]mmHg, p<0.001) and vascular resistance (683.6 [438.5-928.8]dyn*s/cm5/1.73m2, p<0.001), while cardiac index decreased (0.6 [0.40.8]L/min/1.73m2; p<0.001). Systolic BP, augmentation index and SNS-activity were unaffected. Twelve-week liraglutide-treatment did not affect postprandial haemodynamics, while sitagliptin decreased diastolic BP (3.5 [0.0-6.9] mmHg; p=0.050), vascular resistance (309.9 [66.6-553.1]dyn*s/cm5/1.73m2; p=0.013) and cardiac index (0.3 [0.0-0.6]L/min/1.73m2; p=0.040), compared with placebo. Neither liraglutide nor sitagliptin affected SNS-activity or augmentation index. All treatments significantly lowered postprandial glucose levels. Acute exenatide-infusion prevented the meal-induced decline in diastolic BP, although prolonged liraglutide intervention did not affect postprandial haemodynamics. The meal-induced drop in BP was augmented during sitagliptin-treatment.

Smits MM ，Tonneijck L ，Muskiet MH ，Hoekstra T ，Kramer MH ，Diamant M ，van Raalte DH ... -  《-》

Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus.

Hemmingsen B ，Sonne DP ，Metzendorf MI ，Richter B ... -  《Cochrane Database of Systematic Reviews》

Efficacy and safety of long-acting glucagon-like peptide-1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: a systematic review and meta-analysis.

Pinelli NR ，Hurren KM 《-》

Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients.

Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile. A total of 57 type 2 diabetes patients (mean ± SD age, 62.8 ± 6.9 years; BMI, 31.8 ± 4.1 kg/m2 ; HbA1c, 7.3% ± 0.6%), treated with metformin and/or sulfonylureas, were included in this 12-week randomized, placebo-controlled, double-blind, single-centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebo for 12 weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high-fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236). Neither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p > .05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20 µmol/L (95% CI 0.027-0.376), p = 0.024] and postprandial state [AUC 40.71 (13.22-68.21), p = 0.005] and in faeces [ratio 1.5 (1.03-2.19); p = 0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33-8.79), p = 0.012], cholic acid [ratio 3.32 (1.26-8.87), p = 0.017] and ursodeoxycholic acid [ratio 3.81 (1.44-10.14), p = 0.008]. Neither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production.

Smits MM ，Tonneijck L ，Muskiet MH ，Hoekstra T ，Kramer MH ，Diamant M ，Nieuwdorp M ，Groen AK ，Cahen DL ，van Raalte DH ... -  《-》