Comparative Effects of Weight Loss and Incretin-Based Therapies on Vascular Endothelial Function, Fibrinolysis, and Inflammation: A Randomized, Controlled Trial

Abstract

AbstractAims/HypothesisGLP-1 receptor (GLP1R) agonists cause weight loss in obese individuals and decrease cardiovascular events in patients with type 2 diabetes. The objective of this study was to test the hypothesis that GLP1R agonists have beneficial effects on vascular endothelial function, fibrinolysis, and inflammation in obesity through weight loss-independent (GLP1R-dependent) mechanism(s).MethodsWe conducted a randomized, parallel-group, three-arm double-blinded controlled trial at a single center in the United States. Eligibility criteria were as follows: age 18-65 years, body mass index ≥ 30kg/m2, and pre-diabetes defined by the American Diabetes Association criteria. Participants were randomized in a 2:1:1 ratio to 14 weeks of the GLP1R agonist liraglutide, hypocaloric diet, or the dipeptidyl peptidase 4 inhibitor sitagliptin. Treatment with drug was double blind and placebo controlled. Measurements were made at baseline, after 2 weeks of treatment prior to significant anticipated weight loss, and after 14 weeks of treatment. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1), and urine albumin-to-creatinine ratio (UACR).ResultsNinety-three obese pre-diabetic individuals were randomized, and data from 88 individuals who completed at least a single study day are included in the analysis (liraglutide N=44, diet N=22, sitagliptin N=22). Liraglutide and diet reduced weight and insulin resistance, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function as measured by FMD (Liraglutide: 2 weeks: difference from baseline +0.70%, 95% CI [-0.71, 2.11], P=0.33, 14 weeks: +1.38% [-0.01, 2.78], P=0.05; Sitagliptin: 2 weeks: +1.92% [-0.05, 3.88], P=0.06, 14 weeks: +1.59% [-0.30, 3.48], P=0.10; Diet: 2 weeks: +1.24% [-0.69, 3.18], P=0.21, 14 weeks: +1.20% [-0.97, 3.38], P=0.28). As baseline endothelial function was normal in the overall cohort, post hoc subgroup analyses were conducted in participants stratified by FMD below or above the median. Individuals with baseline FMD below the median, indicative of endothelial dysfunction, had higher BMI, waist circumference and insulin resistance as compared to those with baseline FMD above the median. All three treatments improved FMD at 2 and 14 weeks in individuals with baseline FMD below the median (P<0.05 for all). Liraglutide reduced PAI-1 at 2 and 14 weeks (2 weeks: -2.3 U/mL [-4.1, -0.6], P<0.01; 14 weeks: -3.7 U/mL [-5.5, -2.0], P<0.001), and diet reduced PAI-1 at 14 weeks (-3.8 U/mL [-6.6, -1.0], P<0.01), but sitagliptin did not change PAI-1 levels. GLP1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1 in any treatment group. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1) at 2 and 14 weeks (2 weeks: -10.7 pg/mL [-17.6, -3.7], P<0.01; 14 weeks: -10.7 pg/mL [-17.7, -3.7], P<0.01).ConclusionsLiraglutide and diet cause weight loss, improve insulin resistance and reduce PAI-1 concentrations. Liraglutide, sitagliptin and diet do not change FMD in obese pre-diabetic individuals with normal endothelial function after 14 weeks of treatment. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1 at 2 and 14 weeks, indicating that this beneficial cardiovascular effect is independent of weight loss.Clinicaltrials.gov IdentifierNCT03101930Research in contextWhat is already known about this subject?GLP-1 receptor agonists reduce cardiovascular events in patients with type 2 diabetes through unknown mechanism(s).GLP-1 receptor agonists cause weight loss in obese individuals with and without diabetes.What is the key question?Are vascular effects of GLP-1 receptor agonists mediated by weight loss or GLP-1 receptor activation?What are the new findings?The GLP-1 receptor agonist liraglutide and diet-induced weight loss reduce circulating PAI-1, a measure of fibrinolytic balance and inflammation, while the DPP-4 inhibitor sitagliptin does not.Liraglutide reduces the circulating pro-inflammatory chemokine MCP-1, while sitagliptin and diet-induced weight loss do not.Liraglutide, sitagliptin and diet-induced weight loss do not improve flow-mediated dilation, a measure of endothelial vasodilator function, in obese pre-diabetic individuals after 14 weeks of treatment.How might this impact on clinical practice in the foreseeable future?Understanding the mechanisms by which GLP-1 receptor agonists exert vascular effects is critical in improving patient selection and future drug development.