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Randomized Controlled Trial
. 2023 Feb;25(2):570-580.
doi: 10.1111/dom.14903. Epub 2022 Nov 10.

Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial

Affiliations
Randomized Controlled Trial

Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial

Mona Mashayekhi et al. Diabetes Obes Metab. 2023 Feb.

Abstract

Aim: To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms.

Materials and methods: Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. 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).

Results: Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1).

Conclusion: Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.

Keywords: DPP4 inhibitor; GLP-1 receptor agonist; cardiovascular disease; dietary intervention; incretin physiology; randomized trial.

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Conflict of interest statement

None unless noted below:

J.A.B.: Dr. Beckman is a consultant for JanOne, serves on a DSMB for Janssen and Novartis, and has ownership in EMX and Janacare.

J.R.K: Dr. Koethe has served as a consultant to Gilead Sciences, Merck, ViiV Healthcare, Theratechnologies and Janssen. He has also received research support from Gilead Sciences and Merck.

J.M.L: Dr. Luther has served on the advisory board for Mineralys.

N.J.B.: Dr. Brown serves on the scientific advisory board for Alnylam Pharmaceuticals. She serves as a consultant for Pharvaris Gmbh and eBioStar Tech. Dr. Brown owns equity in Abbvie and J and J Pharmaceuticals.

Figures

Figure 1.
Figure 1.. The Effect of Treatment on Weight, Fasting Blood Glucose, Fasting Insulin, and Insulin Resistance.
Plots show mean ± SEM for (A) weight, (B) HOMA-IR, (C) fasting blood glucose, and (D) fasting insulin at 2 and 14 weeks of treatment as change from baseline. Asterisk (*) symbols indicate P<0.05 for estimates of change from baseline, and brackets indicate difference between treatments at 14 weeks. HOMA-IR indicates Homeostatic Model Assessment of Insulin Resistance.
Figure 2.
Figure 2.. The Effect of Treatment on FMD.
Plots show mean ± SEM for (A) FMD in the entire cohort, (B) in subgroup with baseline FMD below median for gender, and (C) in subgroup with baseline FMD above median for gender. Asterisk (*) symbols indicate P<0.05 for estimates of change from baseline, and brackets indicate difference between treatments at 14 weeks. FMD indicates flow-mediated dilation.
Figure 3.
Figure 3.. The Effect of Treatment on PAI-1 and MCP-1.
Plots show mean ± SEM for (A) PAI-1 and (B) MCP-1 at 2 and 14 weeks of treatment as change from baseline. Asterisk (*) symbols indicate P<0.05 for estimates of change from baseline, and brackets indicate difference between treatments at 14 weeks. PAI-1 indicates plasminogen activator inhibitor-1; MCP-1, monocyte chemoattractant protein-1.

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