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Objective: To evaluate the protective effect of Polyethylene Glycol Loxenatide Injection (Glucagon-like peptide-1, GLP-1) on endothelial cells from middle-aged and elderly patients with newly diagnosed or poorly controlled type 2 diabetes mellitus (T2DM). GLP-1 weekly formulation was analyzed for cardiovascular disease protection and correlated with intestinal flora.Design: Stool samples were collected from middle-aged and elderly patients with new-onset or poorly controlled type 2 diabetes in Longhu People’s Hospital and Shantou Central Hospital from June 2019 to November 2019. Samples were collected at week 0, 4, and 8 of treatment with GLP-1 weekly formulations. Samples were analyzed for metagenomic sequencing. Analysis was performed to compare the characteristics of the gut microbiota at week 0, 4, and 8 of GLP-1 treatment and to correlate different microbiota with characteristic clinical parameters.Results: Statistical differences were found in blood glucose lowering, cardiovascular endothelial, and inflammation-related indices between week 0 and W4 and in blood glucose lowering and cardiovascular endothelial indices from week 0 to 8 in the newly diagnosed or poorly controlled type 2 diabetic patients treated with GLP-1. Changes in gut microbiota at week 0, 4, and 8 after using GLP-1 were not statistically different, but had an overall trend of rising and then falling, and with different bacteria, that were correlated with different clinical indicators.Conclusion: GLP-1 improves endothelial cell function indicators in middle-aged and elderly diabetic patients, which may be related to its alteration of the population numbers of gut microbiota such as Acinetobacter, Eubacterium ramulus ATCC 29099, and Bacteroides_faecis. This study provides a guidance for the treatment of type 2 diabetic patients.