7358 Profile of Circulating miRNAs Associated with Body Weight Reduction in Type 2 Diabetes Patients Treated with GLP-1 Receptor Agonist Dulaglutide: Secondary Analysis of AWARD-7 Trial

Disclosure: E. Satake: None. B.E. McFarlin: Employee; Self; Eli Lilly & Company. S.C. Tye: None. J. Ricca: None. J.M. Wilson: Employee; Self; Eli Lilly & Company. K.L. Duffin: Employee; Self; Eli Lilly & Company. A.S. Krolewski: Grant Recipient; Self; Novo Nordisk, NNF14OC0013659. Background: Glucagon-like peptide-1 (GLP-1) receptor agonists have been shown to have beneficial effects on reducing body weight, such as appetite control, reducing fat accumulation, and improving metabolic parameters. However, the underlying mechanism remains unclear, and no biomarker has been established to predict or monitor the effects of GLP-1 receptor agonists. Circulating microRNAs (miRNAs) are short, non-coding RNA molecules known to regulate proteins. In this study, we investigated the effect of the GLP-1 receptor agonist Dulaglutide (DULA) treatment on longitudinal changes in plasma concentrations of circulating miRNAs. We analyzed the correlation with body weight change in patients enrolled in the AWARD-7 trial. Methods: Plasma samples were obtained from patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) stages 3-4 who were treated with Dulaglutide 1.5 mg (n=29) or insulin Glargine (n=31) for 52 weeks. Using the HTG edgeSeq platform, we measured 2,079 miRNAs at baseline, 26 weeks, and 52 weeks. As a sub-cohort of the study, we divided patients receiving DULA treatment into two categories: patients who lost 3 kg of weight during the first 26 weeks of treatment (n=11) and those who did not (n=18). Fold change (FC) values were calculated for each patient and each miRNA by dividing the concentration of miRNA at 26 weeks by its concentration at baseline. Results: Body weight at 26 weeks in the DULA treatment group was significantly reduced compared to the placebo group (p=7.6x 10-4). Among the patients who received DULA treatment and lost 3 kg of body weight during this period, 31 miRNAs were found to be significantly up/downregulated at baseline compared to those who did not lose weight. Out of these miRNAs, 18 showed a significant correlation with the change in body weight between baseline and 26 weeks. Further analysis of the changes in miRNAs from baseline to 26 weeks (delta) revealed that 102 miRNAs differed significantly between the patients who lost body weight and those who did not. Among these miRNAs, 47 were found to be correlated with delta body weight at 26 weeks. Conclusion: This study demonstrated circulating miRNAs associated with body weight reduction in T2D patients treated with a GLP-1 agonist. These miRNAs have the potential to serve as biomarkers to predict or monitor the effect of DULA on body weight in T2D patients and may provide a mechanistic understanding of physiological processes associated with weight reduction. Presentation: 6/3/2024