1687-P: Circulating miRNAs as Predictors of Weight Reduction in Type 2 Diabetes Treated with GLP-1 Receptor Agonist Dulaglutide: Secondary Analysis of AWARD-7 Trial

Introduction and Objective: Glucagon-like peptide-1 (GLP-1) receptor agonists have been shown to have beneficial effects on reducing body weight, and improving metabolic parameters. However, the underlying mechanism and predictive biomarkers of their effects remain unclear. MicroRNAs (miRNAs) are short, non-coding RNA molecules known as key post-transcriptional regulators, and may offer biological insight and serve as predictive biomarkers. We investigated whether baseline plasma miRNAs predict body weight reduction following Dulaglutide (DULA) treatment 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 received DULA 1.5 mg (n=73) or insulin glargine (n=79) for 52 weeks. Using the HTG edgeSeq platform, we measured circulating 2,079 miRNAs at baseline. As a sub-cohort of the study, we divided patients receiving DULA treatment into two categories: patients who lost 5% of weight during the 52 weeks of treatment (Responders, n=20) and those who did not (Non-responders, n=53). Differential expression (fold change) analysis and multivariable logistic regression were applied to identify predictive miRNAs. KEGG and Gene Ontology Biological Process enrichment analyses were also performed using clusterProfiler (FDR< 0.05). Results: At 52 weeks, the DULA group exhibited significantly greater weight loss than the glargine group (p=7.8x 10-5). Forty-nine baseline miRNAs (21 positively- and 28 negatively-associated) were identified as candidate predictors of body weight loss. Pathway enrichment analysis revealed that these miRNAs were linked to neuro-metabolic and epigenetic processes. Conclusion: This study identified circulating miRNAs that predict body weight reduction in T2D patients treated with DULA. These miRNAs may serve as predictive biomarkers for DULA responsiveness and may support a precision-medicine approach to optimize GLP-1-based weight-management strategies. Disclosure A. Nowak-Szwed: None. J. Wilson: Employee; Current; Lilly. D.B. Hoon: None. K. Duffin: Employee; Current; Eli Lilly and Company. A. Krolewski: None. E. Satake: None.