2355-P: Expression of MicroRNAs at Baseline Is Associated with Change in Prediabetes Phenotype Subtype from Baseline to Year 1 in the DPP Trial

Introduction and Objective: Clustering of clinical variables to identify phenotype subtypes of persons with prediabetes shows differing treatment responses and T2D progression risk. The stability of subtype assignment over time is unknown, and individuals may change subtype in response to time, treatment, and biomarkers like microRNAs (miRs). Methods: In a subset of persons with prediabetes (n=960) from the Diabetes Prevention Program (DPP) trial, we used k-means clustering to create subtypes using age, BMI, waist circumference (WC), triglycerides, HDL, FBG, and HbA1c at baseline (Y0) and year 1 (Y1). We conducted principal component (PC) analysis of miRs measured at Y0 and retained seven PCs after scree plot analysis. Logistic regression models stratified by DPP treatment arm and adjusted for sex were used to test associations between miR PCs, Y0 subtype, and change in subtype from Y0 to Y1. Results: We identified five distinct subtypes at Y0 and Y1, with clinical characteristics consistent with previously identified subtypes. Subtypes and their prominent clinical characteristics: 1 - older, lower FBG, 2 - high triglyceride:HDL ratio, 3 - high FBG and HbA1c, 4 - lower age and FBG, 5 - high BMI and WC. A total of 318 participants (33%) changed subtype at Y1. Subtype 5 was associated with reduced odds of subtype change in the placebo arm (OR 0.17, p<0.05) and in the metformin arm (OR 0.27, p<0.05), where miR PC2 expression was also associated with reduced odds of subtype change(OR 0.82, p<0.05). In the lifestyle arm, subtypes 2 (OR 3.6 p<0.05) and 3 (OR 3.29, p<0.05) had significantly increased odds of subtype change at Y1 and miR PC4 was significantly associated with reduced odds of subtype change (OR 0.82, p<0.05). PC2 was prominently loaded by miR-15b and let-7c, and PC4 by miR-151a and miR-151b. Conclusion: Y0 miR expression and Y0 subtype are associated with treatment-specific changes in subtype at Y1. MiRs may provide insights into the physiological pathways associated with prediabetes subtypes, progression, and treatment responses. Disclosure B.M. Stroebel: None. K.D. Longoria: None. M. Gadgil: Advisory Panel; Ended; LumosFit. E. Flowers: None.