Dulaglutide Effect on Proteins Associated With CKD Progression.

INTRODUCTION: In the AWARD-7 clinical trial participants with type 2 diabetes mellitus (T2D) and moderate-to-severe chronic kidney disease (CKD), a once-weekly treatment with dulaglutide slowed kidney function decline compared with insulin glargine. This study evaluated dulaglutide's effect on 6-month changes in plasma concentrations of 21 Joslin Kidney Panel (JKP) proteins, which were previously associated with end-stage kidney disease (ESKD) risk. METHODS: Plasma concentrations of JKP proteins in participants treated with dulaglutide ( = 124) and insulin glargine ( = 125) were measured using a customized Joslin OLINK proteomic platform. Changes in circulating JKP protein concentrations from baseline to 6 months were determined. RESULTS: Baseline JKP protein concentrations were similar between groups. After 6 months, 14 JKP proteins increased in the insulin glargine group and decreased in the dulaglutide group with statistically significant between-group differences. The most significant differences were observed for 8 tumor necrosis factor (TNF)-receptors (TNF-R1, -R2, -R3, -R4, -R6B, -R7, -R19L, and -R27), key mediators of inflammatory and apoptotic pathways. In addition, CD160, WFDC2, DLL1, LAYN, SYND1, and EPHA2 were significantly different between treatments, although to a lesser degree, and 7 other proteins remained unaffected. Kidney injury molecule 1 (KIM1), a marker of proximal tubule stress, declined in both groups without significant differences. Treatment effects were more pronounced in participants with lower baseline estimated glomerular filtration rate or higher baseline urinary albumin-to-creatinine ratio, hemoglobin A1c, or body mass index. CONCLUSION: Six months of dulaglutide treatment significantly lowered concentrations of 14 JKP proteins, particularly those involved in inflammatory and fibrotic pathways. These findings provide insight into biological mechanisms that may underlie the reno-protective effects of dulaglutide.