Dulaglutide Effect on Proteins Associated With CKD Progression.
This post hoc analysis of the AWARD-7 randomized controlled trial examined how dulaglutide (a GLP-1 receptor agonist) affects plasma concentrations of 21 Joslin Kidney Panel (JKP) proteins—biomarkers previously linked to end-stage kidney disease (ESKD) risk—in adults with type 2 diabetes and moderate-to-severe chronic kidney disease (CKD). Researchers used the Joslin OLINK proteomic platform to compare changes in protein concentrations from baseline to 6 months between participants receiving once-weekly dulaglutide (n=124) and those receiving insulin glargine (n=125). The study found that 14 of the 21 JKP proteins increased in the insulin glargine group but decreased in the dulaglutide group, with statistically significant between-group differences. The most notable differences involved 8 TNF-receptor superfamily members, which play roles in inflammation and apoptosis. Additional proteins—including CD160, WFDC2, DLL1, LAYN, SYND1, and EPHA2—also differed significantly between groups. Effects were more pronounced in participants with lower kidney function, higher albuminuria, higher HbA1c, or higher BMI at baseline. The authors suggest these proteomic changes may help explain the kidney-protective effects observed with dulaglutide in AWARD-7. Key limitations include the post hoc, exploratory design, the 6-month follow-up window, and lack of adjustment for multiple comparisons.
Why this grade: Although drawn from a peer-reviewed RCT (AWARD-7) with human participants and a comparator arm, the proteomic analysis is post hoc and exploratory, limiting causal inference and increasing the risk of false-positive findings.
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 post hoc 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 ( n = 124) and insulin glargine ( n = 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.
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