Can Dulaglutide Modify the Proteomic Signature of CKD Progression? Impacts Beyond Glycemic Control

Written by: Bogdan Agavriloaei MD

CKD progression remains highly heterogeneous, with limited understanding of the molecular pathways driving disease evolution beyond traditional clinical markers such as eGFR and albuminuria. Glucagon-like peptide-1 receptor agonists (GLP-1 RA), including Dulaglutide, have demonstrated cardiovascular and potential renal benefits, but their mechanistic effects on kidney disease progression remain incompletely characterized.

This study addresses an important gap by exploring whether dulaglutide modulates circulating proteins associated with CKD progression, offering insight into potential biological pathways underlying its clinical effects. The authors conducted a proteomic analysis in patients with chronic kidney disease treated with dulaglutide. Circulating protein levels were quantified using high-throughput platforms, with a focus on proteins previously associated with CKD progression. Longitudinal analyses were performed to assess changes in protein expression following treatment, and associations with kidney outcomes were explored.

Visual abstract by Cristina Popa MD, article published in KI Reports 2026 by McFarlin BE et al.

Treatment with dulaglutide was associated with significant modulation of multiple circulating proteins implicated in key pathogenic pathways, including proteins related to inflammatory signaling (e.g., IL-6 and TNF receptor–associated pathways), fibrotic processes (e.g., TGF-β–related signaling and extracellular matrix remodeling), and metabolic regulation. Notably, consistent reductions were observed in TNF receptor family members and KIM-1, biomarkers previously associated with inflammation-driven kidney injury and tubular damage.

Several of these proteins have been previously linked to CKD progression, suggesting that dulaglutide may influence key biological pathways involved in kidney function decline, particularly those related to inflammation and tubular injury. These proteomic changes are illustrated in Figure 1.

Figure 1. Median percentage changes in circulating proteins following dulaglutide versus insulin glargine treatment. Dulaglutide was associated with reductions in multiple inflammatory and kidney injury–related biomarkers, including TNF receptor pathways and KIM-1, suggesting modulation of biological pathways implicated in CKD progression.

Importantly, the observed proteomic changes provide a potential mechanistic explanation for the renal benefits suggested in prior clinical studies. Notably, this type of molecular profiling may help bridge the gap between clinical outcomes and underlying disease biology, an area that remains insufficiently explored in CKD therapeutics. These findings support the hypothesis that dulaglutide may exert pleiotropic effects beyond glycemic control, potentially targeting pathways involved in CKD progression.

From a pathophysiological perspective, modulating inflammatory and fibrotic protein signatures is biologically plausible. It provides pathway-level insight, aligning with emerging evidence suggesting that GLP-1 receptor agonists may influence renal outcomes through mechanisms that extend beyond glucose lowering, including anti-inflammatory and anti-fibrotic effects. A conceptual overview integrating these pathway-level effects is presented in Figure 2.

Figure 2. Proposed mechanisms linking dulaglutide to modulation of CKD progression through proteomic pathways

However, the study remains exploratory. Changes in circulating proteins do not necessarily translate into clinically meaningful renal outcomes, and causality cannot be inferred. Moreover, circulating proteomic profiles may reflect systemic rather than kidney-specific processes, raising uncertainty about the direct renal relevance of these findings.

In addition, the absence of direct correlation with hard renal endpoints (such as sustained eGFR decline or progression to kidney failure) limits the ability to position these molecular changes within a clinically actionable framework. Thus, the results should be interpreted as hypothesis-generating, rather than definitive evidence of disease modification.

The study’s main strength lies in its integrative proteomic approach, providing novel insights into the biological effects of dulaglutide in CKD. However, several limitations must be acknowledged. The reliance on surrogate molecular markers, the absence of hard renal outcomes, and the exploratory nature of the analysis limit the clinical applicability of the findings.

Dulaglutide may influence key molecular pathways associated with CKD progression, extending its potential role beyond glycemic control. Proteomic profiling represents a promising tool for understanding disease mechanisms and identifying therapeutic targets.

Future studies integrating proteomic signatures with longitudinal kidney outcomes will be critical to determine whether these molecular changes represent true disease-modifying effects or epiphenomena of systemic metabolic improvement.