GLP-1 RECEPTOR AGONISTS TARGET AUTOPHAGY DYSFUNCTION IN DIABETIC NEPHROPATHY

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease globally. Current therapeutic options remain insufficient to halt disease progression. Emerging evidence implicates dysregulated autophagy as a potential driver of DN pathogenesis. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have demonstrated renoprotective effects beyond glycemic control, but its the exact mechanisms remain incompletely understood.

We conducted a prospective observational study including adult patients with established DN, all under SGLT2 inhibitors and RAAS blockers treatment, and with an estimated glomerular filtration rate (eGFR) >15 ml/min/1.73 mÇ (CKD-EPI 2022). Patients on insulin therapy or with a history of pancreatitis were excluded. Participants initiated weekly subcutaneous dulaglutide (1.5 mg) and were followed for 6 months. Clinical and biochemical data were collected at baseline (T0), 3 months (T3), and 6 months (T6). Autophagy-related proteins (Cx43, ATG5, LC3, p62, Beclin-1, and AMPK) were measured in extracellular vesicles (EVs) isolated from blood samples by western blot at each timepoint. Longitudinal changes were analyzed using linear mixed-effects models (REML), adjusted for weight, HbA1c, and proteinuria.

Six patients were included and followed over 6 months after GLP1 RA initiation. Mean proteinuria decreased from 967.7 mg/g at baseline to 862.7 mg/g at 3 months and 721.5 mg/g at 6 months, without reaching statistical significance. HbA1c declined from 7.25% at baseline to 6.82% at 3 months but rebounded to 7.10% at 6 months. Body weight decreased modestly yet significantly over time (95.4 to 93.0 kg; p=0.022). Among autophagy-related markers, ATG5 and p62 demonstrated temporal variation following GLP-1 RA initiation.ATG5 levels declined significantly over 6 months (p=0.015), with adjusted marginal means progressively decreasing from 1.00 at baseline to 0.78 at 3 months and 0.71 at 6 months. This decline was independent of HbA1c (p=0.60), body weight (p = 0.30), and proteinuria (p=0.50). In contrast, p62 demonstrated a non-significant upward trend over time (p=0.13), with adjusted means increasing from 1.02 at baseline to 1.32 and 1.36 at 3 and 6 months, respectively. Here, body weight was significantly associated with p62 levels (p=0.022), whereas HbA1c (p=0.20) and proteinuria (p=0.97) were not.

In this prospective cohort, GLP-1 RA therapy was associated with a significant reduction in ATG5 levels alongside an increase in p62 in circulating EVs, suggesting a modulation or adaptation of basal autophagic activity. The observed decoupling of these markers from traditional metabolic parameters such as HbA1c and proteinuria highlights a potential direct effect of GLP-1 RA on autophagy independent of glycemic control or renal injury markers. Moreover, the association between body weight and p62 levels highlights the relation between metabolic status and autophagic regulation. This effect could likely translate into renoprotective outcomes, through attenuation of maladaptive autophagy pathways frequently seen in DN. These findings provide novel mechanistic findings on GLP-1 RA, positioning autophagy modulation as a promising therapeutic target.