Combination therapy of RAS inhibition and glucagon-like peptide-1 receptor agonist improves a marker of kidney fibrosis in people with type 2 diabetes

In type 2 diabetes (T2D), kidney fibrosis drives the progression of chronic kidney disease (CKD) and kidney failure. Lower urinary levels of collagen type III degradation (C3M), a biomarker of extracellular matrix (ECM) turnover, have been associated with CKD progression. We investigated the effect of combination therapy with renin-angiotensin system inhibition (RASi) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) on urinary C3M levels in people with T2D. Urinary C3M was measured using the nordicC3M™ ELISA in 229 participants from the Drug Combinations for Rewriting Trajectories of Renal Pathologies in T2D (DC-ren) project. Longitudinal changes in urinary C3M were analyzed using linear regression stratified by treatment group. Risk of kidney disease progression according to baseline urinary C3M was evaluated using Kaplan-Meier analysis. The kidney endpoint was defined as >10% decline in eGFR to <60 ml/min/1.73 m 2 . Combination therapy (RASi + GLP-1 RA) was associated with higher urinary C3M levels compared with RASi monotherapy ( P = 0.036). Urinary C3M was positively associated with future eGFR, with a steeper slope in the combination therapy group than in the RASi monotherapy group ( P < 0.001). Low baseline urinary C3M was associated with a higher risk of kidney disease progression ( P = 0.022). In people with T2D receiving combination therapy with RASi + GLP-1 RA, urinary C3M levels remained stable, whereas levels decreased with RASi monotherapy, suggesting altered kidney ECM turnover.