Urinary Proteomics as a Tool to Identify Kidney Responders to Dipeptidyl Peptidase‐4 Inhibition: A Hypothesis‐Generating Analysis from the MARLINA‐T2D Trial

Purpose Chronic kidney disease (CKD) is a serious complication of hyperglycemia and treatment options to slow its progression are scarce. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are common glucose‐lowering drugs in type 2 diabetes (T2D). Among these, linagliptin has been suggested to exert kidney protective effects. It is investigated whether an effect of linagliptin on kidney function could be unmasked by characterizing the urinary proteome profile (UPP) in albuminuric T2D individuals. Experimental design Participants of the MARLINA‐T2D trial (NCT01792518) are randomized 1:1 to receive either linagliptin 5 mg or placebo for 24 weeks. A previously developed proteome‐based classifier, CKD273, is assessed. Results Results confirm a significant correlation between CKD273 and clinical kidney parameters as well as with eGFR decline. Patient stratification using CKD273 at baseline, show a trend toward attenuation of renal function loss in high CKD‐risk patients treated with linagliptin. Moreover, characterized are linagliptin affected peptides of which the majority contained a DPP‐4 target sequence. Conclusions and clinical relevance CKD273 is a promising tool for identifying patients at high risk for CKD progression and may unmask a potential of linagliptin to slow progressive kidney function loss in high CKD‐risk patients. UPP characterization reveals a significant impact of linagliptin on urinary peptides.