Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study

Objective. To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low‐grade inflammation, growth factors and advanced glycation end products (AGE peptides). Methods. IRMA 2 was a 2‐year multicentre, randomized, double‐blind trial comparing irbesartan (150 and 300mg once daily) versus placebo. The primary end‐point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300mg irbesartan treatment group were used in this post‐hoc analysis (n = 269, 68%). Nine biomarkers were analysed: high sensitivity C‐reactive protein (hs‐CRP), interleukin 6 (IL‐6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble intercellular cell adhesion molecule‐1 (sICAM‐1), sE‐selectin, transforming growth factor‐beta (TGF‐β) and AGE peptides. Mean standard deviation scores (Z‐scores) were used to combine biomarker information. Results. In a Cox enter model with combined Z‐scores for biomarkers of endothelial dysfunction (vWf, sVCAM‐1, sICAM‐1, sE‐selectin) and for biomarkers of inflammation (hs‐CRP, IL‐6, fibrinogen), endothelial dysfunction (hazard ratio for a 28% increase ( = 1 SD) in Z‐score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75% increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL‐6 and vWf predicted the end‐point. In addition, endothelial Z‐score was associated with progression of albuminuria (p = 0.038). Conclusion. Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915.