245-OR: Proteomic Analysis of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA)—Results and Integrated Predictors of Response

Background: Mineralocorticoid receptor (MR) antagonists (MRA) benefit patients with diabetic chronic kidney disease (CKD) and heart failure, and may act upstream on multiple cardioprotective pathways. The NHLBI-sponsored MAGMA trial, a 12-month, randomized, double-blind, placebo-controlled trial compared Spironolactone vs. placebo in Type 2 diabetics with CKD stages 3-4 on maximal renin-angiotensin system blockade and a prior atherosclerotic event and/or left ventricular (LV) hypertrophy.

Methods: Seventy-nine patients were randomized to Spironolactone 25 mg (n = 37) or placebo (n = 42) for 12 months. The primary outcome was % change in total aortic wall volume (TWV) at 12 months by magnetic resonance imaging (MRI). Baseline, 3-month, and 12-month plasma samples were measured for 7,596 protein biomarkers. We used the general linear hypothesis framework and Linear mixed-effect models to generate lists of differentially expressed proteins by effect. A multi-visit matching approach was used to model the association of proteomic expression changes with TWV changes. We fit a Mixed Multivariate Random Forest model to take the experimental design into account and build predictive proteomic predictors associated with primary outcome changes of TWV.

Results: Patients had a mean age of 64±8 years with 50% African Americans and 46% women. Spironolactone reduced PWV versus placebo. Plasma proteome revealed downregulation of MR targets including fibrosis, immune activation/inflammation, leukocyte activation, proliferation and pathways involved in cytokine stimulation. Predictors of plaque progression involved cytokine-receptor, complement-coagulation, cell adhesion and axonal guidance targets.

Conclusions: The changes in plasma proteomic profile with Spironolactone were consistent with downregulation in multiple inflammatory, immune response and profibrotic pathways.