suPAR Identifies Treatment-Resistant Inflammatory Risk Beyond hs-CRP in Type 2 Diabetes With Coronary Artery Disease: An Ancillary Analysis of BARI 2D

<jats:p>&lt;p dir="ltr"&gt;Objective: To determine whether soluble urokinase plasminogen activator receptor (suPAR) is modified by randomized diabetes and revascularization strategies in patients with type 2 diabetes and coronary artery disease, and whether combined suPAR and high-sensitivity C-reactive protein (hs-CRP) classification refines residual cardiovascular risk stratification.&lt;/p&gt;&lt;p dir="ltr"&gt;Research Design and Methods: In this ancillary analysis of BARI 2D, we measured plasma suPAR and hs-CRP at baseline (n=2,277) and 1 year (landmark cohort, n=1,978). The primary outcome was all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Associations were assessed using sequentially adjusted Cox models.&lt;/p&gt;&lt;p dir="ltr"&gt;Results: Over 1 year, suPAR was not reduced by diabetes (insulin-sensitizing vs insulin-provision) or cardiac (revascularization vs medical therapy) treatment strategies (median 2.96 to 3.15 ng/mL; all treatment-arm P≥0.75), while hs-CRP declined substantially (median 2.07 to 1.30 mg/L). suPAR independently predicted the composite outcome (adjusted HR 1.40 per SD [95% CI 1.27-1.55]), unattenuated after hs-CRP adjustment. In an exploratory analysis, suPAR modified the diabetes treatment effect (P-interaction=0.005), with insulin-provision associated with worse outcomes in the highest suPAR tertile (HR 1.33 [1.03-1.72]). Baseline suPAR predicted risk in participants whose hs-CRP normalized (HR 1.45 [1.04-2.03]). Joint classification revealed a 3-fold gradient in event rates (7.1% to 21.6%), with elevated suPAR conferring excess risk even after hs-CRP normalization.&lt;/p&gt;&lt;p dir="ltr"&gt;Conclusions: Over 1 year, suPAR was unmodified by diabetes or revascularization strategies in BARI 2D despite intensive guideline-directed medical optimization, in contrast to hs-CRP, which declined substantially. Combined suPAR and hs-CRP classification produced a graded risk hierarchy that hs-CRP normalization alone did not resolve.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;</jats:p>