suPAR Identifies Treatment-Resistant Inflammatory Risk Beyond hs-CRP in Type 2 Diabetes With Coronary Artery Disease: An Ancillary Analysis of BARI 2D.
prospective_cohort · Level II
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- Also identified by DOI 10.2337/dc26-0899.
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Abstract
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 hs-CRP classification refines residual cardiovascular risk stratification. In this ancillary analysis of Bypass Angioplasty Revascularization Investigation 2 Diabetes (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. Over 1 year, suPAR was not reduced by diabetes (insulin sensitizing vs. insulin provision) or cardiac (revascularization vs. medical therapy) treatment strategies (median 2.96-3.15 ng/mL; all-treatment arm P ≥ 0.75), while hs-CRP declined substantially (median 2.07-1.30 mg/L). suPAR independently predicted the composite outcome (adjusted hazard ratio [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; 95% CI 1.03-1.72). Baseline suPAR predicted risk in participants whose hs-CRP normalized (HR 1.45; 95% CI 1.04-2.03). Joint classification revealed a threefold gradient in event rates (7.1% to 21.6%), with elevated suPAR conferring excess risk even after hs-CRP normalization. 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.