Soluble Urokinase Plasminogen Activator Receptor (suPAR) Mediates the Impact of Diabetes on Adverse Outcomes in Coronary Artery Disease

OBJECTIVE Type 2 diabetes (T2D) is a significant risk factor for adverse outcomes in coronary heart disease (CHD). We investigated whether inflammation and immune dysregulation, measured using soluble urokinase plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein (hs-CRP) levels, mediate this risk. RESEARCH DESIGN AND METHODS Patients with and without CHD enrolled in the Emory Cardiovascular Biobank had suPAR (ViroGates, Denmark) and hs-CRP levels measured and were followed for 1) cardiovascular death, 2) a composite of incident myocardial infarction and cardiovascular death, and 3) all-cause death. Fine and Gray or Cox proportional hazards models adjusted for demographic, clinical, and treatment variables were used. Regression-based causal mediation analyses were performed. RESULTS A total of 4,324 participants (mean [SD] age 64 [11.9] years, 36% women, 31.8% with T2D) were followed for a median of 6.9 years. SuPAR levels were higher in those with T2D (median [interquartile range] 3,260 [2,503–4,463] vs. 2,792 [2,217–3,600] pg/mL). T2D was associated with a higher adjusted risk (hazard ratio [HR] 1.38; 95% CI 1.16, 1.63; P < 0.001) of cardiovascular death that was greatly attenuated (HR 1.18; 95% CI 0.99, 1.40; P = 0.1) after adjustment for suPAR, but not hs-CRP, levels. Similar findings were observed for the other outcomes. SuPAR, but not hs-CRP, levels mediated >50% of the effect of T2D on adverse outcomes. CONCLUSIONS The impact of T2D on adverse outcomes is significantly mediated through chronic inflammation and immune dysregulation, estimated using suPAR levels. Whether novel therapies for reducing suPAR levels will impact CHD risk in T2D warrants further investigation.