Inflammatory biomarkers suPAR, IL-6, and hsCRP and 13-year risk of mortality and MACE in type 2 diabetes: a prospective cohort study

Background The global prevalence of type 2 diabetes (T2D) is rising at an unprecedented rate and is projected to affect over 1.3 billion individuals by 2050. T2D increases the risk of premature mortality, primarily due to cardiovascular disease. Chronic inflammation may contribute to this risk. The associations between the inflammatory biomarkers, soluble urokinase plasminogen activator receptor (suPAR), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) and mortality in T2D are not well-known. Methods In a prospective clinical cohort of patients with T2D, we measured baseline suPAR, IL-6, and hsCRP in blood. Primary and secondary endpoints were all-cause mortality and major adverse cardiovascular events (MACE), respectively. MACE was defined as a composite outcome of all-cause mortality or incident events of hospital admission for ischemic heart disease, heart failure, or stroke. We investigated associations between one biomarker (log2-transformed) and two simultaneously elevated biomarkers (cutoff at the median) with the outcomes. Cox models adjusted for all ten SCORE2-Diabetes risk model variables, albuminuria, and inflammatory biomarkers. Net reclassification improvement (NRI) and C-statistics were calculated. Results Among 925 participants (mean age 65±10, 65% male, 27% with prior cardiovascular disease), the median and interquartile range of the biomarkers were: suPAR 3.1 ng/mL (2.4-4.0), IL-6 2.9 pg/mL (1.0-7.4), and hsCRP 23 mg/L (11-46). The follow-up was 100% (median 11.4 years (max 13.1 years)), and mortality was higher with elevated inflammation. Mortality rates for the upper vs. lower tertile were: suPAR 70% vs. 19%, IL-6 52% vs. 25%, and hsCRP 49% vs 30% (log-rank P<0.002 for all) (Figure 1). In fully adjusted models, all biomarkers were independently associated with mortality. Combining two simultaneously elevated biomarkers demonstrated the highest hazard ratios (HR): IL-6 and suPAR HR 2.4 (95% confidence intervals [CI]: 1.7-3.5, P<0.001), suPAR and hsCRP HR 2.5 (1.7-3.7, P<0.001), hsCRP and IL-6 HR 1.9 (1.4-2.7, P<0.001) (Figure 2). Adding suPAR, IL-6, hsCRP, and especially their combinations to the SCORE2-Diabetes risk model improved NRI and C-statistics. Results were consistent for MACE outcomes. Conclusions Inflammatory biomarkers alone or combined predict all-cause mortality and MACE in T2D independent of SCORE2-Diabetes risk factors and albuminuria.