Neutrophil cathepsin G and risk of cardiovascular events in patients with diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major risk factor for atherosclerosis and cardiovascular events (CVEs), partly due to increased platelet activation and inflammation. Neutrophil-derived cathepsin G (CatG), a prothrombotic protease, may play a role in this process by promoting platelet aggregation. However, its association with CVEs in T2DM has not been previously explored. This study aimed to evaluate whether circulating CatG levels independently predict CVEs in patients with T2DM. METHODS: We included 485 T2DM patients from two prospective cohorts (PLINIO and ATHERO-AF studies). The primary outcome was a composite of cardiovascular death, non-fatal coronary and cerebrovascular events, and peripheral artery events. Cardiovascular death, all-cause death, non-fatal coronary and cerebrovascular events were tested as secondary outcomes. Multivariate Cox-regression was used to assess associations between the top (V) CatG quintile and outcomes. A subgroup analysis was conducted in 312 patients with available neutrophil count data and after a propensity score matching, to test the correlation between CatG and plasma soluble P-selectin (sP-selectin), an in vivo marker of platelet activation. RESULTS: During the follow-up yielding for 2,437.6 person-years, 86 CVEs occurred. Patients developing CVEs had higher CatG (2.9 [1.9-4.4] ng/mL vs. 2.1 [1.6-2.6] ng/mL; p < 0.001) compared to CVEs-free patients. The CVEs incidence rate in patients in the V CatG quintile was 10.4% per year (V quintile versus each other quintile: p < 0.001). V CatG quintile associated with increased CVEs (adjusted Hazard Ratio (aHR) 6.081 [95% confidence interval (CI) 3.887-9.514], p < 0.001) and its component incidence, including cardiovascular mortality or non-fatal coronary events or all-cause mortality. The association between higher CatG levels and CVEs remained significant after adjustment for neutrophil count (aHR 4.051 [95% CI 2.098-7.820], p < 0.001). Neutrophil count was also independently associated with CVEs (aHR 1.177 [95% CI 1.009-1.372], p = 0.038). Finally, in the propensity score matching analysis CatG independently correlated with sP-selectin (Beta: 0.443; p < 0.001). CONCLUSIONS: Circulating CatG is an independent predictor of cardiovascular events in T2DM, suggesting a novel biomarker linking inflammation to athero-thrombosis. PRE-REGISTERED CLINICAL TRIAL NUMBER: NCT01882114, NCT04036357.