Longitudinal Plasma Kallikrein Levels and their Association with the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC

We determined the relationship between plasma kallikrein and cardiovascular disease (CVD) outcomes as well as major adverse cardiovascular events (MACE) in the DCCT/EDIC-cohort of type 1 diabetes (T1D). Plasma kallikrein levels were measured longitudinally in 693 subjects at DCCT baseline (1983-1989), mid-point of DCCT (1988-1991), end of DCCT (1993), and EDIC years 4-6 (1997-1999), 8-10 (2001-2003), and 11-13 (2004-2006). Cox proportional hazards regression models assessed the association between plasma kallikrein levels and the risk of CVD. In unadjusted models, higher plasma kallikrein levels were associated with higher risk of any CVD during DCCT/EDIC (HR=1.16 per 20 nM higher levels of plasma kallikrein; p=0.0177) as well as over the EDIC-only period (HR=1.22; p=0.0024). The association between plasma kallikrein levels and the risk of any CVD remained significant during the EDIC follow-up after adjustment for age and mean HbA1c (HR=1.20; p=0.0082) and in the fully adjusted model for other CVD risk factors (HR=1.17; p=0.0330). For MACE, higher plasma kallikrein levels were associated with higher risk in unadjusted (HR=1.25; p=0.0145), minimally adjusted (HR=1.23; p=0.0417, and fully adjusted (HR=1.27; p=0.0328) models during EDIC-only. These novel findings indicate that plasma kallikrein level associates with the risk of any CVD and MACE in T1D individuals.