Abstract
AIMS/HYPOTHESIS: Chronic hyperglycaemia, as measured by HbA(1c) levels, is a major risk factor for atherosclerosis and cardiovascular disease (CVD) in type 1 diabetes. Our aim was to describe the degree to which the effect of HbA(1c) on the risk of CVD is mediated by its effect on traditional risk factors over time, and how these mediation pathways change over time. METHODS: The DCCT and its observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC), followed 1441 participants for a mean of 27 years, with periodic measurement of HbA(1c) and risk factors over time. We assessed the proportion of the HbA(1c) effect on risk of CVD that was mediated through its effects on systolic BP (SBP), pulse rate, triacylglycerols and LDL-cholesterol (LDLc) levels, and how the proportion mediated changed over time. RESULTS: The association of HbA(1c) with CVD outcomes was stable over time, while that of traditional risk factors (SBP, pulse rate, triacylglycerols and LDLc) increased. At 10 years of follow-up, the effect of HbA(1c) on 10 year CVD risk was minimally mediated by SBP (2.7%), increasing to 26% at 20 years. Likewise, from 10 year follow-up to 20 year follow-up, the proportion of HbA(1c) effect mediated through pulse rate increased from 6.3% to 29.3%, through triacylglycerols from 2.2% to 22.4%, and through LDLc from 9.2% to 30.7%. CONCLUSIONS/INTERPRETATION: As participants age, the predictive association of mean HbA(1c) on subsequent CVD events is increasingly mediated by its effect on standard risk factors. Thus, management of traditional non-glycaemic CVD risk factors may have increasing benefits in an ageing type 1 diabetes population with longstanding hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00360893 and NCT00360815.