Mediation of the Effect of Glycemia on the Risk of CVD Outcomes in Type 1 Diabetes: The DCCT/EDIC Study

Abstract

Objective: The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors.

Research design and methods: In the DCCT, 1,441 participants were randomized to receive either intensive or conventional diabetes therapy. The EDIC observational follow-up study enrolled 96% of the surviving DCCT cohort with 94% of the survivors still actively participating after more than 27 years of follow-up. Mediation of the effect of glycemia, as captured by HbA_1c, on the subsequent CVD risk was quantified using the relative change in the CVD risk associated with HbA_1c between models without and with the potential mediator.

Results: Adjusted for age, only a few factors (e.g., pulse, triglycerides, albumin excretion rate) explained more than 10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ∼50% of the effect of glycemia on the risk of CVD. However, the association between HbA_1c and the risk of CVD remained highly significant even after adjustment for these risk factors.

Conclusions: While HbA_1c is associated with many traditional CVD risk factors, its association with these factors alone cannot explain its effects on risk of CVD. Consequently, aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes.

Figure 1

The PC in the risk of any-CVD and MACE associated with a 1% higher mean updated HbA_1c after adjustment for each risk factor individually (results based on Cox PH models further adjusted for age). AER presented as mg/24 h. eGFR presented as mL/min per 1.73 m². BP, blood pressure; CHL, total cholesterol; TRIG, triglycerides.