Hemoglobin A1c Variability Metrics Predict Coronary Artery Calcium and Cardiovascular Events in Type 1 Diabetes: The CACTI Study

CONTEXT: Interventions that decrease mean glucose have reduced rates of micro- and macrovascular complications in type 1 diabetes (T1D). However, the difference in cardiovascular risk between people with T1D and the general population endures, suggesting that factors beyond hemoglobin A1C (HbA1c) normalization drive cardiovascular outcomes. OBJECTIVE: To determine whether various HbA1c metrics predict anatomic cardiovascular disease (CVD) risk factors and/or CVD events in people with T1D. METHODS: We used linear regression to analyze the relationship of several HbA1c metrics to anatomic CVD risk factors and then used Cox regression to model their relationship to incident CVD events in the CACTI Study (ClinicalTrials.gov Identifier: NCT00005754). RESULTS: In linear regression models adjusted for age, sex, and T1D duration, baseline Hba1c (b = 0.3998, P = 0.0236), mean HbA1c (b = 0.5385, P = 0.0109), and HbA1c SD (b = 1.1521, P = 0.0068) were each positively associated with square root transformed coronary artery calcium volume. Conversely, only mean HbA1c (b = 1.659, P = 0.0048) positively associated with pericardial adipose tissue volume. In survival models adjusted for age, sex, and T1D duration, baseline HbA1c [hazard ratio (HR): 1.471, 95% CI: 1.257-1.721], mean HbA1c (HR: 1.850, 95% CI: 1.511-2.264), time-varying HbA1c (HR: 1.500, 95% CI: 1.236-1.821), and HbA1c SD (HR: 1.665, 95% CI: 1.022-2.711) each independently predicted CVD events over 14.3 ± 5.2 person-years of follow-up. CONCLUSIONS/INTERPRETATION: We found that various HbA1c metrics positively correlated with CAC volume and independently predicted incident CVD events in the CACTI T1D cohort. These associations with CVD events persisted for baseline HbA1c, mean HbA1c, and time-varying HbA1c even after adjustment for numerous CVD risk factors.