Prognostic significance of long-term HbA_1c variability for all-cause mortality in the ACCORD trial

OBJECTIVE The association between high glycemic variability and all-cause mortality has been widely investigated in epidemiological studies but rarely validated in glucose-lowering clinical trials. We aimed to identify the prognostic significance of visit-to-visit HbA_1c variability in treated patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial population. RESEARCH DESIGN AND METHODS We studied the risk of all-cause mortality in relation to long-term visit-to-visit HbA_1c variability, expressed as coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV), from the 8th month to the transition from intensive to standard glycemic therapy. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (HR) and 95% CI. RESULTS Compared with the standard therapy group (n = 4,728), the intensive therapy group (n = 4,755) had significantly lower mean HbA_1c (6.6% [49 mmol/mol] vs. 7.7% [61 mmol/mol], P < 0.0001) and lower CV, VIM, and ARV (P < 0.0001). In multivariate adjusted analysis, all three HbA_1c variability indices were significantly associated with total mortality in all patients as well as in the standard-and intensive-therapy groups analyzed separately. The hazard ratios for a 1-SD increase in HbA_1c variability indices for all-cause mortality were 1.19 and 1.23 in intensive and standard therapy, respectively. Cross-tabulation analysis showed the third tertile of HbA_1c mean and VIM had significantly higher all-cause mortality (HR 2.05; 95% CI 1.17–3.61; P <0.01) only in the intensive-therapy group. CONCLUSIONS Long-term visit-to-visit HbA_1c variability was a strong predictor of all-cause mortality. HbA_1c VIM combined with HbA_1c mean conferred an increased risk for all-cause mortality in the intensive-therapy group.