Effects of intensive glycemic control on microvascular outcomes in type 2 diabetes mellitus are modified by long-term HbA_1c variability: A post hoc analysis of the ACCORD trial

Aims: To assess the impact of long-term visit-to-visit variability in HbA_1c on microvascular outcomes in type 2 diabetes mellitus (T2DM), and its influence on the effects of intensive glycemic control.

Methods: Included were participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) who had at least three measurements of HbA_1c prior to new-onset microvascular outcomes, namely nephropathy, retinopathy and neuropathy. Variability in HbA_1c was defined as the coefficient of variation (CV) across HbA_1c measurements obtained from enrollment to the transition from intensive to standard glycemic therapy.

Results: During a median of 22,005, 23,121, and 13,080 person-years of follow-up, 2,905 nephropathy, 2,655 retinopathy, and 1,974 neuropathy cases were recorded, respectively. Median CV (IQR) was 7.91 % (5.66 %-10.76 %) in the standard treatment group and 9.79 % (7.32 %-13.35 %) in the intensive treatment group. In the standard treatment group, lower HbA_1c-CV (the first versus the second quartile) was associated with a higher risk of all microvascular outcomes, while higher HbA_1c-CV (the fourth quartile) was associated with a higher risk of nephropathy only. In the intensive treatment group, only higher HbA_1c-CV was associated with a higher risk of developing the microvascular outcomes. Intensive therapy reduced all microvascular outcomes among individuals with lower HbA_1c-CV, but increased the risk among those with the highest HbA_1c-CV (all P values for interaction < 0.0001). For example, hazard ratios (95 % CI) of retinopathy comparing intensive with standard treatments were 0.65 (0.56-0.75), 0.84 (0.71-0.98), 0.97 (0.82-1.14) and 1.28 (1.08-1.53) across the lowest to the highest quartiles of HbA_1c variability.

Conclusions: The effects of intensive glycemic control on microvascular outcomes in T2DM appear to be modified by the variability of HbA_1c during the treatment process, suggesting the significance of dynamic monitoring of HbA_1c levels and timely adjustments to the therapeutic strategy among individuals with a high HbA_1c variability.