Effects of intensive glycemic control on microvascular outcomes in type 2 diabetes mellitus are modified by long-term HbA1c variability: A post hoc analysis of the ACCORD trial

Abstract

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.