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

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.