Spotlight on glycemic variability

Greater variability in HbA1c level is associated with increased risk of cardiovascular disease, two recent studies found.

The first study, published by Diabetes Care on March 30, was a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which randomized patients to either standard (n=54,728) or intensive (n=54,755) glucose control. This analysis examined all-cause mortality in relation to long-term visit-to-visit HbA1c variability, expressed as coefficient of variation, variability independent of the mean (VIM), and average real variability. Patients in the intensive therapy group had significantly lower mean HbA1c levels and lower glycemic variability (P<0.0001 on all three variability measures). All three measures were significantly associated with mortality whether patients were in the intensive or standard therapy groups, with hazard ratios of 1.19 and 1.23, respectively, for every standard deviation increase in variability. Cross-tabulation analysis showed the third tertile of mean HbA1c level and VIM were associated with significantly higher all-cause mortality only in the intensive therapy group (hazard ratio, 2.05; 95% CI, 1.17 to 3.61; P<0.01). “These findings raised the issue that visit-to-visit glycemic variability as well as higher levels of glycemia might be important risk factors for all-cause mortality and should be considered in efforts to intensively lower glucose among individuals with type 2 diabetes,” the authors said. Limitations of the study include that it was a post hoc analysis and that it had a highly selected patient population, many of them at high risk for cardiovascular disease.

The second study, published by Diabetes, Obesity and Metabolism on March 20, focused specifically on patients without cardiovascular disease at baseline. It was a prospective cohort study of 147,811 type 2 diabetes patients in China, ages 45 to 84 years. Median follow-up was 7.4 years. The study found positive log-linear associations between HbA1c variability and both cardiovascular disease and all-cause mortality in all studied age groups. The association between variability and the adverse outcomes was inversely associated with age, so a 1% increase in HbA1c variability carried a 28% increased risk of cardiovascular disease or death in patients ages 45 to 54 years compared to a 14% increased risk in those who were ages 75 to 84 years. Variability also posed a significantly greater risk in patients whose mean HbA1c level was under 7% compared to those with a mean HbA1c level of 8% or above. The risk of adverse outcomes with variability was also increased in patients with longer diabetes duration, and variability was more common in patients with shorter durations of diabetes. The authors called for additional research to explore the mechanisms of the association between HbA1c variability and worse outcomes, noting that previous studies have had similar findings. “HbA1c variability may provide additional valuable information as a potential predictor for the development of CVD [cardiovascular disease] and all-cause mortality among patients with diabetes. Clinicians should monitor for HbA1c fluctuations in addition to the absolute value,” they wrote.